Nikola Kresojević

Status dystonicus: Predictors of outcome and progression patterns of underlying disease

Status dystonicus (SD) is a rare, life‐threatening disorder characterized by acute worsening of generalized dystonia.

Neuropsychiatric aspects of treated Wilson's disease ☆

The objective of the current cross-sectional study was to use standardized psychiatric interviews (the Structured Clinical Interview for DSM-IV Axis I Disorders and the Neuropsychiatric Inventory; NPI) in order to better characterize psychiatric symptoms in 50 consecutive, treated and clinically stable patients with Wilsons disease (WD). Nine patients (18%) had one, 7 patients (14%) had two, and 20 (40%) had >or= 3 neuropsychiatric symptoms present. The most often endosed symptoms were anxiety (62%), depression (36%), irritability (26%), as well as disinhibition and apathy (24% each). Twenty two patients (44%) had a score >or= 4 on at least one of the NPI items: again, most frequently anxiety (17 patients; 34%), depression (13 patients; 26%) and apathy (9 patients; 18%). Therefore, even among stable, long-term treated patients with WD approximately 70% experienced psychiatric symptoms.

Glucocerebrosidase mutations in a Serbian Parkinson's disease population.

To screen for glucocerebrosidase (GBA) mutations in a Serbian Parkinsons disease (PD) population.

Transcranial sonography in Wilson's disease

Transcranial sonography (TCS) has been recently recognized as a reliable and sensitive tool in detecting basal ganglia (BG) abnormalities in several movement disorders, where different patterned hyperechogenic lesions were demonstrated. The aim of this study was to investigate changes in TCS in a larger group of clinically stable patients with Wilsons disease (WD), and to correlate them with demographic and clinical data. TCS was conducted in 54 consecutive, clinically stable patients with WD who were classified as predominantly neurologic or hepatic form of the disease and were adequately assessable by TCS from both sides. TCS revealed significantly higher prevalence of SN (p = 0.007) and LN hyperechogenicity (0.001) in WD patients when compared to controls. Moderate to marked SN hyperechogenicity was found in 31.5% of WD patients (in 42% and 7% of those with neurologic and hepatic form of WD, respectively) and in 8% of healthy controls. Disease severity correlated with the hyperechogenicity of SN (r = 0.303; p = 0.029) and with the width of the third ventricle (r = 0.351; p = 0.011). There is only one report of TCS in WD previous to our study. Both studies proved the ability of TCS to detect accumulation of copper and probably other trace metals, such as iron and manganese, in the BG of WD patients.

White matter abnormalities in Parkinson's disease patients with glucocerebrosidase gene mutations

Glucocerebrosidase gene mutations represent a genetic risk factor for the development of Parkinsons disease. This study investigated brain alterations in Parkinsons disease patients carrying heterozygous glucocerebrosidase gene mutations using structural and diffusion tensor magnetic resonance imaging. Among 360 Parkinsons disease patients screened for glucocerebrosidase gene mutations, 19 heterozygous mutation carriers (5.3%) were identified. Of these, 15 patients underwent a neuropsychological evaluation and a magnetic resonance imaging scan. Sixteen age‐ and sex‐matched healthy controls and 14 idiopathic Parkinsons disease patients without glucocerebrosidase gene mutations were also studied. Tract‐based spatial statistics was used to perform a white matter voxel‐wise analysis of diffusion tensor magnetic resonance imaging metrics. Mean fractional anisotropy values were obtained from white matter tracts of interest. Voxel‐based morphometry was used to assess gray‐matter atrophy. Cognitive deficits were found in 9 mutation carrier patients (60%). Compared with controls, Parkinsons disease patients carrying glucocerebrosidase gene mutations showed decreased fractional anisotropy in the olfactory tracts, corpus callosum, and anterior limb of the internal capsule bilaterally, as well as in the right anterior external capsule, and left cingulum, parahippocampal tract, parietal portion of the superior longitudinal fasciculus, and occipital white matter. Mutation carrier patients also had decreased fractional anisotropy of the majority of white matter tracts compared with Parkinsons disease patients with no mutations. No white matter abnormalities were found in Parkinsons disease patients without glucocerebrosidase gene mutations. No gray matter difference was found between patients and controls. In Parkinsons disease patients, verbal fluency scores correlated with white matter abnormalities. Parkinsons disease patients carrying glucocerebrosidase gene mutations experience a distributed pattern of white matter abnormalities involving the interhemispheric, frontal corticocortical, and parahippocampal tracts. White matter pathology in these patients may have an impact on the clinical manifestations of the disease, including cognitive impairment.

Phenotype of non-c.907_909delGAG mutations in TOR1A: DYT1 dystonia revisited.

BACKGROUND In addition to the most frequent TOR1A/DYT1 mutation (c.907_909delGAG), a growing number of TOR1A sequence variants are found in dystonia patients. For most, functional characterization has demonstrated pathogenicity at different levels, implying that TOR1A genetic testing should not be limited to screening for c.907_909delGAG. METHODS We tested 461 Serbian patients with isolated or combined dystonia for changes in the TOR1A gene and performed a systematic literature review of the clinical characteristics of patients carrying TOR1A mutations other than c.907_909delGAG. RESULTS One likely pathogenic TOR1A mutation (c.385G>A, p.Val129Ile) was detected in an adult-onset cervical dystonia patient. This change is in proximity to the previously reported p.Glu121Lys mutation and predicted to decrease the stability of TOR1A-encoded protein TorsinA. CONCLUSIONS Our patient and three other reported carriers of non-c.907_909delGAG-mutations within the first three exons of TOR1A showed similar phenotypes of adult-onset focal or segmental cervical dystonia. This observation raises the possibility of genotype-phenotype correlations in DYT1 and indicates that the clinical spectrum of this type of dystonia might be broader then previous classic descriptions.

Transcranial sonography in patients with Parkinson's disease with glucocerebrosidase mutations.

OBJECTIVES The aim of this study was to search for possible differences in the findings of transcranial sonography (TCS) between groups of patients with glucocerebrosidase (GBA)-associated Parkinsons disease (PD) (4 patients with Gaucher disease type 1 and parkinsonism [GD+PD+] and 18 PD patients with heterozygous GBA mutations; [GBA+PD+]) and groups of 12 patients with Gaucher disease type 1 and no signs of parkinsonism (GD+PD-), 9 asymptomatic carriers of heterozygous GBA mutations (GBA+PD-), 32 sporadic PD patients (sPD), and 43 healthy controls. RESULTS In all groups of patients, except asymptomatic carriers of heterozygous GBA mutations (mean ± SD: 0.16 ± 0.03 cm(2)), the maximal areas of substantia nigra hyperechogenicity (aSN-max) was higher (GD+PD+: 0.28 ± 0.15 cm(2); GD+PD-: 0.18 ± 0.06 cm(2); GBA+PD+: 0.27 ± 0.06 cm(2); sPD: 0.28 ± 0.10 cm(2)) when compared to controls (0.12 ± 0.08 cm(2)) (p = 0.001). In GBA-associated PD (GD+PD+ and GBA+PD+) and sPD, aSNmax values were very similar. Moderate or marked SN hyperechogenicity was present in 87.5% of sPD patients and in 83% of PD patients with heterozygous GBA mutations, but in only 11.6% of controls, and in 22.2% and 33.3% of patients from GBA+PD- and GD+PD- groups, respectively (p < 0.001). The prevalence of interrupted or missing echogenicity of the brainstem raphe differed between the groups (p = 0.046), while no difference was observed in the diameter of the third ventricle. CONCLUSIONS TCS findings in GBA-associated PD were consistent to those of patients with sporadic PD.

Quality of life in patients with treated and clinically stable Wilson's disease

Health‐related quality of life (HRQoL) in Wilsons disease (WD) has not been extensively studied. Therefore, the purpose of this cross‐sectional study was to identify clinical and demographic factors influencing HRQoL in 60 treated, clinically stable patients with WD using a generic questionnaire, the Medical Outcomes Study Short‐Form 36‐Item Health Survey (SF‐36). The level of disability and grading of WD multisystemic manifestations were assessed by the Global Assessment Scale for WD (GAS for WD). The Mini Mental State Examination (MMSE) and the 21‐item Hamilton Depression Rating Scale (HDRS) scoring were also applied by the same trained interviewers. Lower scores on the SF‐36 domains were found in patients with neurological compared with those with a predominantly hepatic form of WD. The HRQoL of patients with WD and psychiatric symptoms was also lower than that of those without them. Finally, significant inverse correlations were obtained between the various SF‐36 domains and all the following: period of latency from the first symptoms/signs appearance and treatment initiation, MMSE and HDRS scores, and different domains of the GAS for WD.

The spread of primary late-onset focal dystonia in a long-term follow up study

OBJECTIVES To determine spread of primary late-onset focal dystonia at a long-term follow up study. METHODS Available patients not lost to follow up from the initial cohort were reexamined to access course and spread of dystonia. In this prolonged follow-up (13.71 ± 5.6 years), it was possible to contact and include 66 out of 132 consecutive patients (50%) who had been diagnosed as primary focal dystonia at the Clinic of Neurology (Belgrade) from January 1990 to January 2000. RESULTS Recalculation after inclusion of the new data for 66 patients revealed that the latency from the disease onset to dystonia spreading to the first new region was 4.9 ± 4.9 years, and to the second region 5.9 ± 8.8 years. An average time to disease progression was 12.39 ± 1.58, 6.34 ± 1.55 and 15.95 ± 1.43 for patients with torticollis, blepharospasm, and those with hand dystonia, respectively. The spread of dystonia in patients with the initial blepharospasm was faster, while patients with the writers cramp could expect further progression even after longer periods of time. Older age at onset (p = 0.061), family history (p = 0.028) and the presence of tremor in the region affected by dystonia (p = 0.047) were the most powerful predictors of disease spreading. The majority of spreading events occurred during the first years of the disease and they appeared to be rare in later period. CONCLUSIONS These findings may be valuable for prognostic information on the disorder.

De novo mutation in the GNAL gene causing seemingly sporadic dystonia in a Serbian patient

Mutations in GNAL (DYT25) have recently been established as the first confirmed cause of focal or segmental adult‐onset dystonia. Mutation carriers show craniocervical involvement; however, the GNAL mutational and phenotypic spectrum remain to be further characterized, and guidelines for diagnostic testing need to be established.