The Spastic Paraplegia Rating Scale (SPRS): A reliable and valid measure of disease severity

IntroductionHereditary spastic paraplegia (HSP) encompasses a diverse group of neurodegenerative disorders that results in significant disability with no curative or disease-modifying treatment. The lack of standardised biomarkers of disease severity has limited the evaluation of potential therapeutic agents. Our aim is to investigate motor evoked potentials (MEPs) as a marker of HSP disease severity.MethodsWe studied 21 subjects (10 male, 11 female; mean age 54.3±13.8 years) with a clinical diagnosis of HSP (10 SPG4, 4 SPG7, 1 SPG3A, 1 SPG 30, 5 genetically undetermined). All patients underwent transcranial magnetic stimulation to measure central motor conduction time (CMCT), resting motor threshold (rMT) and MEP amplitude from the tibialis anterior (TA), abductor hallucis (AH) and abductor digiti minimi (ADM). Clinical disease severity was assessed with the Spastic Paraplegia Rating Scale (SPRS). Pearson correlation coefficient was used to assess correlation between variables, significance was defined as P value<0.05.ResultsTA CMCT was prolonged in 16/21 subjects (76%). AH CMCT was absent in 3/18 subjects (16.7%) and prolonged in 9/18 subjects (50%). ADM CMCT was measured in 19 subjects; all were normal. There was no significant correlation between SPRS scores and MEP amplitude, rMT or CMCT for TA or AH. There was also no significant correlation between these MEP measures and disease duration or patient age. Subgroup analysis of SPG4 HSP (10 subjects) revealed significant correlation between TA and AH CMCT with disease duration (r=0.841, p=0.001; r=0.930, p=0.001) but not SPRS scores.ConclusionLower limb CMCT was absent or prolonged in the majority of subjects. Despite being potentially useful as a diagnostic biomarker for HSP, this study only showed a correlation between lower limb CMCT and disease duration in the SPG4 subgroup. Further genotype-specific studies utilising larger numbers may clarify the relationship between MEP markers and clinical features.

Download Full-text

Informal Caregiving in Amyotrophic Lateral Sclerosis (ALS): A High Caregiver Burden and Drastic Consequences on Caregivers’ Lives

Brain Sciences ◽

10.3390/brainsci11060748 ◽

2021 ◽

Vol 11 (6) ◽

pp. 748

Author(s):

Pavel Schischlevskij ◽

Isabell Cordts ◽

René Günther ◽

Benjamin Stolte ◽

Daniel Zeller ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Functional Status ◽

Disease Severity ◽

Caregiver Burden ◽

Rating Scale ◽

Depression Scale ◽

Anxiety And Depression ◽

Daily Routine ◽

Work Lives ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients’ informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers’ burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients’ CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients’ functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King’s Stages for ALS. The caregivers’ burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers’ burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients’ functional status (rp = −0.555, p < 0.001, n = 242). It was influenced by the CGs’ own mental health issues due to caregiving (+11.36, 95% CI [6.84; 15.87], p < 0.001), patients’ wheelchair dependency (+9.30, 95% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs’ depression (rp = 0.627, p < 0.001, n = 234), anxiety (rp = 0.550, p < 0.001, n = 234), and poorer physical condition (rp = −0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients’ impairment in daily routine (rs = −0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs’ lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs’ work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required.

Download Full-text

Objectively characterizing Huntington’s disease using a novel upper limb dexterity test

Journal of Neurology ◽

10.1007/s00415-020-10375-8 ◽

2021 ◽

Author(s):

Samuel Woodgate ◽

Philippa Morgan-Jones ◽

Susanne Clinch ◽

Cheney Drew ◽

Rebecca Playle ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Severity ◽

Convergent Validity ◽

Rating Scale ◽

Objective Assessment ◽

Prognostic Index ◽

Transfer Task ◽

Clinical Expertise ◽

Clinical Scores

Abstract Background The Clinch Token Transfer Test (C3t) is a bi-manual coin transfer task that incorporates cognitive tasks to add complexity. This study explored the concurrent and convergent validity of the C3t as a simple, objective assessment of impairment that is reflective of disease severity in Huntington’s, that is not reliant on clinical expertise for administration. Methods One-hundred-and-five participants presenting with pre-manifest (n = 16) or manifest (TFC-Stage-1 n = 39; TFC-Stage-2 n = 43; TFC-Stage-3 n = 7) Huntington’s disease completed the Unified Huntington’s Disease Rating Scale and the C3t at baseline. Of these, thirty-three were followed up after 12 months. Regression was used to estimate baseline individual and composite clinical scores (including cognitive, motor, and functional ability) using baseline C3t scores. Correlations between C3t and clinical scores were assessed using Spearman’s R and visually inspected in relation to disease severity using scatterplots. Effect size over 12 months provided an indication of longitudinal behaviour of the C3t in relation to clinical measures. Results Baseline C3t scores predicted baseline clinical scores to within 9–13% accuracy, being associated with individual and composite clinical scores. Changes in C3t scores over 12 months were small ($$\Omega$$ Ω ≤ 0.15) and mirrored the change in clinical scores. Conclusion The C3t demonstrates promise as a simple, easy to administer, objective outcome measure capable of predicting impairment that is reflective of Huntington’s disease severity and offers a viable solution to support remote clinical monitoring. It may also offer utility as a screening tool for recruitment to clinical trials given preliminary indications of association with the prognostic index normed for Huntington’s disease.

Download Full-text

Camptocormia in patients with multiple system atrophy at different disease durations: frequency and related factors

BMC Neurology ◽

10.1186/s12883-021-02210-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ling Yu Zhang ◽

Bei Cao ◽

Qian-Qian Wei ◽

Ru Wei Ou ◽

Bi Zhao ◽

...

Keyword(s):

Multiple System Atrophy ◽

Disease Severity ◽

Disease Duration ◽

Rating Scale ◽

Cox Regression ◽

Age Of Onset ◽

Older Age ◽

Related Factors ◽

Cox Regression Analysis ◽

The Impact

Abstract Background Camptocormia is common in patients with multiple system atrophy (MSA). The current study was aimed at assessing the frequency of camptocormia and its related factors in MSA patients with different disease durations. Also, the impact of camptocormia on disability was evaluated. Methods A total of 716 patients were enrolled in the study. They were classified into three groups based on disease duration (≤ 3, 3–5, ≥ 5 years). Specific scales were used to evaluate the motor and non-motor symptoms. Disease severity was assessed using the Unified Multiple System Atrophy Rating Scale (UMSARS). The binary logistic regression model was used to explore the factors related to camptocormia. To analyze the impact of camptocormia on disability in patients with disease duration less than 5 years, propensity score matching (PSM) and stratified Cox regression analysis were used. Results In the current study, we found that the frequency of camptocormia was 8.9, 19.7 and 19.2% when the disease duration was ≤3, 3–5, ≥ 5 years, respectively. In the disease duration ≤3 years group, we found that MSA-parkinsonian subtype (MSA-P) (OR = 2.043, P = 0.043), higher total UMSARS score (OR = 1.063, P < 0.001), older age of onset (OR = 1.047, P = 0.042), and lower score on the frontal assessment battery (FAB) (OR = 0.899, P = 0.046) were associated with camptocormia. Only greater disease severity was associated with camptocormia in the group of patients with disease duration 3–5 years (OR = 1.494, P = 0.025) and in the group of patients with disease duration ≥5 years (OR = 1.076, P = 0.005). There was no significant impact of camptocormia on disability in patients with a disease duration of < 5 years (HR = 0.687, P = 0.463). Conclusion The frequency of camptocormia increased with prolonged disease duration. Disease severity was related to camptocormia at different stages of the disease. The MSA-P subtype, older age of onset, and lower FAB score were associated with camptocormia in the early stage of the disease.

Download Full-text

Stereopsis Deficits in Parkinson’s Disease and Their Clinical Implications

10.21203/rs.3.rs-106032/v1 ◽

2020 ◽

Author(s):

Fang Ba ◽

Tina T. Sang ◽

Jaleh Fatehi ◽

Wenjing He ◽

Emanuel Mostofi ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Severity ◽

Rating Scale ◽

Disease Status ◽

Cognitive Status ◽

Control Group ◽

Motor Disorder ◽

Healthy Control ◽

Stereo Acuity

Abstract Background: Parkinson's disease (PD) is not exclusively a motor disorder. Among non-motor features, PD patients possess sensory visual dysfunctions. Stereopsis deficit can significantly impact patients' motor performance. However, it is not routinely tested, and its significance is under-investigated. Studying stereopsis using reliable 3D stimuli may help determine its implications in disease status in PD.The objective of the study is to investigate stereopsis abnormalities in PD with reliable and more physiological tools, and their correlation with indicators of PD severity. Methods: Twenty-four healthy control and 20 PD participants were first evaluated for visual acuity, visual field, contrast acuity, and stereoperception with 2D and Titmus stereotests, followed by the assessment with the 3D active shutter system. The correlation between stereopsis and disease severity, Unified Parkinson’s disease rating scale motor scores (UPDRS-III), levodopa equivalent daily dose (LEDD), course of disease and cognitive status were evaluated using univariate regression models. Results: Screening visual tests did not reveal any differences between PD and control group. With the 3D active shutter system, PD patients demonstrated significantly worse stereopsis (i.e p=0.002, 26 seconds of arc). There was a trend that UPDRS-III and LEDD negatively correlate with the stereo acuity, suggesting poorer stereoperception is related to disease severity. Preserved cognitive function correlated with more intact stereo acuity. Conclusion: With more reliable and physiological tools, PD patients exhibit poorer stereopsis. These deficits reflected PD motor and cognitive status. How stereopsis relates to gait, fall risks and navigation warrants more investigations in the future.

Download Full-text

A Quantitative Disease Severity Rating Scale for Northern Corn Leaf Blight

Plant Health Progress ◽

10.1094/php-rs-16-0010 ◽

2016 ◽

Vol 17 (1) ◽

pp. 49-50 ◽

Cited By ~ 1

Author(s):

Trey Price ◽

Myra Purvis ◽

Hunter Pruitt

Keyword(s):

United States ◽

Disease Severity ◽

Rating Scale ◽

The United States ◽

Leaf Blight ◽

Analysis Software ◽

Northern Corn Leaf Blight ◽

Severity Rating ◽

Corn Leaf Blight

Northern corn leaf blight (NCLB) is an annual issue for corn producers throughout the United States. Consequently, researchers are constantly evaluating hybrids for resistance and fungicides for efficacy. In most cases, NCLB severity is evaluated by visually estimating the percentage of affected foliage. Perceptions of disease severity are variable among stakeholders; therefore, a rating scale was created using photo analysis software that may be used to increase accuracy of disease severity estimations. Accepted for publication 15 March 2016. Published 28 March 2016.

Download Full-text

Zonisamide Administration Improves Fatty Acid β-Oxidation in Parkinson’s Disease

Cells ◽

10.3390/cells8010014 ◽

2018 ◽

Vol 8 (1) ◽

pp. 14 ◽

Cited By ~ 2

Author(s):

Shin-Ichi Ueno ◽

Shinji Saiki ◽

Motoki Fujimaki ◽

Haruka Takeshige-Amano ◽

Taku Hatano ◽

...

Keyword(s):

Mass Spectrometry ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Severity ◽

Rating Scale ◽

Statistical Significance ◽

Experimental Studies ◽

Time Of Flight ◽

Metabolome Analysis ◽

Flight Mass Spectrometry

Although many experimental studies have shown the favorable effects of zonisamide on mitochondria using models of Parkinson’s disease (PD), the influence of zonisamide on metabolism in PD patients remains unclear. To assess metabolic status under zonisamide treatment in PD, we performed a pilot study using a comprehensive metabolome analysis. Plasma samples were collected for at least one year from 30 patients with PD: 10 without zonisamide medication and 20 with zonisamide medication. We performed comprehensive metabolome analyses of plasma with capillary electrophoresis time-of-flight mass spectrometry and liquid chromatography time-of-flight mass spectrometry. We also measured disease severity using Hoehn and Yahr (H&Y) staging and the Unified Parkinson’s Disease Rating Scale (UPDRS) motor section, and analyzed blood chemistry. In PD with zonisamide treatment, 15 long-chain acylcarnitines (LCACs) tended to be increased, of which four (AC(12:0), AC(12:1)-1, AC(16:1), and AC(16:2)) showed statistical significance. Of these, two LCACs (AC(16:1) and AC(16:2)) were also identified by partial least squares analysis. There was no association of any LCAC with age, disease severity, levodopa daily dose, or levodopa equivalent dose. Because an upregulation of LCACs implies improvement of mitochondrial β-oxidation, zonisamide might be beneficial for mitochondrial β-oxidation, which is suppressed in PD.

Download Full-text

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia

Brain ◽

10.1093/brain/awz307 ◽

2020 ◽

Cited By ~ 1

Author(s):

Darius Ebrahimi-Fakhari ◽

Julian Teinert ◽

Robert Behne ◽

Miriam Wimmer ◽

Angelica D'Amore ◽

...

Keyword(s):

Disease Severity ◽

Protein Complex ◽

Hereditary Spastic Paraplegia ◽

Adaptor Protein ◽

Allelic Loss ◽

Foot Deformities ◽

Periventricular White Matter ◽

Spastic Paraplegia ◽

Clinical Imaging ◽

The Mean

Abstract Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0–49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2–5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1–46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an ‘AP-4 deficiency syndrome’. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

Download Full-text

Correlational Analysis of ALS Progression and Serum NfL Measured by Simoa Assay in Chinese Patients

Frontiers in Neurology ◽

10.3389/fneur.2020.579094 ◽

2020 ◽

Vol 11 ◽

Author(s):

Kazuo Sugimoto ◽

Yi Han ◽

Yuebo Song ◽

Ying Gao

Keyword(s):

Disease Severity ◽

Single Molecule ◽

Clinical Relevance ◽

Rating Scale ◽

Diagnostic Delay ◽

Chinese Patients ◽

Progression Rate ◽

Neurofilament Light Chain ◽

Potential Biomarker ◽

Als Patients

Background: Neurofilament light chain (NFL) was believed to be a promising biomarker for the diagnosis of Amyotrophic lateral sclerosis (ALS) and disease burden evaluation.Objective: To determine the serum NFL level and its clinical relevance, including its association with disease severity [evaluated by the ALS Functional Rating Scale–revised (ALSFRS-r) score and King's College staging system] and progression (evaluated by the disease progression rate (DPR) and diagnostic delay), in ALS patients in China.Method: Serum NFL levels were detected using the Single Molecule Array (Simoa) technology in 30 ALS patients and 20 healthy controls (HCs).Results: There were significantly elevated levels of serum NFL in patients with ALS than in the HCs (P < 0.001). The serum NFL levels were significantly higher in rapidly progressive ALS and patients in Stage 3 than in slowly progressive ALS and patients in Stage 2 (PDPR < 0.001, PDiagnosticdelay = 0.019; Pstage= 0.033). Furthermore, the serum NFL levels negatively correlated with the diagnostic delay (R2 = 0.23, P = 0.016), the ALSFRS-r score (R2 = 0.15, P = 0.047) and disease duration (R2 = 0.15, P = 0.034), and positively correlated with the DPR (R2 = 0.42, P < 0.001).Conclusions: The present study preliminarily investigated the diagnostic value of serum NFL and its clinical relevance in the Chinese ALS population using the ultrasensitive Simoa technology. The results demonstrated that the level of serum NFL may become a potential biomarker for ALS diagnosis and indicate disease severity and progression.

Download Full-text