Mark Braschinsky

The Prevalence of Hereditary Spastic Paraplegia and the Occurrence of SPG4 Mutations in Estonia

Background: Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous disorder, with a variable reported prevalence ranging from 0.5 to 12 per 100,000. The aim of this retrospective study was to evaluate the prevalence of HSP and estimate the percentage of SPG4 mutations in the Estonian population. Methods: A simple model with multiple data sources was selected to enable as many patients as possible to be detected. All relevant case histories from Estonian regional neurological centers for the last 20 years were reviewed; all neurologists and general practitioners were contacted. Results: A total of 737 case records were captured for secondary evaluation. Among these cases, 88 potential HSP-affected subjects were identified. During this study 59 patients with HSP were identified, giving a crude prevalence rate of 4.4 per 100,000. Eleven persons (21.6% of all studied Estonian HSP patients) with HSP were found to have mutations in the spastin gene (SPG4). Conclusions: Our epidemiological data are comparable with the results from epidemiological studies performed elsewhere, indicating that the clinical diagnostic management of HSP patients in Estonia is adequate and the chosen methodological approach for data collection was reliable.

Bladder dysfunction in hereditary spastic paraplegia: what to expect?

Background Hereditary spastic paraplegia (HSP) comprises a group of rare neurodegenerative disorders characterised by progressive spasticity and hyperreflexia of the legs. Neurogenic bladder dysfunction is a well recognised problem in patients with HSP but it has not yet been described systematically in the literature. The aim of this study was to provide an evidential overview of the ways in which urinary dysfunction presents in HSP. Methods 49 patients with HSP were included and underwent evaluation. A history was followed by a semi-structured interview and, in those patients who consented, measurement of residual volume of urine (PVR) and urodynamic evaluation. Results 38 subjects (77.6%) reported some type of urinary symptom. Subjective complaints of bladder problems showed a correlation with verified urinary dysfunction. There were no significant differences in the occurrence of urinary disturbances between the pure and complex forms of HSP. The most frequent symptoms were incontinence (69.4%), hesitancy (59.2%), increased frequency of micturition (55.1%) and urgency (51.0%). Incomplete bladder emptying was the rarest (36.7%). The most common combination of symptoms was to have all of them (14.3%). Incomplete bladder emptying as a complaint was associated with an increased risk of PVR. Women had a higher risk of increased voiding frequency. Conclusions To our knowledge, this work is the first systematic and disease oriented overview of neurogenic bladder disturbances in patients with HSP. Our results may be useful to the clinicians who work with HSP patients, allowing them to make appropriate screening and management decisions.

Functional Assessment of Lower Extremities in Hereditary Spastic Paraplegia

OBJECTIVES To characterize the spasticity and range of motion (ROM) in patients with hereditary spastic paraplegia (HSP) and to correlate these parameters with walking speed. DESIGN An observational population-based cohort study. SETTING Patient data were acquired from a population-based epidemiologic study performed earlier in Estonia. PARTICIPANTS Persons (N=46) (mean age, 50.1y) with clinically confirmed HSP diagnosis (mean duration, 20.9y) participated in the study. INTERVENTIONS Active and passive ROMs were measured with a plastic 360 degrees goniometer. Spasticity was evaluated by using the modified Ashworth scale (MAS). The time it took a patient to walk 10m was recorded. MAIN OUTCOME MEASURES Measurements included testing of active and passive ROM as a marker for mobility, the MAS for spasticity, and time to complete a 10-m walk. RESULTS A higher degree of spasticity in hip muscles was associated with lower values of active ROM and slower walking. Walking speed was negatively correlated to disease duration and participant age. CONCLUSIONS The present study provides analysis of the contributions of spasticity and ROM to walking speed in HSP, both factors negatively influence gait in persons with HSP.

Unique spectrum of SPAST variants in Estonian HSP patients: presence of benign missense changes but lack of exonic rearrangements

BackgroundHereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous disorder that can be an autosomal-dominant, autosomal-recessive, or X-linked disease. The most common autosomal-dominant form of the disease derives from mutations in the SPAST gene.MethodsThe aim of this study was to analyze 49 patients diagnosed with HSP from the Estonian population for sequence variants of the SPAST gene and to describe the associated phenotypes. Healthy control individuals (n = 100) with no family history of HSP were also analyzed. All patient samples were screened using denaturing high performance liquid chromatography (DHPLC) and multiplex ligation-dependent probe amplification (MLPA) assay. Samples with abnormal DHPLC and MLPA profiles were sequenced, with the same regions sequenced in control samples.ResultsSequence variants of SPAST were identified in 19/49 HSP patients (38.8%), twelve among them had pathogenic mutations. Within the latter group there was one sporadic case. Eight patients had pure, and four - complex HSP. The twelve variants were identified: seven pathogenic (c.1174-1G>C, c.1185delA, c.1276C>T, c.1352_1356delGAGAA, c.1378C>A, c.1518_1519insTC, c.1841_1842insA) and five non-pathogenic (c.131C>T, c.484G>A, c.685A>G, c.1245+202delG, c.1245+215G>C). Only 2 of these mutations had previously been described (c.131C>T, c.1245+202delG). Three mutations, c.1174-1G>C, c.1276 C>T, c.1378C>A, showed intrafamilial segregation.ConclusionThis study identified new variants of the SPAST gene which included benign missense variants and short insertions/deletions. No large rearrangements were found. Based on these data, 7 new pathogenic variants of HSP are associated with clinical phenotypes.

The prevalence of depression in hereditary spastic paraplegia

Objective: To evaluate the prevalence of depression and sensitivity and specificity of the single-item interview ‘Are you depressed?’ for people with hereditary spastic paraplegia in Estonia. Design: Single-item interview ‘Are you depressed?’ was used as a screening question for depression; all participants then completed the Beck Depression Inventory. Setting: People with hereditary spastic paraplegia identified from the epidemiological database who agreed to participate in the study. Main measures: Beck Depression Inventory, clinical interview. Results: The epidemiological database consisted of 59 patients with clinically confirmed diagnosis of hereditary spastic paraplegia. Forty-eight of these consented to participate in the study. The Beck Depression Inventory score was higher than cut-off point in 58% (28/48) and lower in 42% (20/48). Of the study group, 44% (21/48) had mild, 13% (6/48) moderate and one person revealed severe depression. There was a statistically significant correlation between Beck Depression Inventory score and level of mobility; no other significant correlations with other measures were detected. Of the participants, 54% (26/48) had subjective complaints about depression and answered ‘Yes’ to the single-item interview ‘Are you depressed?’. The sensitivity of the one-item interview in the hereditary spastic paraplegia group was 75% and specificity 75%. Conclusions: Our results show that mild depression is prevalent among people with hereditary spastic paraplegia. Although the single question may be helpful, it cannot be relied upon entirely when assessing a person for depression.

Health-related quality of life in patients with hereditary spastic paraplegia in Estonia

Study design:Observational population-based cohort study.Objectives:The main aim of this study was to examine the relative effect of hereditary spastic paraplegia (HSP) on the health-related quality of life (HRQoL).Methods:HRQoL was evaluated using a RAND 36-Item Health Survey 1.0 questionnaire. Fifty-eight patients received a questionnaire through mail and signed an informed consent. The results for the control group were obtained from the RAND-36 data collected in 2004 in the European Social Survey. R2.9.0 and Statistica 6.1 were used to analyze the RAND-36 data.Setting:The study was performed in Estonia, a country with a population of 1.3 million.Results:Completed questionnaires were received from 49 participants (response rate was 84.5%). The control group consisted of 549 individuals from the Estonian population. Patients with HSP had lower mean scores in all categories as compared with the control group. Six of the eight categories showed significant differences, with P<0.0001. For the vitality category, the P-value ranged from 0.000006 from 0.002, and the P-value for the mental health category ranged from 0.001 to 0.055.Conclusions:The HRQoL in patients with HSP was found to be significantly worse than that for the general population. The level of education might affect the HRQoL experienced by HSP patients.

Headache service quality: evaluation of quality indicators in 14 specialist-care centres

BackgroundThe study was a collaboration between Lifting The Burden (LTB) and the European Headache Federation (EHF). Its aim was to evaluate the implementation of quality indicators for headache care Europe-wide in specialist headache centres (level-3 according to the EHF/LTB standard).MethodsEmploying previously-developed instruments in 14 such centres, we made enquiries, in each, of health-care providers (doctors, nurses, psychologists, physiotherapists) and 50 patients, and analysed the medical records of 50 other patients. Enquiries were in 9 domains: diagnostic accuracy, individualized management, referral pathways, patient’s education and reassurance, convenience and comfort, patient’s satisfaction, equity and efficiency of the headache care, outcome assessment and safety.ResultsOur study showed that highly experienced headache centres treated their patients in general very well. The centres were content with their work and their patients were content with their treatment. Including disability and quality-of-life evaluations in clinical assessments, and protocols regarding safety, proved problematic: better standards for these are needed. Some centres had problems with follow-up: many specialised centres operated in one-touch systems, without possibility of controlling long-term management or the success of treatments dependent on this.ConclusionsThis first Europe-wide quality study showed that the quality indicators were workable in specialist care. They demonstrated common trends, producing evidence of what is majority practice. They also uncovered deficits that might be remedied in order to improve quality. They offer the means of setting benchmarks against which service quality may be judged. The next step is to take the evaluation process into non-specialist care (EHF/LTB levels 1 and 2).

Functional MRI of the cortical sensorimotor system in patients with hereditary spastic paraplegia

Objectives:The study aimed to use functional magnetic resonance imaging to ascertain changes in sensorimotor system function in patients with hereditary spastic paraplegia and to correlate it with severity of spasticity and paresis.Setting:Tartu University Hospital, Tartu, Estonia.Methods:Nine patients with autosomal-dominant pure HSP and 14 age- and sex-matched healthy controls were investigated with a 1.5T fMRI scanner during flexion/extension of the right-hand fingers and right ankle. Images were analysed with a general linear model and Statistical Parametrical Mapping software. Highest Z-scores were identified from probability maps, and weighted laterality indices were calculated using combined bootstrap/histogram analysis; these were correlated with clinical severity of spasticity and paresis.Results:During hand movements, clusters located in contralateral primary sensorimotor and premotor areas activated in both controls and patients. Bilateral activation occurred in the supplementary motor area, parietal operculum and cerebellum (predominantly ipsilateral). During the ankle task, bilateral activation was noted in the primary sensorimotor area, supplementary motor area and cerebellum. Activation clusters in HSP patients were smaller than those in controls in the sensorimotor area, especially during the ankle task, and more pronounced ipsilaterally in cerebellum both during hand and ankle motor tasks. Spasticity was significantly associated with contralateral activation in the sensory area and correlated negatively with the highest Z-scores in Brodmann areas 1-2-3 and 4.Conclusion:Our results suggest changes in cortical sensorimotor network function in patients with HSP compared with healthy subjects. Lower activation in patients might reflect damage to the corticospinal tract, be influenced by compensatory mechanisms, and/or be a reflection of neurorehabilitation.

Decades of delayed diagnosis in 4 levodopa-responsive young-onset monogenetic parkinsonism patients

We report 4 patients with young‐onset monogenetic parkinsonism, each of whom was misdiagnosed with either a psychogenic movement disorder or chronic fatigue syndrome for 10 to 23 years after the onset of their first symptoms.

Structured education to improve primary-care management of headache: how long do the benefits last? A follow-up observational study

Our earlier study showed that structured education of general practitioners (GPs) improved their practice in headache management. Here the duration of this effect was assessed.