Hematopoietic Stem Cell Transplantation in CSF1R-Related Leukoencephalopathy: Retrospective Study on Predictors of Outcomes
by
and
Jarosław Dulski
1,2,3, 
Michael G. Heckman
4,
Launia J. White
4,
Kamila Żur-Wyrozumska
5,
Troy C. Lund
6 and
Zbigniew K. Wszolek
1,* 1
Department of Neurology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, USA
2
Division of Neurological and Psychiatric Nursing, Faculty of Health Sciences, Medical University of Gdansk, 80-211 Gdansk, Poland
3
Neurology Department, St Adalbert Hospital, Copernicus PL Ltd., 80-462 Gdansk, Poland
4
Division of Clinical Trials and Biostatistics, Mayo Clinic, Jacksonville, FL 32224, USA
5
Department of Medical Education, Jagiellonian University Medical College, 30-688 Kraków, Poland
6
Department of Pediatrics, Division of Blood and Marrow Transplant, University of Minnesota, Minneapolis, MN 55455, USA
*
Author to whom correspondence should be addressed.
Pharmaceutics 2022, 14(12), 2778; https://doi.org/10.3390/pharmaceutics14122778
Submission received: 30 October 2022
/
Revised: 28 November 2022
/
Accepted: 8 December 2022
/
Published: 12 December 2022
(This article belongs to the Special Issue Novel Therapeutic Approaches in Rare Genetic Diseases)
Abstract
:Mutations in the CSF1R gene are the most common cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a neurodegenerative disease with rapid progression and ominous prognosis. Hematopoietic stem cell transplantation (HSCT) has been increasingly offered to patients with CSF1R-ALSP. However, different therapy results were observed, and it was not elucidated which patient should be referred for HSCT. This study aimed to determine predictors of good and bad HSCT outcomes in CSF1R-ALSP. We retrospectively analyzed 15 patients, 14 symptomatic and 1 asymptomatic, with CSF1R-ALSP that underwent HSCT. Median age of onset was 39 years, and the median age of HSCT was 43 years. Cognitive impairment was the most frequent initial manifestation (43%), followed by gait problems (21%) and neuropsychiatric symptoms (21%). Median post-HSCT follow-up was 26 months. Good outcomes were associated with gait problems as initial (p = 0.041) and predominant (p = 0.017) manifestation and younger age at HSCT (p = 0.044). Cognitive impairment as first manifestation was a predictor of a bad outcome (p = 0.016) and worsening of cognition post-HSCT (p = 0.025). In conclusion, gait problems indicated a milder phenotype with better response to HSCT and good therapy outcomes. In contrast, patients with a higher burden of cognitive symptoms were most likely not to benefit from HSCT.
1. Introduction
Mutations in the Colony Stimulating Factor 1 Receptor (CSF1R) gene are the most common cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) [1,2]. The disease is characterized by progressive cognitive decline, neuropsychiatric features (anxiety, apathy, depression, disinhibition, irritability, and other frontal lobe symptoms), parkinsonism, pyramidal signs, gait difficulty, and imbalance [1,2]. Some patients may also manifest seizures and stroke-like exacerbations of the disease [1,2]. The prognosis is ominous, with rapid progression and death within a few years from the initial symptoms [1,2].
In recent years, advances in research on CSF1R-ALSP have uncovered pathophysiological mechanisms and opened new treatment perspectives for the previously untreatable disease [2,3,4]. The CSF1R protein is primarily expressed in the central nervous system, where it is essential for the normal development, differentiation, function, and maintenance of the microglia [1,2]. CSF1R mutations lead to haploinsufficiency, but the remaining microglia are sufficient to compensate during the first few decades of life. However, with aging, there is a growing accumulation of damage to white matter, and once the compensation abilities are overwhelmed, the symptomatic disease ensues [1]. Microglia replacement by hematopoietic stem cell transplantation (HSCT) offered potential means of stabilizing the disease progression and improving survival [4,5]. Since the first report on the application of HSCT in CSF1R-ALSP by Eichler and colleagues in 2016 [6], there have been several other case reports and series. Many patients significantly benefited from the transplantation; however, some experienced worsening of their condition or even death. To date, no study has evaluated factors that may be predictive of response to HSCT. In the current study, we attempt to fill that gap in knowledge and assess predictors of good and bad HSCT outcomes in CSF1R-ALSP.
2. Methodology
We searched the medical literature databases until 16 September 2022, for all manuscripts reporting HSCT applications in CSF1R-ALSP and found data on 13 patients treated with HSCT [4,6,7,8,9,10,11]. We were able to follow up on 5 of these patients. Additionally, we retrieved data on 2 new unreported cases. Thus, a total of 15 patients (12 from the United States, 1 from Poland, 1 from France, and 1 from Norway) with CSF1R-ALSP treated with HSCT were included in the study. Data extraction and retrospective analysis were performed in a structured manner.
Information was collected regarding demographics (age of onset, sex, age of HSCT, disease duration before HSCT, post-HSCT follow-up duration), initial symptoms, pre-HSCT predominant symptomatology, pre-HSCT activities of daily living (ADLs), pre-HSCT professional activity, pre-HSCT clinical symptoms (cognitive decline, neuropsychiatric symptoms, extrapyramidal symptoms, pyramidal signs, gait problems, and seizures), clinical asymmetry, pre-HSCT brain magnetic resonance imaging (MRI) characteristics (white matter lesions (WMLs), cerebral atrophy, corpus callosum involvement, asymmetry), post-HSCT ADLs, post-HSCT professional activity, post-HSCT clinical outcomes (cognition, neuropsychiatric symptoms, extrapyramidal symptoms, pyramidal signs, gait problems, seizures), and post-HSCT radiological outcomes. Additionally, we calculated two combined measures of the post-HSCT outcome as follows. First, as a dichotomous combined outcome measure, the outcome was considered to be “good” if the patient was assessed as having either no change or improvement for each of the six symptom-related outcomes (allowing for missing data) or independent for ADLs or active for professional activity; all other patients were considered to have a “bad” outcome. Second, we calculated a score for each patient by summing the values for the individual post-HSCT outcomes (Symptoms: 0 = deterioration, 1 = no change, 2 = improvement; ADLs: 0 = dependent, 2 = independent; Professional activity: 0 = not active, 2 = active), where missing data for a post-HSCT outcome was imputed by using the mean value of the patients who did have data for the given outcome in order to avoid scores that are biased too low due to the presence of missing data. Therefore, a higher score indicates better post-HSCT outcomes.
3. Statistical Analysis
Continuous variables were summarized with the sample median and range. Categorical variables were summarized with numbers and percentages. Comparisons of demographics and pre-HSCT characteristics according to outcomes were made using a van Elteren stratified Wilcoxon rank sum test (continuous variables), or a Cochran-Mantel-Haenszel exact test (categorical variables), where the tests were stratified by median follow-up length after HSCT (≤26 months or >26 months). For outcomes that were measured as three-level categorical variables of either deterioration, no change, or improvement, the no change and improvement categories were combined and compared vs. the deterioration category in statistical analysis. Only outcomes that had a minimum of five patients in both categories were examined in statistical comparisons, and only demographics and pre-HSCT characteristics that were measured in at least 10 of the 15 patients were included in these comparisons. Associations of demographics and pre-HSCT characteristics with the combined outcome score were assessed using linear regression models that were adjusted for follow-up length after HSCT as a continuous variable. No adjustment for multiple testing was made in these exploratory analyses, and p-values < 0.05 were considered as statistically significant. All statistical tests were two-sided. Statistical analyses were performed using SAS (version 9.4; SAS Institute, Inc., Cary, NC, USA).
4. Results
Fifteen patients, 14 symptomatic and 1 asymptomatic, with CSF1R-ALSP treated with HSCT were included in the study. All 15 patients harbored different CSF1R mutations (Table 1). Patients’ demographics and pre-HSCT characteristics are summarized in Table 2. The median age of onset was 39 years (range 32–50 years; mean of 39.5 years), 4 patients (26.7%) were male, and the median age of HSCT was 43 years (range 31–52 years). Initial symptoms were cognitive impairment (42.9%), gait problems (21.4%), neuropsychiatric symptoms (21.4%), and other (14.3%). The median length of time from HSCT to the last follow-up evaluation was 26 months (range 3–180 months), including one patient who died 88 days after HSCT. Regarding post-HSCT outcomes (Table 3), an assessment of either no change or improvement occurred in 60.0% of patients for cognition, in 66.7% for neuropsychiatric symptoms, in 53.8% for extrapyramidal symptoms, in 75.0% for pyramidal signs, in 73.3% for gait problems, and in 90.9% for seizures. Post-HSCT ADLs were dependent for 54.5% of patients, and post-HSCT professional activity was not active for 66.7% of patients. For the combined outcome measures, 6 patients (40.0%) had a good outcome, and the median combined outcome score was 7 (Range: 1–14).
Of the individual post-HSCT outcomes, only cognition, neuropsychiatric symptoms, extrapyramidal symptoms, and ADLs had a minimum of 5 patients in both categories and were therefore examined in statistical analysis. Comparisons of demographics and pre-HSCT characteristics according to these outcomes are shown in Table 4 (cognition, neuropsychiatric symptoms) and Table 5 (extrapyramidal symptoms, activities of daily living). Patients with no change or improvement regarding post-HSCT cognition were less likely to have cognitive impairment as their initial symptom (12.5% vs. 83.3%, p = 0.025) and were more likely to have gait problems as their predominant symptom (80.0% vs. 0.0%, p = 0.033) compared to patients with deterioration on cognition (Table 4). Additionally, patients independent in post-HSCT ADLs were less likely to have pre-HSCT pyramidal signs compared to patients who were dependent (60.0% vs. 100.0%, p = 0.048, Table 5). No other statistically significant differences were noted regarding individual post-HSCT outcomes, though several suggestive (p < 0.10) findings were observed (Table 4 and Table 5).
Associations of demographics and pre-HSCT symptoms with combined outcome measures are displayed in Table 6. For the dichotomous combined outcome measure, compared to patients with a bad outcome, patients with a good outcome less often had an initial symptom of cognitive impairment (0.0% vs. 66.7%, p = 0.016), more often had an initial symptom of gait problems (60.0% vs. 0.0%, p = 0.041), had a younger age at HSCT (Median: 38 vs. 45 years, p = 0.044), and more often had a predominant symptom of gait problems (100.0% vs. 0.0%, p = 0.017). Regarding the combined outcome score, this was higher (indicating better outcomes) for patients with an initial symptom of gait problems (p = 0.009) and for patients whose predominant symptom was gait problems (p = 0.001).
5. Discussion
We found that gait problems as the initial and predominant manifestation of the disease were the most consistent predictors of good treatment outcomes. Moreover, younger age and an absence of pyramidal signs before HSCT increased the likelihood of good outcomes. There was also a suggestive association between disease duration before HSCT and treatment outcomes, with the shorter duration having better post-HSCT results, but it did not reach statistical significance. Conversely, prominent cognitive dysfunction was the most consistent predictor of bad outcomes following HSCT. The strongest link was observed for cognitive impairment as the first manifestation; however, there was also a suggestive association with cognitive impairment as the predominant symptom.
We found a significant link between the initial presentation with cognitive symptoms and the worsening thereof after HSCT. There was also a suggestive association between cognitive decline as a predominant symptom before HSCT and deterioration thereof after the treatment. There are no studies on quality of life (QoL) in CSF1R-ALSP; however, in other neurodegenerative diseases, cognition was shown to be one of the most important determinants of the QoL of patients and their caregivers [12,13,14]. Therefore, the HSCT’s positive impact on motor symptoms may be counterbalanced or even thwarted in case of cognitive deterioration. As the patients with a higher burden of cognitive symptoms were the most likely to suffer further decline following HSCT, and cognitive dysfunction was an independent predictor of bad outcomes following HSCT, patients with prominent pre-HSCT cognitive symptoms seem to be bad candidates for HSCT.
The higher-than-expected rate of bad outcomes (60%) in the present study is disconcerting. However, there are no previous studies systemically analyzing the HSCT outcomes in CSF1R-ALSP to compare the results. It may be the case that the HSCT group had a more aggressive form of the disease with a worse prognosis than other CSF1R-ALSP patients. This may be supported by the lower mean age of onset in our cohort (39.5 years) than the previously estimated (43 years) in the group of 122 patients with CSF1R-ALSP [15]. Contrarily, the first manifestation of cognitive impairment and general incidence of thereof was higher in the previously reported patients (59% and 94%, respectively) than in our cohort (43% and 80%, respectively) [15]. The prevalence of pyramidal signs was similar in the previously reported group (81%) and ours (79%) [15]. Comparing other motor symptoms between our cohort and previously reported patients is difficult, as different symptom classifications were used [1,2,15]. Parkinsonism, other involuntary movements, and ataxia were present in 61%, 21%, and 27% of the previously reported group of 122 CSF1R-ALSP patients [15]. In our group, 77% displayed extrapyramidal symptoms, and 73% had gait problems. Gait problems as the primary manifestation in some patients were recognized only recently, and the previous study did not consider them separately [1,2,15]. As gait abnormality may result from various motor symptoms, often coexisting, we think it is a particularly good measure of the motor-predominant phenotype. In the previous study, 19% developed motor symptoms as their first manifestation compared to 21% in the previous group [15]. Thus, our group generally did not differ significantly from other reported patients with CSF1R-ALSP and could be considered a representative sample.
On the other hand, the bad outcome in most patients in the present study may be attributed to applying very strict criteria for good outcomes following HSCT. The reported pre-HSCT high rate of ADLs dependence and low rate of professional activity (46% and 57%, respectively), that only slightly deteriorated during post-HSCT follow-up (55% and 67%, respectively), together with observed in most patients no change or improvement in clinical symptoms post-HSCT, suggest at least stabilization of the disease in the majority of patients. Furthermore, given the aggressive natural course of the disease leading inevitably to death within few years from the onset, we think most patients actually benefited from the treatment.
This study also provides evidence of at least two different subtypes of CSF1R-ALSP, a milder one manifesting primarily with motor phenotype and another more severe with predominant cognitive dysfunction. These subtypes not only differ by clinical manifestations but, most importantly, respond differently to HSCT and thus have distinct prognoses. As the treated group was small, it was impossible to investigate the two subtypes in more detail. The previous studies did not identify genotype-phenotype correlations [1,15]. Neuroimaging studies provided evidence of the volume of WMLs correlating with cognitive dysfunction [16]. Another study showed correlations between the extent of axonal loss on neuropathological examination and global disability and cognition [17,18]. However, CSF1R-ALSP subtypes per se and their radiopathological characteristics were not elucidated.
Understanding the molecular and pathological basis underlying phenotypic dichotomy in CSF1R-ALSP is challenging yet warrants further investigation. CSF1R-ALSP is a very rare disease, with approximately 300 cases reported worldwide. To further confound the picture, cognitive dysfunction and gait disturbances are both heterogenous groups of disorders with various pathological underpinnings. Lastly, the basis of these symptoms is not fully understood even in other, more common disorders, like multiple system atrophy, pseudotumor cerebri, or stroke [19,20,21]. In a study assessing outcomes of HSCT in adult cerebral X-linked adrenoleukodystrophy, the limited motor dysfunction was predictive of better treatment results [22]. Thus, despite some similarities between the disorders, their pathophysiological foundations and treatments must be considered separately.
The main limitation of this study is the small sample size, which results in a lack of power to detect associations with outcomes. Therefore, the possibility of a type II error (i.e., a false-negative finding) is important to consider, and we cannot conclude that no true association exists simply due to the occurrence of a non-significant p-value in this study. The limited sample size also prevents a rigorous multivariable analysis assessing independent predictors of outcome following HSCT, or development of an algorithm or scoring system that can be used to predict outcome. With more patients undergoing HSCT in the future, it might be possible to compare the two distinct phenotypes regarding the age of disease onset, gender, and other important clinical variables to further clarify our observations.
6. Conclusions
Two distinct phenotypes of CSF1R-ALSP with different clinical presentations and responses to HSCT were recognized. Gait problems as initial manifestation and predominant symptomatology before HSCT indicated a milder disease phenotype with better response to HSCT and good therapy outcomes. On the opposite end were the patients who developed cognitive symptoms first, as they were the least likely to benefit from HSCT.
Author Contributions
Conceptualization, J.D. and Z.K.W.; Methodology, J.D., M.G.H., L.J.W. and Z.K.W.; Data collection, J.D.; Data analysis, J.D., M.G.H. and L.J.W.; Clinical patient management, K.Ż.-W., T.C.L. and Z.K.W.; Writing—Original Draft Preparation, J.D. and M.G.H.; Writing—Review and Editing, J.D., M.G.H., L.J.W., K.Ż.-W., T.C.L. and Z.K.W.; Supervision, Z.K.W.; Project Administration, Z.K.W. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The clinical information on the updated and newly reported cases was collected under IRB 21-006198 (10/07/2022): A Natural History Study of Patients with Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia (ALSP). The information on the remaining 8 patients was collected through the literature review, and IRB consent was not required.
Informed Consent Statement
Informed consent was obtained from updated and newly reported cases.
Data Availability Statement
Data (including a detailed description of individual cases) available on request from the corresponding author.
Acknowledgments
Jeffrey M. Gelfand managed and assessed a newly reported patient treated with HSCT.
Conflicts of Interest
The authors declare no conflict of interest.
References
- Konno, T.; Kasanuki, K.; Ikeuchi, T.; Dickson, D.W.; Wszolek, Z.K. CSF1R-related leukoencephalopathy: A major player in primary microgliopathies. Neurology 2018, 91, 1092–1104. [Google Scholar] [CrossRef] [PubMed]
- Papapetropoulos, S.; Pontius, A.; Finger, E.; Karrenbauer, V.; Lynch, D.S.; Brennan, M.; Zappia, S.; Koehler, W.; Schoels, L.; Hayer, S.N.; et al. Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development. Front. Neurol. 2021, 12, 788168. [Google Scholar] [CrossRef] [PubMed]
- Wszolek, Z. First Polish case of CSF1R-related leukoencephalopathy. Neurol. Neurochir. Polska. 2021, 55, 239–240. [Google Scholar] [CrossRef] [PubMed]
- Tipton, P.W.; Kenney-Jung, D.; Rush, B.K.; Middlebrooks, E.H.; Nascene, D.; Singh, B.; Holtan, S.; Ayala, E.; Broderick, D.F.; Lund, T.; et al. Treatment of CSF1R-Related Leukoencephalopathy: Breaking New Ground. Mov. Disord. 2021, 36, 2901–2909. [Google Scholar] [CrossRef]
- Han, J.; Sarlus, H.; Wszolek, Z.K.; Karrenbauer, V.D.; Harris, R.A. Microglial replacement therapy: A potential therapeutic strategy for incurable CSF1R-related leukoencephalopathy. Acta Neuropath. Commun. 2020, 8, 217. [Google Scholar] [CrossRef]
- Eichler, F.S.; Li, J.; Guo, Y.; Caruso, P.A.; Bjonnes, A.C.; Pan, J.; Booker, J.K.; Lane, J.M.; Tare, A.; Vlasac, I.; et al. CSF1R mosaicism in a family with hereditary diffuse leukoencephalopathy with spheroids. Brain 2016, 139, 1666–1672. [Google Scholar] [CrossRef] [Green Version]
- Mochel, F.; Delorme, C.; Czernecki, V.; Froger, J.; Cormier, F.; Ellie, E.; Fergueux, N.; Lehericy, S.; Lumbroso, S.; Schiffmann, R.; et al. Haematopoietic stem cell transplantation in CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. J. Neurol. Neurosurg. Psychiatry 2019, 90, 1375–1376. [Google Scholar] [CrossRef]
- Gelfand, J.M.; Greenfield, A.L.; Barkovich, M.; Mendelsohn, B.A.; Van Haren, K.; Hess, C.P.; Mannis, G.N. Allogeneic HSCT for adult-onset leukoencephalopathy with spheroids and pigmented glia. Brain 2020, 143, 503–511. [Google Scholar] [CrossRef]
- Żur-Wyrozumska, K.; Kaczmarska, P.; Mensah-Glanowska, P. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia associated with an A792D mutation in the CSF1R gene in a Polish patient. Neurol. Neurochir. Pol. 2021, 55, 322–324. [Google Scholar] [CrossRef]
- Żur-Wyrozumska, K.; Mensah-Glanowska, P.; Piątkowska-Jakubas, B. The First Allogeneic Hematopoietic Stem Cell Transplantation in a Polish Patient with Adult-Onset Leukoencephalopathy with Spheroids and Pigmented Glia. Mov. Disord. 2022, 37, 1570–1572. [Google Scholar] [CrossRef]
- Horn, M.A.; Myhre, A.E.; Prescott, T.; Aasly, J.; Sundal, C.H.; Gedde-Dahl, T. Prophylactic Allogeneic Hematopoietic Stem Cell Therapy for CSF1R-Related Leukoencephalopathy. Mov. Disord. 2022, 37, 1108–1109. [Google Scholar] [CrossRef] [PubMed]
- Dulski, J.; Schinwelski, M.; Konkel, A.; Grabowski, K.; Libionka, W.; Wąż, P.; Sitek, E.J.; Slawek, J. The impact of subthalamic deep brain stimulation on polysomnographic sleep pattern in patients with Parkinson’s disease—Preliminary report. Neurol. Neurochir. Pol. 2018, 52, 514–518. [Google Scholar] [CrossRef] [PubMed]
- Dulski, J.; Schinwelski, M.; Konkel, A.; Grabowski, K.; Libionka, W.; Wąż, P.; Sitek, E.J.; Slawek, J. The impact of subthalamic deep brain stimulation on sleep and other non-motor symptoms in Parkinson’s disease. Park. Relat Disord. 2019, 64, 138–144. [Google Scholar] [CrossRef] [PubMed]
- Dulski, J.; Schinwelski, M.; Konkel, A.; Sławek, J. Sleep disorders in Parkinson’s disease. Postępy Psychiatr. Neurol. 2015, 24, 147–155. [Google Scholar] [CrossRef]
- Konno, T.; Yoshida, K.; Mizuno, T.; Kawarai, T.; Tada, M.; Nozaki, H.; Ikeda, S.I.; Nishizawa, M.; Onodera, O.; Wszolek, Z.K.; et al. Clinical and genetic characterization of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia associated with CSF1R mutation. Eur. J. Neurol. 2017, 24, 37–45. [Google Scholar] [CrossRef] [PubMed]
- Mickeviciute, G.C.; Valiuskyte, M.; Plattén, M.; Wszolek, Z.K.; Andersen, O.; Karrenbauer, V.D.; Ineichen, B.V.; Granberg, T. Neuroimaging phenotypes of CSF1R-related leukoencephalopathy: Systematic review, meta-analysis, and imaging recommendations. J. Intern. Med. 2022, 291, 269–282. [Google Scholar] [CrossRef]
- Oyanagi, K.; Kinoshita, M.; Suzuki-Kouyama, E.; Inoue, T.; Nakahara, A.; Tokiwai, M.; Arai, N.; Satoh, J.-I.; Aoki, N.; Jinnai, K.; et al. Adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and Nasu–Hakola disease: Lesion staging and dynamic changes of axons and microglial subsets. Brain Pathol. 2017, 27, 748–769. [Google Scholar] [CrossRef]
- Koga, S.; Tipton, P.W.; Wierenga, K.J.; Dickson, D.W.; Wszolek, Z.K. Neuropathological Findings of CSF1R-Related Leukoencephalopathy After Long-Term Immunosuppressive Therapy. Mov. Disord. 2022, 37, 439–440. [Google Scholar] [CrossRef]
- Weinstock, Z.L.; Benedict, R.H.B. Cognitive Relapse in Multiple Sclerosis: New Findings and Directions for Future Research. J. NeuroSci. 2022, 3, 510–520. [Google Scholar] [CrossRef]
- Fermo, O.; Rao, A.; Schwartzbaum, A.; Sengupta, S.; Zhang, Y.; Wang, J.; Moghekar, A. Predictors of cognitive impairment in pseudotumor cerebri. Neurol. Neurochir. Polska 2021, 55, 394–402. [Google Scholar] [CrossRef]
- Esmael, A.; Elsherief, M.; Eltoukhy, K. Prevalence of cognitive impairment in acute ischaemic stroke and use of Alberta Stroke Programme Early CT Score (ASPECTS) for early prediction of post-stroke cognitive impairment. Neurol. Neurochir. Polska 2021, 55, 179–185. [Google Scholar] [CrossRef] [PubMed]
- Kühl, J.S.; Suarez, F.; Gillett, G.T.; Hemmati, P.G.; Snowden, J.A.; Stadler, M.; Vuong, G.L.; Aubourg, P.; Kohler, W.; Arnold, R. Long-term outcomes of allogeneic haematopoietic stem cell transplantation for adult cerebral X-linked adrenoleukodystrophy. Brain 2017, 140, 953–966. [Google Scholar] [CrossRef] [PubMed]
Table 1.
List of CSF1R mutations of the 15 patients included into the study.
| Mutation | No. (%) of Patients (N = 15) |
|---|---|
| c.2357 T > C | 1 (6.7%) |
| aberrant splice variant c.2442+1G > A | 1 (6.7%) |
| c.1754-2A > G | 1 (6.7%) |
| c.1924 C > T | 1 (6.7%) |
| c.1996 C > T | 1 (6.7%) |
| c.2345 G > A | 1 (6.7%) |
| c.2375 C > A | 1 (6.7%) |
| c.2381T > C | 1 (6.7%) |
| c.2392G > C | 1 (6.7%) |
| c.2450 T > A | 1 (6.7%) |
| c.2498 C > A | 1 (6.7%) |
| c.2624 T > C | 1 (6.7%) |
| c.2625 G > A | 1 (6.7%) |
| c.2677 T > C | 1 (6.7%) |
| c.1990 G > A | 1 (6.7%) |
Table 2.
Summary of patients’ demographics and pre-HSCT characteristics.
| Variable | N | Median (Minimum, Maximum) or No. (%) of Patients |
|---|---|---|
| Age of onset (years) | 14 | 39 (32, 50); mean = 39.5 |
| Sex (Male) | 15 | 4 (26.7%) |
| Initial symptom | 14 | |
| Cognitive impairment | 6 (42.9%) | |
| Gait problems | 3 (21.4%) | |
| Neuropsychiatric symptoms | 3 (21.4%) | |
| Other | 2 (14.3%) | |
| Age of HSCT (years) | 15 | 43 (31, 52) |
| Length of time from disease onset to HSCT (months) | 14 | 24 (11, 144) |
| Pre-HSCT cognitive decline | 15 | 12 (80.0%) |
| Pre-HSCT neuropsychiatric symptoms | 15 | 11 (73.3%) |
| Pre-HSCT extrapyramidal symptoms | 13 | 10 (76.9%) |
| Pre-HSCT pyramidal signs | 14 | 11 (78.6%) |
| Pre-HSCT gait problems | 15 | 11 (73.3%) |
| Pre-HSCT seizures | 13 | 13 (100.0%) |
| Pre-HSCT predominant symptom | 11 | |
| Cognitive impairment | 4 (36.4%) | |
| Gait problems | 4 (36.4%) | |
| Neuropsychiatric symptoms | 2 (18.2%) | |
| Other | 1 (9.1%) | |
| Pre-HSCT activities of daily living (dependent) | 11 | 5 (45.5%) |
| Pre-HSCT professional activity (not active) | 7 | 4 (57.1%) |
| Pre-HSCT clinical asymmetry | 10 | 6 (60.0%) |
| Pre-HSCT imaging white matter lesions | 15 | 14 (93.3%) |
| Pre-HSCT imaging atrophy | 15 | 14 (93.3%) |
| Pre-HSCT corpus callosum involvement | 9 | 8 (88.9%) |
| Pre-HSCT imaging asymmetry | 11 | 6 (54.5%) |
HSCT—hematopoietic stem cell transplantation.
Table 3.
Summary of post-HSCT outcomes.
| Variable | N | Median (Minimum, Maximum) or No. (%) of Patients |
|---|---|---|
| Length of time from HSCT to follow-up evaluation (months) | 15 | 26 (3, 180) |
| Post-HSCT cognition | 15 | |
| Deterioration | 6 (40.0%) | |
| No change | 6 (40.0%) | |
| Improvement | 3 (20.0%) | |
| Post-HSCT neuropsychiatric symptoms | 15 | |
| Deterioration | 5 (33.3%) | |
| No change | 6 (40.0%) | |
| Improvement | 4 (26.7%) | |
| Post-HSCT extrapyramidal symptoms | 13 | |
| Deterioration | 6 (46.2%) | |
| No change | 7 (53.8%) | |
| Improvement | 0 (0.0%) | |
| Post-HSCT pyramidal signs | 12 | |
| Deterioration | 3 (25.0%) | |
| No change | 7 (58.3%) | |
| Improvement | 2 (16.7%) | |
| Post-HSCT gait problems | 15 | |
| Deterioration | 4 (26.7%) | |
| No change | 8 (53.3%) | |
| Improvement | 3 (20.0%) | |
| Post-HSCT seizures | 11 | |
| Deterioration | 1 (9.1%) | |
| No change | 10 (90.9%) | |
| Improvement | 0 (0.0%) | |
| Post-HSCT activities of daily living (dependent) | 11 | 6 (54.5%) |
| Post-HSCT professional activity (not active) | 9 | 6 (66.7%) |
| Dichotomous combined outcome | 15 | |
| Good outcome | 6 (40.0%) | |
| Bad outcome | 9 (60.0%) | |
| Combined outcome score | 15 | 7 (1, 14) |
HSCT—hematopoietic stem cell transplantation.
Table 4.
Associations of patient characteristics with post-HSCT cognition and neuropsychiatric symptoms.
Table 4.
Associations of patient characteristics with post-HSCT cognition and neuropsychiatric symptoms.
| Post-HSCT Cognition | Post-HSCT Neuropsychiatric Symptoms | |||||
|---|---|---|---|---|---|---|
| Median (Minimum, Maximum) or No. (%) of Patients | Median (Minimum, Maximum) or No. (%) of Patients | |||||
| Variable | Deterioration (N = 6) | No Change or Improvement (N = 9) | p-Value | Deterioration (N = 5) | No Change or Improvement (N = 10) | p-Value |
| Age of onset (years) | 42 (36, 50) | 37 (32, 43) | 0.19 | 42 (36, 50) | 37 (32, 43) | 0.25 |
| Sex (Male) | 2 (33.3%) | 2 (22.2%) | 1.00 | 2 (40.0%) | 2 (20.0%) | 1.00 |
| Initial symptom | ||||||
| Cognitive impairment | 5 (83.3%) | 1 (12.5%) | 0.025 | 4 (80.0%) | 2 (22.2%) | 0.065 |
| Gait problems | 0 (0.0%) | 3 (37.5%) | 0.23 | 0 (0.0%) | 3 (33.3%) | 0.47 |
| Neuropsychiatric symptoms | 1 (16.7%) | 2 (25.0%) | 1.00 | 1 (20.0%) | 2 (22.2%) | 1.00 |
| Other | 0 (0.0%) | 2 (25.0%) | 0.47 | 0 (0.0%) | 2 (22.2%) | 0.45 |
| Age of HSCT (years) | 45 (41, 51) | 39 (31, 52) | 0.28 | 44 (41, 51) | 40 (31, 52) | 0.44 |
| Length of time from disease onset to HSCT (months) | 30 (11, 60) | 24 (18, 144) | 0.89 | 24 (11, 60) | 24 (18, 144) | 0.65 |
| Pre-HSCT cognitive decline | 6 (100.0%) | 6 (66.7%) | 0.21 | 5 (100.0%) | 7 (70.0%) | 0.21 |
| Pre-HSCT neuropsychiatric symptoms | 5 (83.3%) | 6 (66.7%) | 0.57 | 4 (80.0%) | 7 (70.0%) | 0.57 |
| Pre-HSCT extrapyramidal symptoms | 5 (83.3%) | 5 (71.4%) | 1.00 | 5 (100.0%) | 5 (62.5%) | 0.50 |
| Pre-HSCT pyramidal signs | 5 (83.3%) | 6 (75.0%) | 1.00 | 5 (100.0%) | 6 (66.7%) | 0.21 |
| Pre-HSCT gait problems | 3 (50.0%) | 8 (88.9%) | 0.24 | 3 (60.0%) | 8 (80.0%) | 1.00 |
| Pre-HSCT seizures | 0 (0.0%) | 0 (0.0%) | 1.00 | 0 (0.0%) | 0 (0.0%) | 1.00 |
| Pre-HSCT predominant symptom | ||||||
| Cognitive impairment | 4 (66.7%) | 0 (0.0%) | 0.060 | 3 (60.0%) | 1 (16.7%) | 0.20 |
| Gait problems | 0 (0.0%) | 4 (80.0%) | 0.033 | 0 (0.0%) | 4 (66.7%) | 0.13 |
| Neuropsychiatric symptoms | 2 (33.3%) | 0 (0.0%) | 0.47 | 2 (40.0%) | 0 (0.0%) | 0.47 |
| Other | 0 (0.0%) | 1 (20.0%) | 0.33 | 0 (0.0%) | 1 (16.7%) | 0.33 |
| Pre-HSCT activities of daily living (dependent) | 3 (60.0%) | 2 (33.3%) | 0.57 | 3 (60.0%) | 2 (33.3%) | 0.57 |
| Pre-HSCT clinical asymmetry | 2 (50.0%) | 4 (66.7%) | 1.00 | 2 (50.0%) | 4 (66.7%) | 1.00 |
| Pre-HSCT imaging white matter lesions | 6 (100.0%) | 8 (88.9%) | 1.00 | 5 (100.0%) | 9 (90.0%) | 1.00 |
| Pre-HSCT imaging atrophy | 6 (100.0%) | 8 (88.9%) | 1.00 | 5 (100.0%) | 9 (90.0%) | 1.00 |
| Pre-HSCT imaging asymmetry | 1 (25.0%) | 5 (71.4%) | 0.26 | 1 (25.0%) | 5 (71.4%) | 0.26 |
p-values result from a van Elteren stratified Wilcoxon rank sum test (continuous variables), or a Cochran-Mantel-Haenszel exact test, where the tests were stratified by median follow-up length after HSCT (≤26 months or >26 months). HSCT—hematopoietic stem cell transplantation.
Table 5.
Associations of patient characteristics with post-HSCT cognition and neuropsychiatric symptoms.
Table 5.
Associations of patient characteristics with post-HSCT cognition and neuropsychiatric symptoms.
| Post-HSCT Extrapyramidal Symptoms | Post-HSCT Activities of Daily Living | |||||
|---|---|---|---|---|---|---|
| Median (Minimum, Maximum) or No. (%) of Patients | Median (Minimum, Maximum) or No. (%) of Patients | |||||
| Variable | Deterioration (N = 6) | No Change or Improvement (N = 9) | p-Value | Dependent (N = 5) | Independent (N = 10) | p-Value |
| Age of onset (years) | 43 (36, 50) | 39 (35, 43) | 0.27 | 41 (36, 50) | 36 (32, 43) | 0.80 |
| Sex (Male) | 2 (33.3%) | 2 (28.6%) | 1.00 | 2 (33.3%) | 1 (20.0%) | 1.00 |
| Initial symptom | ||||||
| Cognitive impairment | 4 (66.7%) | 2 (33.3%) | 0.31 | 4 (66.7%) | 0 (0.0%) | 0.13 |
| Gait problems | 0 (0.0%) | 3 (50.0%) | 0.19 | 0 (0.0%) | 3 (75.0%) | 0.083 |
| Neuropsychiatric symptoms | 1 (16.7%) | 1 (16.7%) | 1.00 | 1 (16.7%) | 0 (0.0%) | 1.00 |
| Other | 1 (16.7%) | 0 (0.0%) | 1.00 | 1 (16.7%) | 1 (25.0%) | 1.00 |
| Age of HSCT (years) | 45 (41, 52) | 43 (31, 49) | 0.38 | 44 (41, 51) | 38 (31, 45) | 0.28 |
| Length of time from disease onset to HSCT (months) | 24 (11, 108) | 30 (24, 144) | 0.63 | 24 (11, 60) | 24 (18, 24) | 0.55 |
| Pre-HSCT cognitive decline | 5 (83.3%) | 6 (85.7%) | 1.00 | 5 (83.3%) | 3 (60.0%) | 0.52 |
| Pre-HSCT neuropsychiatric symptoms | 4 (66.7%) | 5 (71.4%) | 1.00 | 4 (66.7%) | 3 (60.0%) | 1.00 |
| Pre-HSCT extrapyramidal symptoms | 6 (100.0%) | 4 (57.1%) | 0.20 | 6 (100.0%) | 2 (50.0%) | 0.19 |
| Pre-HSCT pyramidal signs | 6 (100.0%) | 4 (57.1%) | 0.21 | 6 (100.0%) | 3 (60.0%) | 0.048 |
| Pre-HSCT gait problems | 5 (83.3%) | 4 (57.1%) | 0.57 | 4 (66.7%) | 4 (80.0%) | 1.00 |
| Pre-HSCT seizures | 6 (100.0%) | 7 (100.0%) | 1.00 | 0 (0.0%) | 0 (0.0%) | 1.00 |
| Pre-HSCT predominant symptom | ||||||
| Cognitive impairment | 2 (40.0%) | 2 (40.0%) | 1.00 | 3 (50.0%) | 0 (0.0%) | 0.44 |
| Gait problems | 0 (0.0%) | 3 (60.0%) | 0.17 | 0 (0.0%) | 3 (100.0%) | 0.056 |
| Neuropsychiatric symptoms | 2 (40.0%) | 0 (0.0%) | 0.47 | 2 (33.3%) | 0 (0.0%) | 1.00 |
| Other | 1 (20.0%) | 0 (0.0%) | 1.00 | 1 (16.7%) | 0 (0.0%) | 1.00 |
| Pre-HSCT activities of daily living (dependent) | 4 (80.0%) | 0 (0.0%) | 0.057 | 4 (66.7%) | 1 (20.0%) | 0.21 |
| Pre-HSCT clinical asymmetry | 4 (80.0%) | 2 (40.0%) | 0.53 | 3 (60.0%) | 1 (33.3%) | 1.00 |
| Pre-HSCT imaging white matter lesions | 6 (100.0%) | 6 (85.7%) | 1.00 | 6 (100.0%) | 4 (80.0%) | 0.29 |
| Pre-HSCT imaging atrophy | 6 (100.0%) | 6 (85.7%) | 1.00 | 6 (100.0%) | 4 (80.0%) | 0.29 |
| Pre-HSCT imaging asymmetry | 3 (60.0%) | 2 (40.0%) | 1.00 | 2 (40.0%) | 2 (50.0%) | 1.00 |
p-values result from a van Elteren stratified Wilcoxon rank sum test (continuous variables), or a Cochran-Mantel-Haenszel exact test, where the tests were stratified by median follow-up length after HSCT (≤26 months or >26 months). HSCT—hematopoietic stem cell transplantation.
Table 6.
Associations of patient characteristics with post-HSCT combined outcome measures.
| Dichotomous Combined Outcome | Combined Outcome Score | |||||
|---|---|---|---|---|---|---|
| Median (Minimum, Maximum) or No. (%) of Patients | Median (Minimum, Maximum) or No. (%) of Patients | |||||
| Variable | Bad Outcome (N = 9) | Good Outcome (N = 6) | p-Value | Score ≤ 7 (N = 8) | Score > 7 (N = 7) | p-Value |
| Age of onset (years) | 42 (36, 50) | 35 (32, 43) | 0.25 | 41 (35, 50) | 37 (32, 43) | 0.16 |
| Sex (Male) | 3 (33.3%) | 1 (16.7%) | 1.00 | 2 (25.0%) | 2 (28.6%) | 0.75 |
| Initial symptom | ||||||
| Cognitive impairment | 6 (66.7%) | 0 (0.0%) | 0.016 | 5 (62.5%) | 1 (16.7%) | 0.070 |
| Gait problems | 0 (0.0%) | 3 (60.0%) | 0.041 | 0 (0.0%) | 3 (50.0%) | 0.009 |
| Neuropsychiatric symptoms | 2 (22.2%) | 1 (20.0%) | 1.00 | 2 (25.0%) | 1 (16.7%) | 0.60 |
| Other | 1 (11.1%) | 1 (20.0%) | 1.00 | 1 (12.5%) | 1 (16.7%) | 0.80 |
| Age of HSCT (years) | 45 (41, 52) | 38 (31, 45) | 0.044 | 44 (37, 52) | 39 (31, 49) | 0.26 |
| Length of time from disease onset to HSCT (months) | 36 (11, 144) | 24 (18, 24) | 0.086 | 24 (11, 108) | 24 (18, 144) | 0.76 |
| Pre-HSCT cognitive decline | 8 (88.9%) | 4 (66.7%) | 0.51 | 7 (87.5%) | 5 (71.4%) | 0.62 |
| Pre-HSCT neuropsychiatric symptoms | 7 (77.8%) | 4 (66.7%) | 0.57 | 6 (75.0%) | 5 (71.4%) | 0.78 |
| Pre-HSCT extrapyramidal symptoms | 8 (88.9%) | 2 (50.0%) | 0.48 | 7 (100.0%) | 3 (50.0%) | 0.10 |
| Pre-HSCT pyramidal signs | 8 (88.9%) | 3 (60.0%) | 0.25 | 7 (100.0%) | 4 (57.1%) | 0.14 |
| Pre-HSCT gait problems | 6 (66.7%) | 5 (83.3%) | 1.00 | 6 (75.0%) | 5 (71.4%) | 0.62 |
| Pre-HSCT seizures | 0 (0.0%) | 0 (0.0%) | N/A | 0 (0.0%) | 0 (0.0%) | N/A |
| Pre-HSCT predominant symptom | ||||||
| Cognitive impairment | 4 (57.1%) | 0 (0.0%) | 0.067 | 3 (42.9%) | 1 (25.0%) | 0.37 |
| Gait problems | 0 (0.0%) | 4 (100.0%) | 0.017 | 1 (14.3%) | 3 (75.0%) | 0.001 |
| Neuropsychiatric symptoms | 2 (28.6%) | 0 (0.0%) | 1.00 | 2 (28.6%) | 0 (0.0%) | 0.18 |
| Other | 1 (14.3%) | 0 (0.0%) | 1.00 | 1 (14.3%) | 0 (0.0%) | 0.74 |
| Pre-HSCT activities of daily living (dependent) | 4 (66.7%) | 1 (20.0%) | 0.21 | 4 (66.7%) | 1 (20.0%) | 0.16 |
| Pre-HSCT clinical asymmetry | 5 (71.4%) | 1 (33.3%) | 0.50 | 4 (66.7%) | 2 (50.0%) | 0.80 |
| Pre-HSCT imaging white matter lesions | 9 (100.0%) | 5 (83.3%) | 0.25 | 8 (100.0%) | 6 (85.7%) | 0.60 |
| Pre-HSCT imaging atrophy | 9 (100.0%) | 5 (83.3%) | 0.25 | 8 (100.0%) | 6 (85.7%) | 0.60 |
| Pre-HSCT imaging asymmetry | 4 (57.1%) | 2 (50.0%) | 1.00 | 3 (50.0%) | 3 (60.0%) | 0.35 |
For analysis of the dichotomous combined outcome, p-values result from a van Elteren stratified Wilcoxon rank sum test (continuous variables), or a Cochran-Mantel-Haenszel exact test, where the tests were stratified by median follow-up length after HSCT (≤26 months or >26 months). For analysis of the combined outcome score, p-values results from linear regression models that were adjusted for follow-up length after HSCT (where follow-up length is considered as a continuous variable); the combined outcome score was assessed as a continuous variable in linear regression analysis, and was dichotomized based on the sample median (≤7 vs. >7) for purposes of presentation only. HSCT—hematopoietic stem cell transplantation.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Dulski, J.; Heckman, M.G.; White, L.J.; Żur-Wyrozumska, K.; Lund, T.C.; Wszolek, Z.K. Hematopoietic Stem Cell Transplantation in CSF1R-Related Leukoencephalopathy: Retrospective Study on Predictors of Outcomes. Pharmaceutics 2022, 14, 2778. https://doi.org/10.3390/pharmaceutics14122778
AMA Style
Dulski J, Heckman MG, White LJ, Żur-Wyrozumska K, Lund TC, Wszolek ZK. Hematopoietic Stem Cell Transplantation in CSF1R-Related Leukoencephalopathy: Retrospective Study on Predictors of Outcomes. Pharmaceutics. 2022; 14(12):2778. https://doi.org/10.3390/pharmaceutics14122778
Chicago/Turabian StyleDulski, Jarosław, Michael G. Heckman, Launia J. White, Kamila Żur-Wyrozumska, Troy C. Lund, and Zbigniew K. Wszolek. 2022. "Hematopoietic Stem Cell Transplantation in CSF1R-Related Leukoencephalopathy: Retrospective Study on Predictors of Outcomes" Pharmaceutics 14, no. 12: 2778. https://doi.org/10.3390/pharmaceutics14122778
APA StyleDulski, J., Heckman, M. G., White, L. J., Żur-Wyrozumska, K., Lund, T. C., & Wszolek, Z. K. (2022). Hematopoietic Stem Cell Transplantation in CSF1R-Related Leukoencephalopathy: Retrospective Study on Predictors of Outcomes. Pharmaceutics, 14(12), 2778. https://doi.org/10.3390/pharmaceutics14122778
Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.
