Multiple Sclerosis Misdiagnosis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy
Open accessAbstract
Background and Objectives: variants may be higher among Asian populations. Misdiagnosis may delay appropriate management and expose patients to ineffective and potentially harmful therapies. This study aimed to estimate the proportion of CADASIL patients with prior MS misdiagnosis presenting to a multicenter tertiary-care cohort and to identify associated clinical and genetic features and consequences of this diagnostic error. Methods: variant in the epidermal growth factor-like repeat (EGFr) domain. Prespecified logistic regression models were used to evaluate factors independently associated with MS misdiagnosis, adjusting for age, sex, race, and prior stroke history. Results: Of 107 CADASIL patients (mean age 57.5 ± 13.4 years), 11 (10.2%) were misdiagnosed with MS. In prespecified adjusted logistic regression models, absence of prior stroke (adjusted odds ratio [OR] 4.60; 95% CI 1.02-20.68), Asian race (adjusted OR 20.74; 95% CI 3.21-134.18), asymmetric external capsule white matter hyperintensity (WMH) (adjusted OR 53.34; 95% CI 4.06-701.08), and absence of infratentorial WMH (adjusted OR 12.48; 95% CI 1.90-82.01) were independently associated with misdiagnosis. The median time to diagnostic correction was 14.45 months (range 1.18-138.07), during which 5 patients (45.5%) received unnecessary MS therapies and 2 experienced documented adverse events. Medium-risk EGFr variants were more frequent among misdiagnosed patients in unadjusted comparisons but were not independently associated after adjustment. Discussion: In this multicenter tertiary-care cohort, approximately 1 in 10 patients with CADASIL had been misdiagnosed as MS, an error associated with Asian race, absence of a stroke history, and atypical neuroimaging patterns leading to worse functional outcomes and inappropriate treatments. A high index of suspicion for CADASIL is critical in patients presenting with atypical or late-onset demyelinating disease. Larger studies are needed to understand the role of medium-risk variants in misdiagnosis.
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Written from the paper’s full text.
TL;DR
In a multicenter retrospective cohort of 107 genetically or histopathologically confirmed CADASIL patients, 10.2% had been misdiagnosed with multiple sclerosis. Misdiagnosis was associated with Asian race, absence of prior stroke, asymmetric external capsule white matter hyperintensity, and absence of infratentorial white matter hyperintensity, and 45.5% of misdiagnosed patients received unnecessary MS-directed therapies.
Key findings
- Of 107 CADASIL patients (mean age 57.5 ± 13.4 years), 11 (10.2%) had a prior MS misdiagnosis; the initial MS diagnosis was made outside the Mayo system in 72% (8/11) and at Mayo-affiliated sites in 27% (3/11).
- In prespecified adjusted logistic regression models, MS misdiagnosis was independently associated with absence of prior stroke (adjusted OR 4.60; 95% CI 1.02–20.68), Asian race (adjusted OR 20.74; 95% CI 3.21–134.18), asymmetric external capsule WMH (adjusted OR 53.34; 95% CI 4.06–701.08), and absence of infratentorial WMH (adjusted OR 12.48; 95% CI 1.90–82.01).
- Median time to diagnostic correction was 14.45 months (range 1.18–138.07); during this interval, 5 patients (45.5%) received unnecessary MS therapies and 2 had documented adverse events (injection site reactions).
- Medium-risk EGFr variants were more frequent among misdiagnosed patients in unadjusted comparisons (60% vs 30.7%) but were not independently associated after adjustment; misdiagnosis occurred only in high-risk and medium-risk EGFr groups.
Methods
- Retrospective multicenter cohort of genetically or histopathologically confirmed CADASIL patients identified by consecutive case ascertainment from 1999 to 2024 using ICD code I67.850 searches across 3 Mayo Clinic sites; baseline was CADASIL confirmation by genetic testing (n = 98) or skin biopsy (n = 9).
- Patients with a documented MS diagnosis before CADASIL confirmation were classified as the MS misdiagnosis group and compared with all others; brain MRI studies were re-reviewed by a single board-certified neuroradiologist, and NOTCH3 variants were classified by EGFr domain into high-, medium-, low-, or unknown-risk categories.
- Prespecified multivariable logistic regression used MS misdiagnosis as the dependent variable, with core covariates age at CADASIL diagnosis, sex, race (Asian vs non-Asian), and prior stroke history; each imaging or genetic predictor was evaluated in a separate adjusted model because of the limited number of misdiagnosis events (n = 11).
Limitations
- The paper states that the cohort, though large for a rare disease, remains modest; the retrospective design may introduce bias from incomplete or inconsistent documentation; cases could not be reliably reclassified under 2024 McDonald criteria; the small MS-misdiagnosed subgroup limits statistical robustness; the short interval between misdiagnosis and CADASIL confirmation constrained detection of clinical or radiologic changes; and the tertiary-care racial/ancestral composition is not population representative, so race-related associations—especially Asian ancestry—should be interpreted cautiously.
- The text also notes that the cohort lacked high-resolution 3T/7T MRI brain imaging, so advanced MS biomarkers such as the central vein sign and paramagnetic rim lesions could not be assessed, and the CSF kappa-free light chain index was not measured.
- Evident from the reported results: adjusted odds ratios have very wide confidence intervals (e.g., asymmetric external capsule WMH 4.06–701.08; Asian race 3.21–134.18), consistent with the authors’ caution that analyses are exploratory and need confirmation in larger populations.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
25 of 34 cited sources checked · 6 supported · 0 flagged · accuracy not yet measured
- Premisecitation
CADASIL can be misdiagnosed as multiple sclerosis.
“Despite these characteristic features, CADASIL can be misdiagnosed as multiple sclerosis (MS).2-4”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [2] Mandia D, Shor N, Carlson AK, et al. Genetic diseases misdiagnosed as multiple sclerosis: observational study and review of literature. Mult Scler Relat Disord. 2025; 99: 106439. doi: 10.1016/j.msard.2025.106439 40446704 source
- cites [3] Mandler JM, Härtl J, Cordts I, et al. Uncovering genetic mimics in multiple sclerosis: a single-center clinical exome sequencing study. Mult Scler J Exp Transl Clin. 2024; 10(3): 20552173241263491. doi: 10.1177/20552173241263491 39072298 PMC11273569 source
- cites [4] Hung K, Chen CH, Wu WC, Su JJ, Chen YF, Tang SC. Comparing the imaging characteristics of middle-aged patients with multiple sclerosis and CADASIL: a retrospective cross-sectional study. Mult Scler Relat Disord. 2024; 91: 105856. doi: 10.1016/j.msard.2024.105856 39265269 source
- Premisecitation
Diagnostic confusion between CADASIL and MS stems from overlapping clinical and radiologic features such as migraine, transient neurologic symptoms, and widespread white matter lesions on MRI, which, when combined with an absent or unrecognized stroke history, can push clinicians toward an MS diagnosis.
“The diagnostic confusion stems from overlapping clinical and radiologic features such as migraine, transient neurologic symptoms, and widespread white matter lesions on MRI, which, when combined with an absent or unrecognized stroke history, can push clinicians toward an MS diagnosis.2,3”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [2] Mandia D, Shor N, Carlson AK, et al. Genetic diseases misdiagnosed as multiple sclerosis: observational study and review of literature. Mult Scler Relat Disord. 2025; 99: 106439. doi: 10.1016/j.msard.2025.106439 40446704 source
- cites [3] Mandler JM, Härtl J, Cordts I, et al. Uncovering genetic mimics in multiple sclerosis: a single-center clinical exome sequencing study. Mult Scler J Exp Transl Clin. 2024; 10(3): 20552173241263491. doi: 10.1177/20552173241263491 39072298 PMC11273569 source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
- Premisecitation
CADASIL may initially lack classic temporal pole or external capsule involvement, leading to misclassification as demyelinating disease.
“The diagnostic challenge is further compounded by the fact that CADASIL may initially lack classic temporal pole or external capsule involvement, leading to misclassification as demyelinating disease.4”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [4] Hung K, Chen CH, Wu WC, Su JJ, Chen YF, Tang SC. Comparing the imaging characteristics of middle-aged patients with multiple sclerosis and CADASIL: a retrospective cross-sectional study. Mult Scler Relat Disord. 2024; 91: 105856. doi: 10.1016/j.msard.2024.105856 39265269 source
The Results (section 3.2; page not provided) report external capsule involvement in 56.7% of patients with CADASIL, so it was absent in others. The Discussion (section 4) says anterior temporal lobe involvement varies, and the Introduction (section 1) reports that CADASIL has been initially misdiagnosed as MS. This retrospective cross-sectional study does not establish that either feature was absent initially or that its absence led to misclassification. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
A subsequent CADASIL diagnosis is often made after progressive ischemic events, characteristic white matter changes, or as clear family history emerges.
“A subsequent CADASIL diagnosis is often made after progressive ischemic events, characteristic white matter changes, or as clear family history emerges.2-5”
Quote in the paperNot a substantial claim3 of 4 sources checked- cites [2] Mandia D, Shor N, Carlson AK, et al. Genetic diseases misdiagnosed as multiple sclerosis: observational study and review of literature. Mult Scler Relat Disord. 2025; 99: 106439. doi: 10.1016/j.msard.2025.106439 40446704 source
- cites [3] Mandler JM, Härtl J, Cordts I, et al. Uncovering genetic mimics in multiple sclerosis: a single-center clinical exome sequencing study. Mult Scler J Exp Transl Clin. 2024; 10(3): 20552173241263491. doi: 10.1177/20552173241263491 39072298 PMC11273569 source
The Results section describes one patient whose CADASIL diagnosis followed evolving CADASIL-typical MRI changes and a reevaluation of family history; the Discussion says the diagnosis was corrected from MS to CADASIL. The paper does not establish that this sequence occurs often, or that progressive ischemic events generally prompt the later diagnosis. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [4] Hung K, Chen CH, Wu WC, Su JJ, Chen YF, Tang SC. Comparing the imaging characteristics of middle-aged patients with multiple sclerosis and CADASIL: a retrospective cross-sectional study. Mult Scler Relat Disord. 2024; 91: 105856. doi: 10.1016/j.msard.2024.105856 39265269 source
The Introduction (page unavailable) identifies stroke and transient ischemic attacks as CADASIL manifestations and white matter lesions as characteristic MRI findings; it also notes that some patients are initially misdiagnosed with MS. The paper does not say that CADASIL is often diagnosed only after progressive ischemic events or as family history emerges. The Study population section (page unavailable) says diagnosis was confirmed by NOTCH3 genetic testing. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [5] Rieder E, Li J, Rodriguez-Flores JL, Taimur Malik M, Abedi V, Zand R. Cysteine-altering NOTCH3 variants are associated with an increased risk of autoimmune diseases. J Clin Med. 2023; 12(19): 6278. doi: 10.3390/jcm12196278 37834922 PMC10573689 source
The Discussion mentions possible misdiagnosis because CADASIL and multiple sclerosis can have similar imaging findings, but it does not describe when CADASIL is subsequently diagnosed. Searches for white matter changes, family history, ischemic events, and diagnosis found no passage establishing the claimed diagnostic pattern. (LLM, conf=0.76)
Experimental — accuracy not yet measured
- Premisecitation
Population-based genetic studies demonstrate higher frequencies of pathogenic NOTCH3 variants in East and South Asians compared with the general population.
“Population-based genetic studies demonstrate higher frequencies of pathogenic NOTCH3 variants in East and South Asians compared with the general population.8,15”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [8] Gravesteijn G, Rutten JW, Cerfontaine MN, et al. Disease severity staging system for NOTCH3-Associated small vessel disease, including CADASIL. JAMA Neurol. 2025; 82(1): 49- 60. doi: 10.1001/jamaneurol.2024.4487 39610302 PMC13340440 source
The Discussion (page unavailable) reports NOTCH3 cysteine-altering variants in about 1 in 300 people worldwide and 1 in 100 Asian individuals, supporting a higher frequency in Asians. It does not report separate frequencies for East and South Asians, so the claim’s specificity is not supported. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [15] Grami N, Chong M, Lali R, et al. Global assessment of mendelian stroke genetic prevalence in 101 635 individuals from 7 ethnic groups. Stroke. 2020; 51(4): 1290- 1293. doi: 10.1161/strokeaha.119.028840 32106772 source
The Pathogenic Clinical Variants section reports that pathogenic NOTCH3 variants were about four times more prevalent in South Asians (1.2%) and East Asians (1.1%) than in the next most frequent ethnic group. This supports higher frequencies relative to other ethnic groups, but the paper does not make the stated comparison with the general population. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Interpretationcitation
Medium-risk genetic variants may result in atypical phenotypes that complicate recognition of CADASIL and predispose patients to MS misdiagnosis.
“Owing to their intermediate penetrance and variable expressivity,9 medium-risk genetic variants may result in atypical phenotypes that complicate the recognition of CADASIL and predispose patients to MS misdiagnosis.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [9] Hack RJ, Gravesteijn G, Cerfontaine MN, et al. Three-tiered EGFr domain risk stratification for individualized NOTCH3-small vessel disease prediction. Brain. 2023; 146(7): 2913- 2927. doi: 10.1093/brain/awac486 36535904 PMC10316769 source
The Discussion (page unavailable) says medium-risk NOTCH3 variants are associated with a broad disease spectrum, including very mild subclinical phenotypes. That supports variable presentation, but our copy does not link these variants to difficulty recognizing CADASIL or to MS misdiagnosis. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Findingcitation
All 4 treated patients who underwent genetic analysis had NOTCH3 variants located outside the classic high-risk EGFr 1-6 domains.
“In addition, all 4 had NOTCH3 variants located outside the classic high-risk EGFr 1–6 domains.14”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [14] Rutten JW, Van Eijsden BJ, Duering M, et al. The effect of NOTCH3 pathogenic variant position on CADASIL disease severity: NOTCH3 EGFr 1-6 pathogenic variant are associated with a more severe phenotype and lower survival compared with EGFr 7-34 pathogenic variant. Genet Med. 2019; 21(3): 676- 682. doi: 10.1038/s41436-018-0088-3 30032161 PMC6752295 source
The Discussion (page not provided) identifies EGFr 1–6 variants as associated with a more severe CADASIL phenotype than EGFr 7–34 variants, supporting the description of EGFr 1–6 as higher risk. The paper does not identify the four treated patients or report their genetic-analysis results, so it does not support the claim that all four had variants outside those domains. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Interpretationown data
Prominent microbleeds favor a small vessel disease diagnosis rather than MS.
“Furthermore, a high CMB burden (>10) and region-specific CMB distribution were observed only in correctly diagnosed patients, suggesting that prominent microbleeds favor a small vessel disease diagnosis rather than MS.1,4,10”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [1] Meschia JF, Worrall BB, Elahi FM, et al. Management of inherited CNS small vessel diseases: the CADASIL example: a scientific statement from the American Heart Association. Stroke. 2023; 54(10): e452- e464. doi: 10.1161/str.0000000000000444 37602377 source
The Brain Imaging for Detecting and Characterizing Disease section identifies cerebral microbleeds as an imaging feature of cerebral small vessel disease, and its table (p. e455) describes lobar-predominant microhemorrhages in hereditary cerebral amyloid angiopathy. It does not compare microbleeds in small vessel disease with those in multiple sclerosis or establish that a prominent burden favors one diagnosis over the other. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [4] Hung K, Chen CH, Wu WC, Su JJ, Chen YF, Tang SC. Comparing the imaging characteristics of middle-aged patients with multiple sclerosis and CADASIL: a retrospective cross-sectional study. Mult Scler Relat Disord. 2024; 91: 105856. doi: 10.1016/j.msard.2024.105856 39265269 source
- cites [10] McGinley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and treatment of multiple sclerosis: a review. Jama 2021; 325(8): 765- 779. doi: 10.1001/jama.2020.26858 33620411 source
- Premisecitation
A true codiagnosis of CADASIL and MS is possible.
“While rare, a true codiagnosis of CADASIL and MS is possible.19,20”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [19] Khan A, Abedi V, Li J, Malik MT, Esch M, Zand R. CADASIL vs. multiple sclerosis: is it misdiagnosis or concomitant? A case series. Front Neurol. 2020; 11: 860. doi: 10.3389/fneur.2020.00860 33013620 PMC7500095 source
- cites [20] Schiess N, Huether K, Szolics M, Agarwal G, El-Hattab AW, Sathe S. Multiple sclerosis or “Inflammatory CADASIL?”: case report and review of the literature. Clin Neurol Neurosurg. 2018; 173: 196- 199. doi: 10.1016/j.clineuro.2018.01.035 29449082 source
- Findingown data
In prespecified adjusted models, absence of prior stroke history was independently associated with MS misdiagnosis.
“In prespecified adjusted models, Asian race, absence of prior stroke history, presence of asymmetric external capsule WMH, and absence of infratentorial WMH on MRI brain were independently associated with MS misdiagnosis.”
Quote in the paperSubstantial claim- Rests on an assumption: The recorded MS misdiagnosis in the cohort is accurate and not due to historical miscoding or diagnostic uncertainty.
- Findingown data
In adjusted logistic regression, absence of prior stroke is independently associated with MS misdiagnosis (adjusted OR 4.60; 95% CI 1.02-20.68).
“absence of prior stroke (adjusted odds ratio [OR] 4.60; 95% CI 1.02–20.68)”
- Also stated in: § Results · plain
“absence of prior stroke (adjusted OR 4.60; 95% CI 1.02–20.68)”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Findingown data
Compared with patients correctly diagnosed with CADASIL at initial presentation, those initially misdiagnosed with MS were more frequently Asian (36.4% vs 3.1%).
“those who were initially misdiagnosed with MS were more frequently Asian (36.4% vs 3.1%)”
Quote in the paperNot a substantial claim - Findingown data
When anterior temporal pole WMH was present, it was symmetric in nearly all cases in both groups (5/5, 100% vs 77/79, 97.5%).
“When present, anterior temporal pole WMH was symmetric in nearly all cases in both groups (5/5, 100% vs 77/79, 97.5%).”
Quote in the paperNot a substantial claim - Findingown data
Among 9 of 11 patients with prior MS misdiagnosis who had spinal MRI, none showed spinal cord lesions.
“Among the 9 of 11 patients with prior MS misdiagnosis had spinal MRI, none of which showed spinal cord lesions.”
Quote in the paperNot a substantial claim - Findingown data
By the time of CADASIL confirmation, patients with a prior MS misdiagnosis had higher median mRS scores than those diagnosed correctly at initial presentation.
“By the time of CADASIL confirmation, patients with a prior MS misdiagnosis had higher median mRS scores and were at a higher N3SVD stage than those diagnosed correctly at initial presentation.”
Quote in the paperSubstantial claim - Findingown data
Among 10 misdiagnosed patients who underwent lumbar puncture, CSF oligoclonal bands were present in 1 patient.
“Among the 10 misdiagnosed patients who underwent lumbar puncture, CSF oligoclonal bands were present in 1 patient.”
Quote in the paperNot a substantial claim - Findingown data
45.5% of misdiagnosed patients received MS-directed treatments for a median of 10 months.
“While no significant clinical or radiologic progression was observed during the typically short interval between misdiagnosis and diagnostic correction, 45.5% of misdiagnosed patients received MS-directed treatments for a median of 10 months, incurring financial costs and avoidable risks.2,3”
Quote in the paperSubstantial claim - Findingown data
Nearly 1 in 10 patients with CADASIL had previously been misdiagnosed with MS.
“We found that nearly 1 in 10 patients with CADASIL had previously been misdiagnosed with MS.”
Quote in the paperSubstantial claim- Rests on an assumption: The recorded MS misdiagnosis in the cohort is accurate and not due to historical miscoding or diagnostic uncertainty.
- Findingown data
External capsule WMHs were common in both groups.
“External capsule WMHs were common in both groups.”
Quote in the paperNot a substantial claim - Findingown data
Half of the misdiagnosed patients carried medium-risk variants clustered in EGFr domains 13, 13.5, and 14.
“Half of the misdiagnosed patients carried medium-risk variants clustered in EGFr domains 13, 13.5, and 14 (eFigure 1).”
Quote in the paperNot a substantial claim - Findingown data
No significant clinical or radiologic progression occurred between MS misdiagnosis and CADASIL diagnosis.
“During this interval, although there was no significant clinical and radiologic progression (Table 4), 5 patients (45.5%) received unnecessary MS-directed treatments that resulted in adverse events.”
Quote in the paperSubstantial claim - Findingown data
CMBs involving the anterior temporal pole or external capsule were observed only in the non-misdiagnosed group (9.4%) and were absent in patients with prior MS misdiagnosis.
“Furthermore, CMBs involving the anterior temporal pole or external capsule were observed only in the non-misdiagnosed group (9.4%) and were absent in patients with prior MS misdiagnosis.”
Quote in the paperSubstantial claim - Findingown data
During the interval to diagnostic correction, 5 patients (45.5%) received unnecessary MS therapies.
“during which 5 patients (45.5%) received unnecessary MS therapies”
Quote in the paperNot a substantial claim - Findingown data
In prespecified adjusted models, presence of asymmetric external capsule WMH was independently associated with MS misdiagnosis.
“In prespecified adjusted models, Asian race, absence of prior stroke history, presence of asymmetric external capsule WMH, and absence of infratentorial WMH on MRI brain were independently associated with MS misdiagnosis.”
Quote in the paperSubstantial claim- Rests on an assumption: The recorded MS misdiagnosis in the cohort is accurate and not due to historical miscoding or diagnostic uncertainty.
- Findingown data
In prespecified adjusted models, Asian race was independently associated with MS misdiagnosis.
“In prespecified adjusted models, Asian race, absence of prior stroke history, presence of asymmetric external capsule WMH, and absence of infratentorial WMH on MRI brain were independently associated with MS misdiagnosis.”
Quote in the paperSubstantial claim- Rests on an assumption: The recorded MS misdiagnosis in the cohort is accurate and not due to historical miscoding or diagnostic uncertainty.
- Findingown data
Within the medium-risk stratum, patients with prior MS misdiagnosis (n = 6) rarely demonstrated infratentorial WMH (16.7% vs 74.1%) compared with medium-risk patients without misdiagnosis.
“Within the medium-risk stratum, patients with a prior MS misdiagnosis (n = 6) rarely demonstrated anterior temporal pole WMH (16.7% vs 70.4%) or infratentorial WMH (16.7% vs 74.1%) compared with medium-risk patients without misdiagnosis.”
Quote in the paperSubstantial claim - Findingown data
External capsule WMH was observed in 50.0% (3/6) of medium-risk misdiagnosed patients.
“Although external capsule WMH was observed in 50.0% (3/6) of misdiagnosed patients, none exhibited symmetric involvement (0% vs 86.4%).”
Quote in the paperNot a substantial claim - Findingown data
Two individuals experienced injection-site reactions from first-line injectable agents such as glatiramer acetate and interferon β formulations.
“Two individuals experienced injection-site reactions from first-line injectable agents such as glatiramer acetate and interferon β formulations.”
Quote in the paperNot a substantial claim - Findingown data
MS-directed treatments resulted in adverse events.
“During this interval, although there was no significant clinical and radiologic progression (Table 4), 5 patients (45.5%) received unnecessary MS-directed treatments that resulted in adverse events.”
Quote in the paperSubstantial claim - Findingown data
At the time of CADASIL diagnosis, anterior temporal pole WMH was present in 45.5% of patients with prior MS misdiagnosis compared with 82.3% of those without misdiagnosis.
“At the time of CADASIL diagnosis (Table 2), anterior temporal pole WMH was present in 45.5% of patients with prior MS misdiagnosis compared with 82.3% of those without misdiagnosis.”
Quote in the paperSubstantial claim - Findingown data
Five patients (45.5%) with prior MS misdiagnosis received MS-directed treatments.
“During this interval, although there was no significant clinical and radiologic progression (Table 4), 5 patients (45.5%) received unnecessary MS-directed treatments that resulted in adverse events.”
Quote in the paperSubstantial claim - Findingown data
Within the medium-risk stratum, patients with prior MS misdiagnosis (n = 6) rarely demonstrated anterior temporal pole WMH (16.7% vs 70.4%) compared with medium-risk patients without misdiagnosis.
“Within the medium-risk stratum, patients with a prior MS misdiagnosis (n = 6) rarely demonstrated anterior temporal pole WMH (16.7% vs 70.4%) or infratentorial WMH (16.7% vs 74.1%) compared with medium-risk patients without misdiagnosis.”
Quote in the paperSubstantial claim - Findingown data
In adjusted logistic regression, asymmetric external capsule WMH is independently associated with MS misdiagnosis (adjusted OR 53.34; 95% CI 4.06-701.08).
“asymmetric external capsule white matter hyperintensity (WMH) (adjusted OR 53.34; 95% CI 4.06–701.08)”
- Also stated in: § Results · plain
“asymmetric external capsule WMH (adjusted OR 53.34; 95% CI 4.06–701.08)”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Findingown data
Misdiagnosed patients were more likely to have undergone lumbar puncture (90.9% vs 26.0%).
“more likely to have undergone lumbar puncture (90.9% vs 26.0%)”
Quote in the paperNot a substantial claim - Findingown data
The association between medium-risk EGFr variants and MS misdiagnosis did not persist after prespecified adjustment.
“Genetic analysis showed that medium-risk EGFr variants were more frequent among misdiagnosed patients in unadjusted comparisons, but this association did not persist after prespecified adjustment.”
Quote in the paperNot a substantial claim - Findingown data
Medium-risk EGFr variants were more frequent among misdiagnosed patients in unadjusted comparisons.
“Genetic analysis showed that medium-risk EGFr variants were more frequent among misdiagnosed patients in unadjusted comparisons, but this association did not persist after prespecified adjustment.”
Quote in the paperNot a substantial claim - Findingown data
In adjusted logistic regression, absence of infratentorial WMH is independently associated with MS misdiagnosis (adjusted OR 12.48; 95% CI 1.90-82.01).
“absence of infratentorial WMH (adjusted OR 12.48; 95% CI 1.90–82.01)”
- Also stated in: § Results · plain
“absence of infratentorial WMH (adjusted OR 12.48; 95% CI 1.90–82.01)”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Findingown data
The median time to diagnostic correction was 14.45 months (range 1.18-138.07).
“The median time to diagnostic correction was 14.45 months (range 1.18–138.07)”
Quote in the paperNot a substantial claim - Findingown data
The median time to correct the MS misdiagnosis to CADASIL was 14.45 months (range 1.18-138.07).
“The median time to correct the MS misdiagnosis to CADASIL was 14.45 months (range 1.18–138.07).”
Quote in the paperSubstantial claim - Findingown data
Documented adverse events included injection site reactions in 2 patients.
“Documented adverse events included injection site reactions in 2 patients.”
Quote in the paperNot a substantial claim - Findingown data
Misdiagnosed patients were less likely to have a history of stroke (36.4% vs 73.8%).
“less likely to have a history of stroke (36.4% vs 73.8%)”
Quote in the paperNot a substantial claim - Findingown data
In prespecified adjusted models, absence of infratentorial WMH on MRI brain was independently associated with MS misdiagnosis.
“In prespecified adjusted models, Asian race, absence of prior stroke history, presence of asymmetric external capsule WMH, and absence of infratentorial WMH on MRI brain were independently associated with MS misdiagnosis.”
Quote in the paperSubstantial claim- Rests on an assumption: The recorded MS misdiagnosis in the cohort is accurate and not due to historical miscoding or diagnostic uncertainty.
- Findingown data
In adjusted logistic regression, Asian race is independently associated with MS misdiagnosis (adjusted OR 20.74; 95% CI 3.21-134.18).
“Asian race (adjusted OR 20.74; 95% CI 3.21–134.18)”
- Also stated in: § Results · plain
“Asian race (adjusted OR 20.74; 95% CI 3.21–134.18)”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Findingown data
Among patients with external capsule WMH, symmetric involvement was less frequent in the misdiagnosed group than in those without MS misdiagnosis (14.3% vs 86.5%).
“However, among patients with external capsule WMH, symmetric involvement was less frequent in the misdiagnosed group than in those without MS misdiagnosis (14.3% vs 86.5%).”
Quote in the paperSubstantial claim - Findingown data
By the time of CADASIL confirmation, patients with a prior MS misdiagnosis were at a higher N3SVD stage than those diagnosed correctly at initial presentation.
“By the time of CADASIL confirmation, patients with a prior MS misdiagnosis had higher median mRS scores and were at a higher N3SVD stage than those diagnosed correctly at initial presentation.”
Quote in the paperSubstantial claim - Findingown data
In this multicenter tertiary-care cohort, 11 of 107 CADASIL patients (10.2%) had a prior MS misdiagnosis.
“Of 107 CADASIL patients (mean age 57.5 ± 13.4 years), 11 (10.2%) were misdiagnosed with MS.”
- Also stated in: § Results · plain
“Of 107 patients with CADASIL (mean age 57.5 ± 13.4 years), 11 (10.2%) had a prior MS misdiagnosis (Table 1).”
Quote in the paperSubstantial claim- Rests on an assumption: A documented prior MS diagnosis in the electronic medical record represents a misdiagnosis rather than comorbid MS.
- Also stated in: § Results · plain
- Findingcitation
A high CMB burden (>10) and region-specific CMB distribution were observed only in correctly diagnosed patients.
“Furthermore, a high CMB burden (>10) and region-specific CMB distribution were observed only in correctly diagnosed patients, suggesting that prominent microbleeds favor a small vessel disease diagnosis rather than MS.1,4,10”
Quote in the paperSubstantial claim - Findingown data
In our cohort, CSF oligoclonal bands were absent in 91% of patients misdiagnosed with MS.
“Similarly, in our cohort, CSF oligoclonal bands were absent in 91% patients misdiagnosed with MS.”
Quote in the paperSubstantial claim - Findingown data
Among misdiagnosed patients in our cohort who underwent spinal MRI, no spinal cord lesions were identified.
“Notably, among misdiagnosed patients in our cohort who underwent spinal MRI, no spinal cord lesions were identified, highlighting the absence of a key MS-supportive imaging marker.”
Quote in the paperSubstantial claim- Rests on an assumption: A spinal cord lesion strongly supports an MS diagnosis and is generally absent in cerebrovascular disease.
- Findingown data
In our study, all patients treated for MS were older than 50 years.
“In our study, all patients treated for MS were older than 50 years, an age group in which a new diagnosis of MS is uncommon (∼5% cases).21”
Quote in the paperSubstantial claim - Study design and conductown data
The small number of misdiagnosis events resulted in wide CIs.
“However, the small number of misdiagnosis events resulted in wide CIs, and these findings should be interpreted with caution pending confirmation in other populations and larger samples.”
Quote in the paperSubstantial claim - Interpretationown data
The MS-directed treatments received by misdiagnosed patients were unnecessary.
“During this interval, although there was no significant clinical and radiologic progression (Table 4), 5 patients (45.5%) received unnecessary MS-directed treatments that resulted in adverse events.”
Quote in the paperSubstantial claim - Interpretationcitation
The observed association between MS misdiagnosis and Asian race may reflect underlying differences in CADASIL genetic epidemiology and phenotype expression.
“The observed association between MS misdiagnosis and the Asian race may reflect underlying differences in CADASIL genetic epidemiology and phenotype expression.”
Quote in the paperSubstantial claim - Interpretationown data
Atypical neuroimaging patterns contribute to diagnostic confusion.
“Beyond clinical factors, atypical neuroimaging patterns contribute to diagnostic confusion.”
Quote in the paperSubstantial claim - Interpretationown data
Misdiagnosis created the potential for treatment-related harm.
“Beyond the effects of diagnostic delay, misdiagnosis created the potential for treatment-related harm.”
Quote in the paperSubstantial claim - Premisecitation
A new diagnosis of MS is uncommon in people older than 50 years (∼5% of cases).
“In our study, all patients treated for MS were older than 50 years, an age group in which a new diagnosis of MS is uncommon (∼5% cases).21”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Naseri A, Nasiri E, Sahraian MA, Daneshvar S, Talebi M. Clinical features of late-onset multiple sclerosis: a systematic review and meta-analysis. Mult Scler Relat Disord. 2021; 50: 102816. doi: 10.1016/j.msard.2021.102816 33571792 source
- Interpretationreasoning
Atypical or incomplete CADASIL markers create a plausible pathway to misclassification, particularly in late-onset or stroke-naïve presentations where confluent supratentorial WMH may be interpreted within an MS framework.
“Together, these atypical or incomplete CADASIL markers create a plausible pathway to misclassification, particularly in late-onset or stroke-naïve presentations where confluent supratentorial WMH may be interpreted within an MS framework.”
Quote in the paperSubstantial claim - Study design and conductown data
The study assembled a genetically confirmed cohort of more than 100 patients with CADASIL.
“Although CADASIL is rare, we assembled a genetically confirmed cohort of more than 100 patients, representing one of the larger series reported to date.”
Quote in the paperSubstantial claim - Interpretationown data
CSF oligoclonal bands help distinguish true codiagnosis from misdiagnosis.
“These findings highlight the role of CSF oligoclonal bands in distinguishing true codiagnosis from misdiagnosis.”
Quote in the paperSubstantial claim - Interpretationown data
EGFr-stratified imaging suggests that medium-risk variants may be linked to atypical radiologic patterns that reduce recognition of CADASIL and increase diagnostic ambiguity.
“EGFr-stratified imaging suggests that these variants may be linked to atypical radiologic patterns that reduce recognition of CADASIL and increase diagnostic ambiguity.”
Quote in the paperSubstantial claim - Study design and conductreasoning
The cohort size remains modest compared with the broad clinical heterogeneity of CADASIL, which may limit ability to detect more subtle between-group differences.
“While our cohort size is large for a rare disease, it remains modest compared with the broad clinical heterogeneity of CADASIL, which may limit our ability to detect more subtle between-group differences.”
Quote in the paperNot a substantial claim - Study design and conductreasoning
The retrospective design introduces potential bias due to incomplete or inconsistent documentation.
“The retrospective design introduces potential bias due to incomplete or inconsistent documentation.”
Quote in the paperNot a substantial claim - Interpretationown data
Many patients with prior MS misdiagnosis were exposed to unnecessary and potentially harmful MS-directed therapies.
“At the time of CADASIL confirmation, patients with a prior MS misdiagnosis were more likely to be at an advanced N3SVD disease stage and had greater functional disability, and many were exposed to unnecessary and potentially harmful MS-directed therapies.”
Quote in the paperSubstantial claim - Study design and conductnone given
The short interval between misdiagnosis and CADASIL confirmation in some patients constrained ability to detect meaningful clinical or radiologic changes.
“In addition, the short interval between misdiagnosis and CADASIL confirmation in some patients constrained our ability to detect meaningful clinical or radiologic changes.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The presence of clinical and radiographical mimics, such as cerebral small vessel disease (including CADASIL), migraine-related white matter changes, and certain inflammatory conditions in the same age group increases risk of misdiagnosis.
“The presence of clinical and radiographical mimics, such as cerebral small vessel disease (including CADASIL), migraine-related white matter changes, and certain inflammatory conditions in the same age group increases risk of misdiagnosis.”
Quote in the paperSubstantial claim - Study design and conductnone given
The small size of the MS-misdiagnosed subgroup limits the robustness of statistical analyses.
“The small size of the MS-misdiagnosed subgroup limits the robustness of our statistical analyses.”
Quote in the paperNot a substantial claim
- May combine two claims. 23
- Classified as probably not a substantial claim. 13
May combine two claims.
PremisecitationCADASIL is characterized by migraine, recurrent ischemic strokes, and progressive cognitive decline.
“It is characterized by migraine, recurrent ischemic strokes, and progressive cognitive decline.1”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [1] Meschia JF, Worrall BB, Elahi FM, et al. Management of inherited CNS small vessel diseases: the CADASIL example: a scientific statement from the American Heart Association. Stroke. 2023; 54(10): e452- e464. doi: 10.1161/str.0000000000000444 37602377 source
May combine two claims.
PremisecitationCysteine-altering NOTCH3 variants have been linked to increased susceptibility to autoimmune disorders, which may reinforce an erroneous MS diagnosis.
“In addition, cysteine-altering NOTCH3 variants have been linked to increased susceptibility to autoimmune disorders, which may reinforce an erroneous MS diagnosis.5”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [5] Rieder E, Li J, Rodriguez-Flores JL, Taimur Malik M, Abedi V, Zand R. Cysteine-altering NOTCH3 variants are associated with an increased risk of autoimmune diseases. J Clin Med. 2023; 12(19): 6278. doi: 10.3390/jcm12196278 37834922 PMC10573689 source
The Discussion reports more autoimmune diagnoses among NOTCH3-variant carriers in one cohort, though that difference was not statistically significant, and describes a possible association between the variants and immune dysregulation. It also mentions MS–CADASIL misdiagnosis, but attributes that possibility to similarities in imaging phenotype; it does not say increased autoimmune susceptibility reinforces an erroneous MS diagnosis. Page numbers were not available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCADASIL is caused by pathogenic variants in the NOTCH3 gene on chromosome 19.
“Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), the most common inherited small vessel disease, is caused by pathogenic variants in the NOTCH3 gene on chromosome 19.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [1] Meschia JF, Worrall BB, Elahi FM, et al. Management of inherited CNS small vessel diseases: the CADASIL example: a scientific statement from the American Heart Association. Stroke. 2023; 54(10): e452- e464. doi: 10.1161/str.0000000000000444 37602377 source
The Molecular Genetics of CADASIL and Other CSVDs section identifies disease-associated NOTCH3 mutations, supporting the genetic-cause portion of the claim. The passages do not state that NOTCH3 is on chromosome 19 (searched: “chromosome 19” and “19p13”), so that location is not verified by our copy; page numbers were unavailable. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
Interpretationown dataMS-directed treatments incurred financial costs and avoidable risks.
“While no significant clinical or radiologic progression was observed during the typically short interval between misdiagnosis and diagnostic correction, 45.5% of misdiagnosed patients received MS-directed treatments for a median of 10 months, incurring financial costs and avoidable risks.2,3”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [2] Mandia D, Shor N, Carlson AK, et al. Genetic diseases misdiagnosed as multiple sclerosis: observational study and review of literature. Mult Scler Relat Disord. 2025; 99: 106439. doi: 10.1016/j.msard.2025.106439 40446704 source
- cites [3] Mandler JM, Härtl J, Cordts I, et al. Uncovering genetic mimics in multiple sclerosis: a single-center clinical exome sequencing study. Mult Scler J Exp Transl Clin. 2024; 10(3): 20552173241263491. doi: 10.1177/20552173241263491 39072298 PMC11273569 source
The Discussion says that identifying a genetic MS mimic can prevent unnecessary immunomodulatory treatment and its potentially harmful side effects, supporting the avoidable-risks point. Our copy does not state that these treatments incurred financial costs; its mention of reimbursement regulations concerns genetic testing, not treatment costs. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationCADASIL in Asian patients often lacks classic radiologic phenotype, such as anterior temporal pole involvement, and may present later in life with confluent WMHs and cognitive impairment, increasing the risk of misdiagnosis.
“Moreover, CADASIL in Asian patients often lacks classic radiologic phenotype, such as anterior temporal pole involvement, and may present later in life with confluent WMHs and cognitive impairment, increasing the risk of misdiagnosis.16-18”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [16] Ni W, Zhang Y, Zhang L, Xie JJ, Li HF, Wu ZY. Genetic spectrum of NOTCH3 and clinical phenotype of CADASIL patients in different populations. CNS Neurosci Ther. 2022; 28(11): 1779- 1789. doi: 10.1111/cns.13917 35822697 PMC9532899 source
The Results (Clinical features of CADASIL patients in different populations; page unavailable) report later age at onset, more cognitive impairment, and less frequent temporal-pole involvement in Asian than Caucasian patients, though temporal-pole involvement still occurred in 68.64% of Asian patients. The Introduction describes white matter hyperintensities, but our copy does not establish that they are confluent or that this presentation increases misdiagnosis risk. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [17] Liao YC, Hsiao CT, Fuh JL, et al. Characterization of CADASIL among the han Chinese in Taiwan: distinct genotypic and phenotypic profiles. PLoS One. 2015; 10(8): e0136501. doi: 10.1371/journal.pone.0136501 26308724 PMC4550240 source
The Discussion and Results (pages not provided) report less frequent anterior temporal pole involvement and later symptom onset in Taiwanese CADASIL patients, particularly those with R544C; Table 5 also reports more cognitive dysfunction in that subgroup. A neuroimaging figure shows diffuse white-matter lesions without significant temporal pole involvement, and the Discussion cautions against excluding CADASIL on that basis. The paper does not establish that Asian patients generally present with the full combination of confluent lesions and cognitive impairment, or directly measure a risk of misdiagnosis. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [18] Langer-Gould AM, Gonzales EG, Smith JB, Li BH, Nelson LM. Racial and ethnic disparities in multiple sclerosis prevalence. Neurology. 2022; 98(18): e1818- e1827. doi: 10.1212/wnl.0000000000200151 35501161 PMC9109151 source
The Discussion addresses multiple sclerosis prevalence among Asian populations and misdiagnosis of MS, not CADASIL. Searches of our copy for CADASIL, anterior temporal pole involvement, white-matter hyperintensities, and cognitive impairment found no passage addressing the attributed claim. The cited paper therefore cannot verify it. (LLM, conf=0.78)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationPatients receiving MS therapies were at risk of additional adverse events including flu-like symptoms, hepatotoxicity, autoimmune complications, recurrent infections, and in rare cases progressive multifocal leukoencephalopathy.
“Patients were also at risk of additional adverse events from these therapies, including flu-like symptoms, hepatotoxicity, autoimmune complications, recurrent infections, and in rare cases, progressive multifocal leukoencephalopathy.10,12,13”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [10] McGinley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and treatment of multiple sclerosis: a review. Jama 2021; 325(8): 765- 779. doi: 10.1001/jama.2020.26858 33620411 source
- cites [12] Luna G, Alping P, Burman J, et al. Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies. JAMA Neurol. 2020; 77(2): 184- 191. doi: 10.1001/jamaneurol.2019.3365 31589278 PMC6784753 source
The Abstract reports increased infection risk with some MS therapies, and Risk of Infections reports two cases of progressive multifocal leukoencephalopathy (PML). The paper does not substantiate the listed flu-like symptoms, hepatotoxicity, or autoimmune complications; it also does not establish that the PML cases were caused by the therapies patients were receiving at diagnosis, since both had recently switched from natalizumab. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [13] Ng HS, Zhu F, Zhao Y, et al. Adverse events associated with disease-modifying drugs for multiple sclerosis: a multiregional population-based study. Neurology. 2024; 102(3): e208006. doi: 10.1212/wnl.0000000000208006 38181306 PMC11097763 source
The Results (page not available) report liver injury or disease with select MS drugs and increased infection-related physician visits, while the Discussion describes alemtuzumab-associated autoantibodies. The paper does not establish flu-like symptoms, recurrent infections specifically, or rare progressive multifocal leukoencephalopathy as adverse events; it also reports lower infection-related hospitalization risk with virtually all drugs studied. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationNOTCH3 variants were classified by exon and EGFr domain and stratified into high-risk, medium-risk, low-risk, or undetermined-risk categories according to published criteria.
“For patients who underwent genetic testing, NOTCH3 variants were classified by exon and epidermal growth factor–like repeat (EGFr) domain and stratified into high-risk, medium-risk, low-risk, or undetermined-risk categories according to published criteria.9”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [9] Hack RJ, Gravesteijn G, Cerfontaine MN, et al. Three-tiered EGFr domain risk stratification for individualized NOTCH3-small vessel disease prediction. Brain. 2023; 146(7): 2913- 2927. doi: 10.1093/brain/awac486 36535904 PMC10316769 source
The Materials and methods section (page unavailable) defines high-, medium-, low-, and unknown-risk EGFr domains; the Results Figure 2 caption (page unavailable) identifies the exons encoding those domains. However, the risk criteria apply specifically to cysteine-altering NOTCH3 variants, not to NOTCH3 variants generally, and the paper does not set out a separate exon-based risk classification. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCysteine-altering NOTCH3 variants could increase autoimmune susceptibility.
“This is supported by evidence that cysteine-altering NOTCH3 variants could increase autoimmune susceptibility.5”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [5] Rieder E, Li J, Rodriguez-Flores JL, Taimur Malik M, Abedi V, Zand R. Cysteine-altering NOTCH3 variants are associated with an increased risk of autoimmune diseases. J Clin Med. 2023; 12(19): 6278. doi: 10.3390/jcm12196278 37834922 PMC10573689 source
May combine two claims.
Findingown dataMS misdiagnosis occurred in both high-risk and medium-risk genetic variant groups, with no cases in low-risk or unknown-risk categories.
“Misdiagnosis was observed in both high-risk and medium-risk genetic variant groups, with no cases in low-risk or unknown-risk categories (Figure 2).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown data2 patients experienced documented adverse events.
“and 2 experienced documented adverse events.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMost therapies for MS were disease-modifying agents, whereas only 1 patient had corticosteroid exposure.
“Most therapies for MS were disease-modifying agents, whereas only 1 patient had corticosteroid exposure.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataNone of the medium-risk misdiagnosed patients exhibited symmetric external capsule involvement, compared with 86.4% of medium-risk patients without misdiagnosis.
“Although external capsule WMH was observed in 50.0% (3/6) of misdiagnosed patients, none exhibited symmetric involvement (0% vs 86.4%).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAmong patients without prior MS misdiagnosis, 65.9% had no CMBs, 24.2% had 1-10 CMBs, and 9.9% had >10 CMBs (5.2% ungradable).
“By contrast, among patients without prior MS misdiagnosis, 65.9% had no CMBs, 24.2% had 1–10 CMBs, and 9.9% had >10 CMBs (5.2% were ungradable).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCMB burden was low in the MS-misdiagnosed group, with 90.9% having no CMBs, 9.1% having 1-10 CMBs, and none having >10 CMBs.
“CMB burden was low in the MS-misdiagnosed group, with 90.9% of patients having no CMBs, 9.1% having 1–10 CMBs, and none had >10 CMBs.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAmong 11 patients with prior MS misdiagnosis, 10 had available NOTCH3 genetic testing, and 1 was diagnosed by skin biopsy without genotyping.
“Among the 11 patients with prior MS misdiagnosis, 10 had available NOTCH3 genetic testing, while 1 was diagnosed by skin biopsy without genotyping.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe MS treatment regimens included glatiramer acetate (n = 2), interferon β-1a (n = 1), interferon β-1b with subsequent transition to dimethyl fumarate and later diroximel fumarate (n = 1), and methylprednisolone (n = 1).
“The regimens (eTable 1), 80% of which were disease-modifying therapies, included glatiramer acetate (n = 2), interferon β-1a (n = 1), interferon β-1b with subsequent transition to dimethyl fumarate and later diroximel fumarate (n = 1), and methylprednisolone (n = 1).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMedium-risk EGFr variants were more frequent among misdiagnosed patients in unadjusted comparisons but were not independently associated after adjustment.
“Medium-risk EGFr variants were more frequent among misdiagnosed patients in unadjusted comparisons but were not independently associated after adjustment.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAmong the 4 treated patients with genetic testing, 3 (75%) carried medium-risk variants and 1 had a high-risk variant.
“Notably, among the 5 patients who received treatment, 4 had genetic testing. Of these, 3 (75%) carried medium-risk variants, while 1 had a high-risk variant.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataAmong the 5 patients who received treatment, 4 had genetic testing.
“Notably, among the 5 patients who received treatment, 4 had genetic testing. Of these, 3 (75%) carried medium-risk variants, while 1 had a high-risk variant.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAt the time of CADASIL confirmation, patients with a prior MS misdiagnosis were more likely to be at an advanced N3SVD disease stage and had greater functional disability.
“At the time of CADASIL confirmation, patients with a prior MS misdiagnosis were more likely to be at an advanced N3SVD disease stage and had greater functional disability, and many were exposed to unnecessary and potentially harmful MS-directed therapies.”
Quote in the paperSubstantial claim- Rests on an assumption: The recorded MS misdiagnosis in the cohort is accurate and not due to historical miscoding or diagnostic uncertainty.
Classified as probably not a substantial claim.
Study design and conductown dataPatients were identified through consecutive case ascertainment between 1999 and 2024 using ICD code searches followed by manual verification across the 3 Mayo Clinic sites.
“identified through consecutive case ascertainment between 1999 and 2024 using International Classification of Diseases code (I67.850) searches in the electronic medical record (Epic Inc., Verona, WI) followed by manual verification across the 3 Mayo Clinic sites (Mayo Clinic FL [MCF], Mayo Clinic Rochester [MCR], and Mayo Clinic Arizona [MCA]).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataGiven the small sample size of the misdiagnosed subgroup, statistical comparisons should be regarded as exploratory and interpreted with caution.
“Given the small sample size of the misdiagnosed subgroup, statistical comparisons should be regarded as exploratory and interpreted with caution.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenAll available brain MRI studies were re-reviewed by a single-board-certified neuroradiologist to systematically adjudicate CADASIL-associated and MS-associated imaging features.
“All available brain MRI studies were re-reviewed by a single-board–certified neuroradiologist to systematically adjudicate CADASIL-associated and MS-associated imaging features”
Quote in the paperSubstantial claim- Rests on an assumption: The single neuroradiologist's re-review of MRI features is reliable and accurate.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenCore covariates were selected a priori based on clinical plausibility.
“Core covariates were selected a priori based on clinical plausibility and included age at CADASIL diagnosis, sex, race (modeled as Asian vs non-Asian due to sparse counts among other subgroups), and prior stroke history.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductreasoningTo reduce overfitting given the limited number of events, each imaging or genetic predictor was evaluated in a separate adjusted model rather than combining multiple candidate predictors in a single model.
“To reduce overfitting given the limited number of events, each imaging or genetic predictor was evaluated in a separate adjusted model rather than combining multiple candidate predictors in a single model.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataMS misdiagnosis in CADASIL leads to worse functional outcomes and inappropriate treatments.
“an error associated with Asian race, absence of a stroke history, and atypical neuroimaging patterns leading to worse functional outcomes and inappropriate treatments.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataMisdiagnosis delays appropriate genetic counseling and vascular risk management and may expose patients to unnecessary therapies.
“Misdiagnosis not only delays appropriate genetic counseling and vascular risk management but also may expose patients to unnecessary therapies.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataThe cohort lacked high-resolution 3T/7T MRI brain imaging, so central vein sign and paramagnetic rim lesions could not be assessed.
“Because our cohort lacked high-resolution 3T/7T MRI brain imaging, these markers could not be assessed.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe CSF kFLC index was not measured in our cohort.
“Third, while the CSF kappa-free light chain (kFLC) index is an accepted alternative to traditional oligoclonal bands (OCBs) for demonstrating CNS inflammatory activity, it was not measured in our cohort.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIn a retrospective study across 7 MS tertiary centers, CSF oligoclonal bands were absent in 100% of patients with CADASIL misdiagnosed as MS, but present in 83% of those with confirmed codiagnosis of neurogenetic disease and MS.
“In a retrospective study conducted across 7 MS tertiary centers, CSF oligoclonal bands were absent in 100% of patients with CADASIL misdiagnosed as MS, but present in 83% of those with confirmed codiagnosis of neurogenetic disease and MS.2”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Mandia D, Shor N, Carlson AK, et al. Genetic diseases misdiagnosed as multiple sclerosis: observational study and review of literature. Mult Scler Relat Disord. 2025; 99: 106439. doi: 10.1016/j.msard.2025.106439 40446704 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductreasoningBecause all sites are tertiary-care centers, referral biases remain, and generalization of results must be interpreted with caution.
“However, because all sites are tertiary-care centers, referral biases remain, and generalization of results must be interpreted with caution.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown dataInitial clinical and radiologic data at the time of MS labeling were often incomplete or predated contemporary diagnostic standards, so cases could not be reliably reclassified under 2024 McDonald criteria and historical miscoding or diagnostic uncertainty cannot be fully excluded.
“Because initial clinical and radiologic data at the time of MS labeling were often incomplete or predated contemporary diagnostic standards, we were unable to reliably reclassify cases under 2024 McDonald criteria and thus cannot fully exclude historical miscoding or diagnostic uncertainty.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductreasoningThe centralized multicenter design improves generalizability by encompassing diverse clinical presentations and practice patterns across diverse regions of the United States while ensuring standardized data collection.
“The centralized multicenter design improves generalizability by encompassing diverse clinical presentations and practice patterns across diverse regions of the United States while ensuring standardized data collection.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductreasoningThe racial and ancestral composition of the tertiary-care cohort is not population representative, so race-related associations, particularly with Asian ancestry, should be interpreted cautiously.
“Although Mayo Clinic serves a national and international referral population, the racial and ancestral composition of this tertiary-care cohort is not population representative and race-related associations, particularly with Asian ancestry, should therefore be interpreted cautiously.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
A documented prior MS diagnosis in the electronic medical record represents a misdiagnosis rather than comorbid MS.
“The unified electronic medical record (Epic) was reviewed to determine whether a diagnosis of MS had been documented at any time prior to CADASIL confirmation. Patients with such a diagnosis were classified as the MS misdiagnosis group, while all others comprised the non-misdiagnosed group.”
The paper relies on this without support.
The single neuroradiologist's re-review of MRI features is reliable and accurate.
“All available brain MRI studies were re-reviewed by a single-board–certified neuroradiologist to systematically adjudicate CADASIL-associated and MS-associated imaging features”
The paper relies on this without support.
The recorded MS misdiagnosis in the cohort is accurate and not due to historical miscoding or diagnostic uncertainty.
“Because initial clinical and radiologic data at the time of MS labeling were often incomplete or predated contemporary diagnostic standards, we were unable to reliably reclassify cases under 2024 McDonald criteria and thus cannot fully exclude historical miscoding or diagnostic uncertainty.”
The paper relies on this without support.
A spinal cord lesion strongly supports an MS diagnosis and is generally absent in cerebrovascular disease.
“First, a spinal cord lesion should be investigated because its presence strongly supports an MS diagnosis while being generally absent in cerebrovascular disease.”
The paper relies on this without support.
Advanced MRI biomarkers such as the central vein sign and paramagnetic rim lesions are highly specific for MS and seldom seen in mimics.
“Second, advanced MRI biomarkers such as the central vein sign and paramagnetic rim lesions are highly specific for MS and seldom seen in mimics.”
The paper relies on this without support.
The CSF kFLC index is an accepted alternative to traditional OCBs for demonstrating CNS inflammatory activity.
“Third, while the CSF kappa-free light chain (kFLC) index is an accepted alternative to traditional oligoclonal bands (OCBs) for demonstrating CNS inflammatory activity, it was not measured in our cohort.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Genetically confirmed cohort is described as exceeding 100
MinorThe paper describes more than 100 patients as genetically confirmed, but states that only 98 were confirmed by genetic testing; the other 9 were confirmed by skin biopsy.
“Although CADASIL is rare, we assembled a genetically confirmed cohort of more than 100 patients, representing one of the larger series reported to date.”
“Baseline was defined as the date CADASIL was confirmed by genetic testing (n = 98) or skin biopsy (n = 9).”
Unadjusted age odds ratio has the opposite direction from the group means
MinorThe misdiagnosed group has a lower mean age than the non-misdiagnosed group. A univariable logistic regression of misdiagnosis on that same age variable must therefore have an odds ratio below 1 per year, whereas the reported unadjusted OR is 1.01.
“| Age at CADASIL diagnosis | 1.01 (0.96–1.05) | 1.00 (0.95–1.05) |”
“| Age, mean (SD) | 55.7 (12.8) | 57.8 (13.5) |”
Claim of higher median disability contradicts Table 1
MinorThe text says the misdiagnosed group had higher median mRS scores, but Table 1 gives both groups a median of 1.
“By the time of CADASIL confirmation, patients with a prior MS misdiagnosis had higher median mRS scores and were at a higher N3SVD stage than those diagnosed correctly at initial presentation.”
“| Modified Rankin scale-median (min-max) | 1 (0–3) | 1 (0–4) |”
Cites
Diagnosis and Treatment of Multiple Sclerosis: A Review
McGinley, M. P., Goldschmidt, C. H., & Rae-Grant, A. D. (2021) · JAMA · doi:10.1001/jama.2020.26858 · Cited by 1,205 · see citing works
Diagnosis of multiple sclerosis: 2024 revisions of the McDonald criteria
Montalban, X., Lebrun-Frénay, C., Oh, J., Arrambide, G., Moccia, M., Pia Amato, M., Amezcua, L., Banwell, B., Bar-Or, A., Barkhof, F., et al. (2025) · The Lancet Neurology · doi:10.1016/s1474-4422(25)00270-4 · Cited by 551 · see citing works
Luna, G., Alping, P., Burman, J., Fink, K., Fogdell-Hahn, A., Gunnarsson, M., Hillert, J., Langer-Gould, A., Lycke, J., Nilsson, P., et al. (2020) · JAMA Neurology · doi:10.1001/jamaneurol.2019.3365 · Cited by 521 · see citing works
Saver, J. L., Chaisinanunkul, N. N., Campbell, B. C. V., et al. (2021) · Stroke · doi:10.1161/strokeaha.121.034480 · Cited by 328 · see citing works
Rutten, J. W., Van Eijsden, B. J., Duering, M., Jouvent, E., Opherk, C., Pantoni, L., Federico, A., Dichgans, M., Markus, H. S., Chabriat, H., et al. (2019) · Genetics in Medicine · doi:10.1038/s41436-018-0088-3 · Cited by 169 · see citing works
Clinical Features of Late-Onset Multiple Sclerosis: a Systematic Review and Meta-analysis
Naseri, A., Nasiri, E., Sahraian, M. A., Daneshvar, S., & Talebi, M. (2021) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2021.102816 · Cited by 142 · see citing works
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Racial and Ethnic Disparities in Multiple Sclerosis Prevalence
Langer-Gould, A. M., Gonzales, E. G., Smith, J. B., Li, B. H., & Nelson, L. M. (2022) · Neurology · doi:10.1212/wnl.0000000000200151 · Cited by 123 · see citing works
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Hack, R. J., Gravesteijn, G., Cerfontaine, M. N., Santcroos, M. A., Gatti, L., Kopczak, A., Bersano, A., Duering, M., Rutten, J. W., & Lesnik Oberstein, S. A. J. (2023) · Brain · doi:10.1093/brain/awac486 · Cited by 60 · see citing works
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Self-citationGlobal Assessment of Mendelian Stroke Genetic Prevalence in 101 635 Individuals From 7 Ethnic Groups
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Self-citationCADASIL vs. Multiple Sclerosis: Is It Misdiagnosis or Concomitant? A Case Series
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Cysteine-Altering NOTCH3 Variants Are Associated with an Increased Risk of Autoimmune Diseases
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Flagged first, then by citations
- Authors
- Mendis, D. D., Vallamchetla, S. K., Marin Collazo, I. V., Sandhu, S. J. S., & Meschia, J. F.
- Affiliations
- Mayo Clinic in Florida (US)
- Neurology, Mayo Clinic, FL; and
- Corresponding author
- Mendis, Dinith D.
- Vallamchetla, Sai Krishna
- ORCID
- Venue
- Neurology Genetics
- Published
- 2026-10
- Volume
- 12
- Issue
- 5
- Pages
- e200430-e200430
- ISSN
- 2376-7839 (ISSN-L)
- PMC
- PMC13537471
- OpenAlex
- W7204231478
- Semantic Scholar
- 786dc45f1192150d7b3ff867675b43fff3d8513c
- Cited by
- 0
- References
- 21
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Neurology Genetics (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Topics
- Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Vasculitis and related conditions
- Keywords
- CADASIL, multiple sclerosis misdiagnosis, diagnostic errors, white matter hyperintensities, Asian race, stroke history, EGFR variants, demyelinating disease, adverse events
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-22.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-22.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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