Transcranial sonography in dopa-responsive dystonia.

BACKGROUND AND PURPOSE: Mutations in the GCH1 gene, encoding GTP cyclohydrolase 1, the enzyme critically important for dopamine production in nigrostriatal neurons, are the most common cause of dopa-responsive dystonia (DRD), characterized predominantly by limb dystonia, although parkinsonian features may also be present. It has been suggested that DRD is a neurochemical rather than neurodegenerative disorder. METHODS: Transcranial brain sonography, which might be a risk marker for nigral injury, was obtained from 141 subjects divided into four groups: (i) 11 patients with genetically confirmed DRD; (ii) 55 consecutive patients with Parkinson's disease (PD); (iii) 30 patients diagnosed as isolated adult-onset focal dystonia; and (iv) 45 healthy controls (HCs). RESULTS: Substantia nigra hyperechogenicity was present in 63.6% of patients with DRD, which was significantly different in comparison to patients with dystonia (20%) and HCs (6.7%), but not in comparison to the PD group (87.3%). Also, values of the maximal areas of substantia nigra hyperechogenicity in patients with DRD were higher in comparison to HCs, but significantly lower than among the PD group. CONCLUSIONS: We suggested that the observed transcranial brain sonography features in patients with DRD might primarily be risk markers for particular clinical features (parkinsonism, dystonia) occurring in the specific genetic context (i.e. GCH1 mutations), or might reflect compensated neurodegenerative processes triggered by the long-lasting dopamine deficiency due to the profound delay in levodopa treatment in our patients with DRD.

Transcranial brain sonography findings in two main variants of progressive supranuclear palsy.

BACKGROUND AND PURPOSE: Progressive supranuclear palsy (PSP) can occur with two main clinical presentations, classified as classical Richardson's syndrome (PSP-RS) and as PSP-parkinsonism (PSP-P), the most common atypical PSP variant. The differential diagnosis between them is challenging. Therefore, we studied different ultrasound markers by transcranial sonography in individuals with PSP-RS and PSP-P, to test their value in the diagnostic work up of these patients. METHODS: Transcranial sonography was performed in 21 patients with PSP-RS and 11 patients with PSP-P. Echogenic sizes of the substantia nigra (SN) and the lenticular nuclei (LN), as well as the width of the third ventricle, were measured. RESULTS: Among the patients with PSP-RS and PSP-P, three (14%) and eight (73%) patients had a hyperechogenic SN (P = 0.020), respectively. Uni- or bilateral hyperechogenicity of the LN was observed in 67% and 36% of patients with PSP-RS and PSP-P, respectively (P = 0.101). Third ventricle was significantly wider in patients with PSP-RS (11.2 ±â€…2.3 mm) when compared with patients with PSP-P (7.5 ±â€…1.4 mm; P = 0.001). CONCLUSION: Our data, possibly reflecting pathological differences, primarily contribute supporting the view that the neurodegenerative process differs in the two PSP variants.

Glucocerebrosidase mutations in a Serbian Parkinson's disease population.

BACKGROUND AND PURPOSE: To screen for glucocerebrosidase (GBA) mutations in a Serbian Parkinson's disease (PD) population. METHODS: Glucocerebrosidase exons 8-11 harbouring the most common mutations were sequenced in 360 patients with PD and 348 controls from Serbia. Haplotype analysis was performed for the N370S mutation and compared with German and Ashkenazi Jewish carriers. RESULTS: Glucocerebrosidase mutations were significantly more frequent in patients with PD (21/360; 5.8%) vs. controls (5/348; 1.4%; OR = 4.25; CI, 1.58-11.40; P = 0.0041). Two patients with PD carried homozygous or compound heterozygous mutations in GBA. The N370S mutation accounted for about half of the mutated alleles in patients (10/23) but was absent amongst controls. Three novel variants were detected including two non-synonymous variants (D380V, N392S) in the patient group and one synonymous change (V459V) in a control. Carriers of the D409H mutation were also sequenced for H255Q, and all were found to carry the [D409H; H255Q] double-mutant allele. Genotyping suggested a common haplotype for all N370S carriers. CONCLUSION: Glucocerebrosidase mutations represent a PD risk factor in the Serbian population.

Long-term outcome in Serbian patients with Wilson disease.

BACKGROUND AND PURPOSE: To investigate survival rates, prognostic factors, and causes of death in Wilson disease (WD). METHODS: In the years 1980-2007, a cohort of 142 patients with WD was prospectively registered (54 presented with neurologic symptoms, 49 with hepatic symptoms, 33 had mixed form, and data were missing for six patients). The duration of follow-up for patients alive was 11.1 +/- 8.8 years. RESULTS: After initiation of treatment (d-penicillamine and zinc salts), 79% of patients had a stable or improved course of disease. Despite early diagnosis and appropriate therapy, 15 patients still had a relentlessly progressive course. Thirty patients died. The cumulative probability of survival in a 15-year period for the whole group was 76.7 +/- 4.9%. Better prognosis of WD was associated with male sex, younger age at onset, neurologic form of the disease, and treatment continuity. Causes of death were predominantly related to hepatic failure (16 patients), but also suicide (four patients) and cancer (three patients). CONCLUSION: Despite the relatively early diagnosis and treatment of our patients with WD, mortality was still considerably high.

Identification of mutations in the PARK2 gene in Serbian patients with Parkinson's disease.

Mutations in the PARK2 (PRKN) gene are the most common cause of autosomal-recessive (AR) juvenile parkinsonism and young-onset Parkinson's disease (YOPD). >100 different variants have been reported, including point mutations, small indels and single or multiple exon copy number variations. Mutation screening of PARK2 was performed in 225 Serbian PD patients (143 males and 82 females) with disease onset before 50 years and/or positive family history with apparent AR inheritance. All coding regions and their flanking intronic sequences were amplified and directly sequenced. Whole exon multiplications or deletions were detected using Multiple Ligation Probe Amplification (MLPA) method. We identified 12 PD patients with PARK2 mutations (5.3%). Five patients (2.2%) had biallelic mutations and seven (3.1%) were single mutation carriers. Patients with compound heterozygous mutations had earlier onset of the disease compared to non-carriers (p = 0.005) or heterozygotes (p = 0.001). Other clinical features in mutation carriers were not different compared to non-carriers. In our cohort, sequence and dosage variants were equally represented in patients, inducing their first symptoms mainly before the age of 30. For efficient genetic testing strategy, patients with early, especially juvenile onset of PD were strong candidates for both dosage and sequence variants screening of PARK2 gene.

DYT1 mutation in primary torsion dystonia in a Serbian population.

Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous movement disorder. A GAG deletion at position 946 in the DYT1 gene is responsible for most cases of autosomal dominant early-onset PTD. We analysed the DYT1 mutation in 50 patients from a Serbian population, selected according to the proposed guidelines for diagnostic testing: (a) 38 patients with PTD onset < 26 years, and (b) 12 patients with the disease onset +/- 26 years, but with at least one affected family member with early-onset dystonia. Only three apparently sporadic patients among the 50 individuals tested were positive for the GAG deletion in the DYT1 gene: one with typical, generalized, one with long-lasting, non-progressive segmental, and one with multifocal dystonia. Molecular analysis of relatives in 2 families revealed that the lack of family history was due to reduced penetrance.

Correlation between triplet repeat expansion and computed tomography measures of caudate nuclei atrophy in Huntington's disease.

Huntington's disease (HD) is an autosomal dominant, progressive disorder characterized by choreic movements, cognitive decline, and psychiatric manifestations. Eleven patients with HD were retrospectively selected from a larger group of 42 patients based on the similar, early onset of the disease (between 21 and 30 years) and the same duration of HD at the moment of computed tomography (CT) examination (5 years). A significant correlation between the number of CAG trinucleotides and the bicaudate index or the frontal horn index, two indices of caudate atrophy, was found in this group of patients. Our results, although in a small number of patients, suggest that the striatal degeneration, assessed by CT measures, is primarily regulated by the size of expanded CAG repeats.

Impairment of cortical inhibition in writer's cramp as revealed by changes in electromyographic silent period after transcranial magnetic stimulation.

Changes in silent period (SP) duration following transcranial magnetic stimulation (TMS) set at 20% above the motor threshold were studied in six subjects suffering from writer's cramp, while performing dystonic movement and during voluntary isometric contraction of the muscles mostly involved in the dystonic movement. Dependency of SP duration on the intensity of preceding muscle contraction was compared on both affected and healthy side. In all subjects SP duration during dystonic contraction was shorter than during voluntary contraction of the similar strength performed with the same hand. Also, in five subjects, SP duration during dystonic contraction was shorter than during voluntary contraction of the similar strength performed with the healthy hand. In addition, the SP duration on the affected side was negatively associated with the intensity of the preceding contraction (i.e. the stronger contraction the shorter SP), while on the healthy side it was not the case. It is concluded that central inhibitory mechanisms are abnormal in writer's cramp.

Correlation between Bereitschaftspotential and reaction time measurements in patients with Parkinson's disease. Measuring the impaired supplementary motor area function?

For a long time, reaction time (RT) testing has been used for objective assessment of characteristics of the movement impairments in patients with Parkinson's disease (PD). On the other hand, it is supposed that Bereitschaftspotential (BP) reflects CNS preparatory activity for the execution of voluntary movements, and amplitudes of BP are generally smaller in PD. In order to analyze possible correlations between two methods, we studied 15 drug-naive patients with idiopathic PD (Hoehn and Yahr stage from 1 to 2.5). BP was recorded from three scalp locations: Cz, C3, and C4, and Lateralized Potential (LP) was additionally calculated as a C3-C4 difference waveform. We recorded amplitudes of the initial part of BP (at 650 ms before movement-NS1), the maximal amplitude immediately before movement onset (N1), and the N1-NS1 difference (NS2), from the Cz and LP recordings. Two RT testing paradigms were used: Simple Reaction Time (SRT) and Choice Reaction Time (ChRT). The only significant correlation between RT parameters and BP amplitudes from Cz was negative correlation between dT (difference time between Choice Reaction Time and Simple Reaction Time), on one hand, and NS1 (P = 0.006) and N1 (P = 0.026), on the other. However, Cz-NS2 did not correlate with any of the RT parameters. Our data suggest that PD patients with smaller difference between ChRT and SRT, that is presumably caused by the lesser capacity of the movement pre-programming, have smaller (i.e., less negative) BP amplitudes. This association is especially pronounced for the earlier, NS1 amplitude that is supposed to reflect the activity of the supplementary motor area (SMA). The diminished capacity of SMA activation may be the cause of the both, smaller early BP amplitudes, and smaller ChRT-SRT difference, in PD patients.

The therapeutic effect of moclobemide, a reversible selective monoamine oxidase A inhibitor, in Parkinson's disease.

In this open study, the therapeutic effect of moclobemide, a reversible selective monoamine oxidase A inhibitor, was tested in 20 patients with Parkinson's disease who developed levodopa-induced motor response complications. Moclobemide as adjunct therapy reduced "off" time duration for 27%, without an overall motor and functional improvement during their "on" periods. Since it was well tolerated, moclobemide may be specially indicated in elderly or depressed fluctuating parkinsonian patients.

Depression in Parkinson's disease: an EEG frequency analysis study.

Although depression is a common finding in Parkinson's disease (PD), its neurobiological mechanism is still unknown. The purpose of this study was to determine whether there are specific spectral electroencephalographic (EEG) characteristics that distinguish depressed from non-depressed PD patients. The study was performed in 24 patients with idiopathic PD whose antiparkinson medication was stopped 24h beforehand. They were divided into two groups of 12 patients each, one with depressive symptomatology, and one without. The groups did not differ with respect to age, sex distribution, and disease severity and duration. All recordings were conducted using a 16-channel electroencephalograph, and artifact-free EEG was processed using a Fast Fourier Transformation. The EEG of depressed PD patients showed significantly less absolute and relative power in spectral band 7.5-10Hz (alpha1), and slightly more relative power in spectral band 10.513Hz (alpha2), while there was no difference in other spectral bands. Topographic analysis of the alpha1 absolute power revealed that, while in non-depressed patients this activity has a clear occipital maximum (and thus corresponds to the standard background activity), in depressed patients its maximum was shifted anteriorally toward the parietal region. Topographic analysis of the significance of the difference between the groups in the relative power of alpha1 and alpha2 bands revealed opposite gradients, posterior to anterior and anterior to posterior directions, respectively. The spectral EEG characteristics of the depressed PD patients not only differed from the spectral EEG characteristics of non-depressed PD patients, but they were also different from the usually reported spectral EEG characteristics of depressed patients without neurological disease. We propose that our data are sufficient to raise the possibility for the existence of a distinctive neurobiological substrate of depression in PD. This is not just a simple addition of two neurobiological substrata, one of depression (as it is determined in non-neurological patients) and one of PD, but rather a complex product of their interaction.

Symptomatic dystonias associated with structural brain lesions: report of 16 cases.

BACKGROUND: Symptomatic (secondary) dystonias associated isolated lesions in the brain provide insight into etiopathogenesis of the idiopathic form of dystonia and are a basis for establishing the possible correlation between the anatomy of a lesion and the type of dystonia according to muscles affected. METHODS: In 358 patients with differently distributed dystonias, a group of 16 patients (4.5%) was encountered in whom dystonia was associated with focal brain lesions. RESULTS: Of the 16 patients, 3 patients had generalized, 3 segmental and 4 hemidystonia, while the remaining 6 patients had focal dystonia. The most frequent etiologies were infarction in 7, and tumor in 4 patients. These lesions were usually found in the lenticular and caudate nucleus, thalamus, and in the case of blepharospasm in the upper brainstem. CONCLUSIONS: Our results support the suggestion that dystonia is caused by a dysfunction of the basal ganglia.

Are irreversible morphological [corrected] signs of portal hypertension in neurological form of Wilson's disease associated with treatment delay? A pilot study.

Aim of this study was to evaluate the rate of morphological liver and spleen abnormalities in patients with neurological clinical presentation of Wilson's disease (WD). Fourteen patients with neurological presentation of WD divided into group A (5 patients who initiated chelating therapy <24 months from the first symptoms) and group B (9 patients whose therapy started ≥24 months after the initial symptoms) underwent abdominal MRI examination. Abnormal findings on abdominal MRI were present in 28% of patients with neurological form of WD. Significant hepatosplenomegaly was present in none of the patients from group A and in 4 (44%) patients from group B. In addition, macronodular liver cirrhosis and peritoneal effusion were evident in two and one patient from group B, respectively, and in none of the patients from group A. Our results suggest that severe portal hypertension and liver damage in patients with neurological presentation of WD might be reversible or do not even develop if chelating treatment is initiated <2 years after the onset of symptoms.

Vestibular function after spinal cord injury: preliminary results.

STUDY DESIGN: The excitability of the vestibular apparatus and pathways was studied in 10 patients with acute spinal cord injury (ASCI) and in 7 patients with chronic spinal cord injury (CHSCI). OBJECTIVES: Proprioceptive input that may be lost after spinal cord injury (SCI) is needed for integration with vestibular signals to produce proper postural control and perception of movement. This study examined whether there is a change in vestibular excitability after the disruption of the afferent proprioceptive input due to the spinal cord lesion. This study was carried out at Spine Injury Centre and Institute of Rehabilitation, Belgrade, Serbia. METHODS: A total of 10 patients with ASCI and 7 with CHSCI were compared to a group of 50 age-matched healthy subjects. The excitability of the vestibular pathways was studied by means of a modified caloric test in which the duration of postcaloric nystagmus was measured. RESULTS: ASCI patients with cervical lesions showed significantly reduced response durations (P<0.05). There was no difference in control values for ASCI and for CHSCI patients with thoracic or lumbal lesions. There was no difference in control values for cervical CHSCI patients. CONCLUSIONS: These results suggest that the vestibular response to caloric stimulation is supported by spinally mediated sensory input and that the loss of such input is compensated for over time. Further, these results show that the caloric test may be a useful tool for assessing the degree to which SCI disrupts multisensory integration in the vestibular system and tracking the process of reintegration.

Regression of nodular liver lesions in Wilson's disease.

Long-term follow-up abdominal imaging studies have not been reported previously in patients with the hepatic form of Wilson's disease (WD). This paper reports the case of a 35-year-old woman with symptoms dating back several months and with multiple, nodular liver lesions. The lesions were hyperdense on non-enhanced computed tomography and hypointense on T2-weighted magnetic resonance (MR) images. A diagnosis of WD was established several weeks after her admission to hospital, and chelating treatment was commenced promptly. No abnormalities were found on follow-up MR examinations of the abdomen and brain 4.5 years later. These imaging features suggest that so long as WD is diagnosed in the initial stages, liver nodules can regress with time and complete healing can be achieved with continuous decoppering treatment.

A variant of the Kleine-Levin syndrome following head trauma.

A 19-year-old man developed the Kleine-Levin syndrome three weeks after the head trauma and subsequent neurosurgical evacuation of right-sided, fronto-temporal epidural hematoma. The expression of periodic episodes was observed for hypersomnolence and, to a lesser degree, for behavioral disturbances, while the hyperphagia was constantly present during a period of 1.5 years. These clinical features were associated with the focal, right-sided hypothalamic lesion and ipsilateral posttraumatic parenchymal temporal lobe damage on NMR imaging.

[Effect of slow repetitive transcranial magnetic stimulation on depression in patients with Parkinson disease]. / Uticaj spore repetitivne transkranijumske stimulacije magnetom na depresiju kod bolesnika s Parkinsonovom bolescu.

Parkinson's disease (PD), that has usually been associated with movement disorders, is also associated with depression in about 40% of patients [1-9]. Transcranial magnetic stimulation (TMS) is a new non-invasive technique for direct stimulation of the cerebral cortical neurons [1]. Several open studies have shown that repetitive TMS (rTMS) at both rapid (rapid rTMSi > 1 Hz) and low frequencies (slow rTMSi < 1 Hz) may have antidepressant action [2-6]. The study included 8 patients diagnosed as PD fulfilling the DSM-IV criteria for major depression (5 patients) and dysthymia (3 patients). Magnetic stimulator, 200 Mag-Stim, total output 2 T and a circular coil of 90 mm, were used. For ten consecutive days, between noon and 1 p.m. the patients were stimulated with apprx. 80% of the output (1.6 T) at 0.5 Hz. The daily treatment implied stimulation of both sides of the head (first the right, then the left) at four sites (prefrontal, frontal, parietal and occipital regions) with 5 stimulations each site (20 stimulations per hemisphere). Before the beginning of the study, 2-3 hours after the last stimulation (day 10), 7 and 14 days after completion of the treatment, the patients were subjected to scoring on the Hamilton Depression Rating Scale [11] and Unified Parkinson's Disease Rating Scale (UPDRS) [12]. The HDRS values before initiation of rTMS were 19.2 +/- 3.1, with significant fall (p < 0.01) after 10 days of stimulation (14.9 +/- 3.2), 17 days (12.2 +/- 2.7) and 24 days (13.6 +/- 5.3) after the beginning of the study, suggesting that the antidepressive effect persisted even two weeks after discontinuation of stimulation. The UPDRS values were monitored concomitantly. The values on this scale failed to alter significantly. In conclusion, rTMS is a relatively safe and painless method associated with antidepressant action in PD patients. Treatment of depression in PD is of great importance, but the choice of medication is accompanied with numerous limitations [20]. Antidepressant action of rTMS and its maintenance for two weeks after discontinuation of stimulation enables usage of this method in PD in phases of exacerbation of depressive symptoms at least over the period required to reach the full effect of selected medication.

[Effect of slow repetitive transcranial magnetic stimulation on depression in patients with Parkinson 's disease]. / Uticaj spore repetitivne transkranijumske stimulacije magnetom na depresiju kod bolesnika s Parkinsonovom bolescu.

Parkinson's disease (PD), that has usually been associated with movement disorders, is also associated with depression in about 40% of patients [9]. Transcranial magnetic stimulation (TMS) is a new non-invasive technique for direct stimulation of the cerebral cortical neurons [1]. Several open studies have shown that repetitive TMS (rTMS) at both rapid (rapid rTMSi: > 1 Hz) and low frequencies (slow rTMSi: < 1 Hz) may have antidepressant action [2-6]. The study included 8 patients diagnosed as PD fulfilling the DSM-IV criteria for major depression (5 patients) and dysthymia (3 patients). Magnetic stimulator, 200 Mag-Stim, total output 2 T and a circular coil of 90 mm, were used. For ten consecutive days, between noon and 1 p.m. the patients were stimulated with apprx. 80% of the output (1.6 T) at 0.5 Hz. The daily treatment implied stimulation of both sides of the head (first the right, then the left) at four sites (prefrontal, frontal, parietal and occipital regions) with 5 stimulations each site (20 stimulations per hemisphere). Before the beginning of the study, 2-3 hours after the last stimulation (day 10), 7 and 14 days after completion of the treatment, the patients were subjected to scoring on the Hamilton Depression Rating Scale [11] and Unified Parkinson's Disease Rating Scale (UPDRS) [12]. The HDRS values before initiation of rTMS were 19.2 +/- 3.1, with significant fall (p < 0.01) after 10 days of stimulation (14.9 +/- 3.2), 17 days (12.2 +/- 2.7) and 24 days (13.6 +/- 5.3) after the beginning of the study, suggesting that the antidepressive effect persisted even two weeks after discontinuation of stimulation. The UPDRS values were monitored concomitantly. The values on this scale failed to alter significantly. In conclusion, rTMS is a relatively safe and painless method associated with antidepressant action in PD patients. Treatment of depression in PD is of great importance, but the choice of medication is accompanied with numerous limitations [20]. Antidepressant action of rTMS and its maintenance for two weeks after discontinuation of stimulation enables usage of this method in PD in phases of exacerbation of depressive symptoms at least over the period required to reach the full effect of selected medication.