Katrin Gross-Paju

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.

Subjective complaints compared to the results of neuropsychological assessment in patients with epilepsy: The influence of comorbid depression

The aim of the study was to compare subjective complaints of epilepsy patients with objective results of neuropsychological assessment and to investigate the possible influence of depression on self-reported complaints. 62 patients from the neurology clinic were included in the study. They were asked to fill the subjective complaints questionnaire, Beck Depression Inventory and a series of neuropsychological tests. The results indicated that self-reported cognitive complaints are not strongly associated with objective tests of different cognitive performance measures. We conclude that the discrepancy between subjective and objective cognitive functioning does not only affect the area of memory but a wide range of cognitive domains. Depression is an important factor influencing the level of different subjective complaints.

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.

Changes in Blood B Cell-Activating Factor (BAFF) Levels in Multiple Sclerosis: A Sign of Treatment Outcome.

Multiple sclerosis (MS) is mediated primarily by autoreactive T cells. However, evidence suggesting the involvement of humoral immunity in brain diseases has increased interest in the role of B cells and their products during MS pathogenesis. The major survival factor for B cells, BAFF has been shown to play a role in several autoimmune conditions. Elevated BAFF levels have been reported in MS animal model and during MS relapse in patients. Moreover, disease-modifying treatments (DMT) reportedly influence blood BAFF levels in MS patients, but the significance of these changes remains unclear. The present study addresses how blood BAFF levels are associated with the clinical course of relapsing-remitting MS and the effectiveness of DMT and short-term steroid treatment. During a prospective longitudinal follow-up of 2.3 years, BAFF was measured in the blood of 170 MS patients in the stable phase and within 186 relapses. BAFF levels were significantly higher in MS patients compared to healthy controls. However, stable MS patients without relapses exhibited significantly higher BAFF levels than relapsing patients. Treatment with interferon-β and immunosuppressants raised BAFF blood levels. Interestingly, a similar effect was not seen in patients treated with glatiramer acetate. Short-term treatment with high doses of intravenous methylprednisolone did not significantly alter plasma BAFF levels in 65% of relapsing-remitting MS patients. BAFF were correlated weakly but significantly with monocyte and basophil counts, but not with other blood cell types (neutrophils, lymphocytes, or eosinophils) or inflammatory biomarkers. To our knowledge, this is the first report demonstrating that higher blood BAFF levels may reflect a more stable and effective MS treatment outcome. These results challenge hypotheses suggesting that elevated blood BAFF levels are associated with more severe disease presentation and could explain the recent failure of pharmaceutical trials targeting BAFF with soluble receptor for MS treatment.

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.

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.

123I-ADAM SPET imaging of serotonin transporter in patients with epilepsy and comorbid depression

BackgroundPurpose of the study was to investigate alterations in midbrain serotonin transporter (SERT) binding in patients with epilepsy and symptoms of depression compared to patients with epilepsy with no symptoms of depression.MethodsWe studied 12 patients with epilepsy (7 patients had focal and 5 had generalized epilepsy syndromes). The presence of self-reported symptoms of depression was assessed using Beck Depression Inventory (BDI) and the Emotional State Questionnaire (EST-Q). The binding potential of the SERT was assessed by performing brain single photon emission tomography (SPET) using the SERT radioligand 2-((2-((dimethylamino)methyl)phenyl)thio)-5-(123)iodophenylamine (123I-ADAM).ResultsSeven patients had BDI and EST-Q subscale scores greater than 11 points, which was interpreted as the presence of symptoms of depression. We found that 123I-ADAM binding was not significantly different between patients with epilepsy with and without symptoms of depression. In addition, 123I-ADAM binding did not show a significant correlation to either BDI or EST-Q depression subscale scores and did not differ between patients with focal vs. generalized epilepsy.ConclusionThe results of our study failed to demonstrate alterations of SERT binding properties in patients with epilepsy with or without symptoms of depression.