Botulinum toxin type-A preparations are not the same medications - clinical studies (Part 2).

The growing number of Botulinum neurotoxin type A (BoNT/A) preparations on the market has resulted in a search for pharmacological, clinical and pharmacoeconomic differences. Patients are occasionally switched from one botulinum toxin formulation to another. The aim of this paper was to review studies that have made direct comparisons of the three major BoNT/A preparations presently on the market: ona-, abo- and incobotulinumtoxinA. We also review the single medication Class I pivotal and occasionally Class II-IV studies, as well as recommendations and guidelines to show how effective doses have been adopted in well-established indications such as blepharospasm, hemifacial spasm, cervical dystonia and adult spasticity. Neither direct head-to-head studies nor single medication studies between all preparations allow the formation of universal conversion ratios. All preparations should be treated as distinct medications with respect to their summary of product characteristics when used in everyday practice.

Opposite effects of l-dopa and DBS-STN on saccadic eye movements in advanced Parkinson's disease.

OBJECTIVE: To assess the effects of l-dopa and deep brain stimulation of the subthalamic nucleus (DBS-STN) on saccadic eye movements in patients with Parkinson's disease (PD). METHODS: Visually and internally guided horizontal saccades were evaluated using a saccadometer in 64 patients with advanced PD and 48 healthy controls. Forty-four pharmacologically treated patients were assessed in their "med-off" (OFF) and "med-on" (ON) status, whereas 20 DBS-STN treated patients were assessed in their "med-off, stim-off" (OFF) and "med-off, stim-on" (ON) status. RESULTS: In all PD patients the saccades in the OFF status were delayed, slower and smaller (p<0.01) than in controls. In pharmacologically treated patients all studied parameters showed tendency to worsen in the ON status as compared to the OFF status. In contrast, activating DBS-STN showed tendency to improve all studied parameters. Comparison of the studied saccade parameters between the ON status of DBS-STN treated patients, ON status of the pharmacologically treated patients and the controls showed that 73% of these parameters in the DBS-STN treated patients were similar as in the controls. While in the pharmacologically treated patients only 26% of these parameters were similar as in the controls. CONCLUSION: This prospective study comparing the influence of l-dopa and DBS-STN on saccades in advanced PD showed contrasting results between these two treatments; the majority of the studied parameters in patients on DBS-STN were similar as in the controls.

The effect of the rehabilitation program on balance, gait, physical performance and trunk rotation in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a progressive, neurodegenerative disease which leads to postural and gait disorders, limitation in mobility, activities of daily living and disability. AIMS: The aim of the study is to assess the effects of the rehabilitation program on balance, gait, motor performance and trunk rotations in PD patients. METHODS: Sixty-four patients with 1.5-3.0 stage PD in the Hoehn and Yahr scale were randomly allocated to rehabilitation and control groups. Sixty-one patients completed the study. Patients were assessed three times, at month intervals. Between the first and second assessments, the rehabilitation group participated in a rehabilitation training program focused on mobility, balance and gait exercises, consisting of 28 sessions. Balance was assessed with tandem stance and the Pastor test (shoulder tug). Gait was assessed with a 10 m walk at preferred speed and 360° turn. Motor performance was evaluated by means of the Physical Performance Test (PPT) and timed motor activities. The trunk rotations were measured in the lumbar and thoraco-lumbar spine with a tape measure. RESULTS: The rehabilitation group significantly improved (p < 0.05) in balance and gait outcomes, PPT score, timed activities and trunk rotations both in comparison to the control group and baseline results. The positive effects of the exercise program maintained for at least 1 month. CONCLUSION: The 4-week rehabilitation training program focused on mobility, balance and gait exercises improved balance, gait, physical performance and trunk rotations in patients with PD.

A case report of patient with cerebellar variant of stiff person syndrome.

Stiff person syndrome (SPS) is a rare autoimmune neurological disorder with antibodies against antigens involved in neurotransmission of gamma-aminobutyric acid (GABA). About 10% of patients with SPS may develop ataxia. This cerebellar variant is a distinct subset of SPS with more severe and complex clinical phenotype. We report the clinical, neuropsychological and neuroradiological findings in a 39-year-old female with cerebellar variant of SPS.

Is hypertension a risk factor of hemifacial spasm?

OBJECTIVES: The published data on the relation between arterial hypertension (AH) and hemifacial spasm (HFS) are controversial. The aim of the study was to determine the prevalence of AH in HFS patients and the relation of AH and compression of the brainstem at the region of vasomotor center. MATERIALS AND METHODS: The study included 60 of primary HFS patients and 60 healthy controls matched by age. AH was defined according to WHO criteria. The vessel compression of the brainstem was measure on MRI scans in selected region of vasomotor center located in the ventro-lateral medulla (VLM), between the pontomedullary junction, retro-olivary sulcus and the root entry zone (REZ) of the IX and X nerves. Modeling and compression severity of the VLM was graded in the 0-3 scale. RESULTS: The prevalence of AH in HFS patients did not differ significantly from the control group (61.6% vs 45.0%, p=ns). VML compression by vessel was frequently found in HFS patients with AH than without AH (97.2% vs 60.9%, χ(2)=11.0, p=0.0009). A similar relation was also found in the control group. The higher rate of VML vascular compression was related to the presence of AH in both, HFS patients and control group. CONCLUSION: The prevalence of AH in HFS patients does not differ from controls. The VLM compression in HFS patients and controls is related to AH diagnosis. The association between AH and VLM compression is stronger in patients with higher degree of VLM compression.

Role of Gα(olf) in familial and sporadic adult-onset primary dystonia.

The vast majority of patients with primary dystonia are adults with focal or segmental distribution of involuntary movements. Although ~10% of probands have at least one first- or second-degree relative to dystonia, large families suited for linkage analysis are exceptional. After excluding mutations in known primary dystonia genes (TOR1A, THAP1 and CIZ1), whole-exome sequencing identified a GNAL missense mutation (c.682G>T, p.V228F) in an African-American pedigree with clinical phenotypes that include cervical, laryngeal and hand-forearm dystonia. Screening of 760 subjects with familial and sporadic primary dystonia identified three Caucasian pedigrees with GNAL mutations [c.591dupA (p.R198Tfs*13); c.733C>T (p.R245*); and c.3G>A (p.M1?)]. These mutations show incomplete penetrance. Our findings corroborate those of a recent study which used whole-exome sequencing to identify missense and nonsense GNAL mutations in Caucasian pedigrees of mixed European ancestry with mainly adult-onset cervical and segmental dystonia. GNAL encodes guanine nucleotide-binding protein G(olf), subunit alpha [Gα(olf)]. Gα(olf) plays a role in olfaction, coupling D1 and A2a receptors to adenylyl cyclase, and histone H3 phosphorylation. African-American subjects harboring the p.V228F mutation exhibited microsmia. Lymphoblastoid cell lines from subjects with the p.V228F mutation showed upregulation of genes involved in cell cycle control and development. Consistent with known sites of network pathology in dystonia, immunohistochemical studies indicated that Gα(olf) is highly expressed in the striatum and cerebellar Purkinje cells, and co-localized with corticotropin-releasing hormone receptors in the latter.

An exploratory double-blind, randomized clinical trial with selisistat, a SirT1 inhibitor, in patients with Huntington's disease.

AIMS: Selisistat, a selective SirT1 inhibitor is being developed as a potentially disease-modifying therapeutic for Huntington's disease (HD). This was the first study of selisistat in HD patients and was primarily aimed at development of pharmacodynamic biomarkers. METHODS: This was a randomized, double-blind, placebo-controlled, multicentre exploratory study. Fifty-five male and female patients in early stage HD were randomized to receive 10 mg or 100 mg of selisistat or placebo once daily for 14 days. Blood sampling, clinical and safety assessments were conducted throughout the study. Candidate pharmacodynamic markers included circulating soluble huntingtin and innate immune markers. RESULTS: Selisistat was found to be safe and well tolerated, and systemic exposure parameters showed that the average steady-state plasma concentration achieved at the 10 mg dose level (125 nm) was comparable with the IC50 for SirT1 inhibition. No adverse effects on motor, cognitive or functional readouts were recorded. While circulating levels of soluble huntingtin were not affected by selisistat in this study, the biological samples collected have allowed development of assay technology for use in future studies. No effects on innate immune markers were seen. CONCLUSIONS: Selisistat was found to be safe and well tolerated in early stage HD patients at plasma concentrations within the anticipated therapeutic concentration range.

The effects of physiotherapy with PNF concept on gait and balance of patients with Huntington's disease - pilot study.

BACKGROUND AND PURPOSE: Huntington's disease (HD) is a neurodegenerative, progressive disorder of the central nervous system which causes significant gait and balance disturbances. This is a pilot study which aims to determine the effects of a physiotherapy programme with use of Proprioceptive Neuromuscular Facilitation (PNF) on gait and balance in HD patients. MATERIAL AND METHODS: 30 HD patients aged 21-60 with genetically confirmed diagnosis participated in the study. Participants followed a 3-week-long PNF-based physiotherapy programme. Gait and balance were evaluated twice in each participant: first at baseline and then after the course of physiotherapy. The following methods were used for gait disturbances: Tinetti Gait Assessment Tool, Up and Go Test, Timed Walking Tests for 10m and 20m (TWT10m, TWT20m). Balance was assessed with use of Berg Balance Scale, Pastor Test and Functional Reach Test. RESULTS: There was a significant improvement in all measures of balance and gait. CONCLUSION: PNF-based physiotherapy is effective and safe in HD patients.

[Systemic lupus erythematosus of the nervous system--selected aspects]. / Toczen rumieniowaty ukladowy z zajeciem ukladu nerwowego--wybrane zagadnienia.

Neurological symptoms in SLE are still the challenge for the practitioners. It is assumed that that the central nervous system (CNS) is affected in 95% patients with SLE. It is a cause significantly worsening the prognosis, responsible for the mortality increase in this disease. In 1999 American Academy of Rheumatology published the first formal classification of the neurological symptoms in SLE. 19 types of the neuropsychiatric systemic lupus erythematosous (NPSLE) are distinguished. Ischaemic strokes of CNS, transistent ischaemic attaks, epileptic seizures and mobility disturbances are the most common symptoms. It is assumed that antiphospholipid antibodies are the most important factors in the NPSLE pathogenesis. These antibodies reveal prothrombotic and proinflammatory activities with vasculitis as the effect of this action. However it should be stressed that cause-effect relationship between the action of specific antibodies and neurological symptoms are still unclear. Better understanding of neurological and psychiatric symptoms of SLE may allow faster diagnosis, as well as the disease exacerbation and the application of proper therapy.

[Clinical variability of Juvenile Huntington's Disease phenotype]. / Odmiennosc kliniczna mlodzienczej postaci choroby Huntingtona.

Huntington's disease is rare, genetically determinated, neurodegenerative disorder. It is determined by dynamic mutation of IT15 gene on short arm of 4 chromosome. Characteristic symptomatology include involuntary movements, cognitive decline and wide spectrum of mood and behaviour disorders. It typically becomes noticeable in mid-adult life, but there are reported cases of appaers of symptoms between 2 and 80 year of life. Especially interesting is juvenile Huntington's disease- the Westphal variant with the beginning in childchood (before 20 year of age) because of clinical differences causing diagnostic difficulties. It affects 5-10% of carries of the mutant gene. Symptoms became noticeable before 10 year of age only in 1% of them.

Small volume of the posterior cranial fossa and arterial hypertension are risk factors of hemifacial spasm.

OBJECTIVES: So far, there are only two studies evaluating the relation between the small volume of the posterior cranial fossa (VPCF) and the occurrence of HFS, both on Asian population. The aim of the study was to determine small VPCF and arterial hypertension (AH), as risk factors for hemifacial spasm (HFS) and their relation to neurovascular conflict (NVC) in Polish Caucasian-origin patients. MATERIALS AND METHODS: The study included 60 patients with idiopathic HFS and 60 healthy volunteers matched by sex and age. AH was defined according to WHO. The VPCF measured the volume of the prepontine, prespinal and both cerebellopontine angle cisterns in MRI scans. RESULTS: There were no significant differences between occurrence of AH and the VPCF of patients and controls but the mean VPCF in women was significantly smaller than in men, In the multivariate regression analysis model only NVC was the statistically significant. In the subgroup of >50-year-old patients the most dominant risk factor was NVC (OR 71.09; 95% CI 21.08-239.77; p=0.0000), followed by the AH duration (OR 1.07; 95% CI 1.00-1.16; p=0.047). In the subgroup of <50 years, NVC was also the dominant risk factor, followed by the lower VPCF (Walad test: OR 0.4; 95% CI 0.16-1.04; p=0.045). CONCLUSION: There was no significant difference in VPCF and in frequency of AH diagnosis in HFS patients and age- and sex-related controls, but the logistic regression analysis showed that small VPCF and AH duration are risk factors of HFS in younger and older patients respectively.

Saccadic eye movements in juvenile variant of Huntington disease.

BACKGROUND AND PURPOSE: Huntington disease (HD) is a neurodegenerative disease leading to involuntary movements, cognitive and behavior decline. The juvenile variant of HD (JHD) manifests in people younger than 21 and is characterized by a different clinical presentation, i.e. rigidity and bradykinesia. Rapid eye movements were not extensively studied in patients with JHD. Aims of our study were to describe the saccadic eye movements in JHD patients and to find a correlation between the saccade abnormalities, severity of the disease and cognitive and behavior deterioration. MATERIALS AND METHODS: We studied 10 patients with JHD and 10 healthy subjects. Reflexive and volitional saccades were assessed with the Saccadometer Advanced. The battery of cognitive and behavior tests was performed as well. RESULTS: We found a prolonged latency, slowness and decreased velocity of reflexive and voluntary saccades and reduced amplitude of voluntary saccades. Moreover, patients with JHD executed a significantly lower number of volitional saccades and made more incorrect cued saccades than controls. We noted a significant correlation between prolonged latency of reflexive saccades with gap task and disease severity and significant inverse correlation between prolonged latency of reflexive saccades with overlap task, an increased number of incorrect saccades made on a cue and impairment in working memory. CONCLUSION: Abnormalities of saccade eye movements in patients with JHD were similar to those reported in patients with HD. Our findings did not confirm abnormalities previously reported in patients with early onset HD. Abnormal saccade parameters correlated also with a disease severity and cognitive deterioration.

Cognitive impairment in carriers of glucocerebrosidase gene mutation in Parkinson disease patients.

AIM: Parkinson disease (PD) is the common neurodegenerative disease with motor and numerous non-motor symptoms, including cognitive impairment. Mutation of glucocerebrosidase (GBA) gene is the most common genetic risk factor of sporadic PD. The aim of this study was to assess clinical features of PD associated with GBA mutation. METHODS: One hundred and thirty-eight PD patients were involved and examined by the movement disorder specialist using several scales including Unified Parkinson Disease Rating Scale (UPDRS) part II and III, Hoehn and Yahr (H&Y) staging, Mini-Mental State Examination (MMSE) and Hamilton Depression Scale (HDS). The exons 8 and 9 of GBA was sequenced and screened for variants. RESULTS: The GBA variants were found in 16 (11.6%) PD patients: N370S mutation in 5 (3.6%) and T369M variant in 11 (7.9%). No significant differences between the group of mutation carriers and non-carriers were found in relation to clinical features except for dementia (MMSE score<26) occurring more often in N370S mutation carriers (60.0% vs 19.6%, p=0.03). CONCLUSION: The N370S GBA mutation is the risk factor for cognitive impairment in PD patients.

Deep brain stimulation in the treatment of Holmes tremor - a long-term case observation.

We present the patient with Holmes tremor secondary to the infarction of thalamus, successfully treated with the deep brain stimulation (DBS) of the area between ventralis oralis anterior and zona incerta for a long time, in whom the severe tremor reappeared after removal of the DBS lead. This is the first presentation of the effective DBS on this location. Our case does not support the hypothesis that the DBS treatment could lead to sustained relief of symptoms after cessation of stimulation.

[Psychotic disorder in the course of Systemic Lupus Erythematosus with subcortical calcifications--case report]. / Zaburzenia psychotyczne w przebiegu tocznia rumieniowatego ukladowego ze zwapnieniami struktur podkorowych--opis przypadku.

UNLABELLED: Systemic Lupus Erythematosus (SLE) is autoimmunological disease of connective tissue which is characterized with clinical symptoms of many systems and organs injury. There are often neuropsychiatric symptoms. Psychotic disorder is the least frequent syndrome. Neuropsychiatric symptoms are important because they deteriorate the quality of life and are poor prognostic factor. AIM: The aim of the study is to present the patient with chronic, lasting for many years, skin lesions and laboratory tests results characteristic for SLE, who had psychotic disorder diagnosed as schizophrenia and in the next few years there were observed other neuropsychiatric symptoms including cognitive impairment and mood disorder. CONCLUSIONS: Psychotic disorder is rare syndrome of neuropsychiatric SLE (NPSLE). It may primarily originate from SLE or be secondary either to the therapy or the complications of the disease. It is not possible to define if the psychosis is the primary schizophrenic process or secondary to the autoimmune disease in presented patient. However the clinical picture pays attention to the significance of careful diagnostic process, including neuroimaging. In head CT of presented patient there were revealed massive, bilateral, calcifications of subcortical structures which probably substantially enhanced neuropsychiatric symptoms.

Tremor in neuropathies of different origin.

BACKGROUND AND PURPOSE: Tremor accompanies some poly-neuropathies, but its prevalence and its clinical and electrophysiological manifestations are not well known. The aim of the study was to assess the occurrence and characteristics of hand tremor in patients with polyneuropathy of different origins, as well as relations between the occurrence of tremors and clinical and neurographic findings of polyneuropathy. MATERIAL AND METHODS: Eighty-nine patients diagnosed with polyneuropathy of known aetiology, and 50 age- and sex-matched healthy volunteers were included in the study. All subjects were interviewed regarding the occurrence of tremor. Tremor was assessed clinically and objectively using a triaxial accelerometer and electromyographic (EMG) recordings. A load test with a weight of 500 γ was performed in order to differentiate between enhanced physiological tremor (EPT) and essential tremor-like (ET-L) tremor. RESULTS: Tremor was found in 59.5% of patients in clinical assessment and in 74% of patients in objective evaluation, significantly more often than in controls (12%). Tremor was detected in all types of polyneuropathy apart from paraproteinaemic IgM polyneuropathy. Tremor was postural (70%), but resting (51%) or kinetic (32%) tremor was also present. In the majority of cases, the severity of the tremor was mild. Essential tremor-like tremor prevailed in the study group. The occurrence of hand tremor was not related to the axonal or demyelinating type of polyneuropathy, nor to the conduction velocity or other electrophysiological findings of the investigated upper limb nerves. CONCLUSION: Tremor accompanies 60-70% of patients with polyneuropathy; it is mostly postural, ET-L type with mild severity, and unrelated to other typical clinical and electrophysiological findings of neuropathy.

Epidemiology of Blastocystis Infection: A Review of Data from Poland in Relation to Other Reports.

Blastocystis is a common gut protist of humans and various animals worldwide, with a high level of genetic diversity. Neither its zoonotic potential and transmission routes nor its pathogenicity are fully known. This fact, and the fact that Blastocystis is the most abundant eukaryote in human faeces, raises the question of its relevance to public health. Here, we summarise (in relation to other reports) the results of studies on the prevalence and genotypic variation of Blastocystis, which were carried out in animals, humans, and in water environments in Poland. In humans, the prevalence ranged between 0.14 and 23.6%, in some animals reached 58.97%, and in water environments was 5.1%. Seven subtypes were identified in humans (ST1-ST4, ST6, ST7, and ST9), of which ST3 was the most common. Among animals (wild, livestock, and pet animals), eleven STs were identified, with differential host specificity. Humans and animals shared ST1, ST2, ST3, ST6, and ST7, while ST1 and ST3 were present in humans, animals, and water sources. These observations indicate the possibility of Blastocystis transmission between animals and humans. Further studies should be continued in search of the sources and transmission routes of Blastocystis in order to prevent the spread of infections among humans and animals.

Mesenchymal Chondrosarcoma from Diagnosis to Clinical Trials.

Mesenchymal chondrosarcoma (MCS) is a rare subtype of chondrosarcoma with a poor prognosis. Although these tumors are sensitive to radiotherapy/chemotherapy, the standard treatment for localized MCS is only surgical resection, and there are no established treatment guidelines for patients with advanced and metastatic MCS. Due to the low incidence of MCS, the pathology of these tumors is still unknown, and other therapeutic options are lacking. Some studies show the potential role of the PDGF/PPI3K/AKT, PKC/RAF/MEK/ERK, and pRB pathways, and BCL2 overexpression in the pathogenesis of MCS. These findings provide an opportunity to use protein kinases and BCL2 inhibitors as potential therapy in MCS. In this review, we summarize the current knowledge about MCS diagnosis and treatment options. We show the immunological and molecular biomarkers used in the diagnosis of MCS. In addition, we discuss the known prognostic and predictive factors in MCS. Finally, we present the novel trends, including targeted therapies and ongoing clinical trials using protein kinase inhibitors and the death receptor 5 (DR5) agonist, which may be the focus of future MCS treatment studies.

Huntington's disease from the patient, caregiver and physician's perspectives: three sides of the same coin?

The aim of this study was to identify determinants of functional disability, patient's quality of life (QoL) and caregivers' burden in Huntington's disease (HD). Eighty HD patients participated in the study. Motor and behavioral disturbances as well as cognitive impairment were assessed using motor, behavioral and cognitive parts of the Unified Huntington Disease Rating Scale (UHDRS); Hamilton Depression Rating Scale was used to assess depression. Disability, health-related QoL and the impact of the disease on the caregivers were assessed using the following methods: UHDRS Functional Assessment Score, SF-36 Scale and Caregiver Burden Inventory. Multiple regression analysis showed that motor disturbances, cognitive impairment, apathy and disease duration were the independent predictors of disability. Depression and cognitive disturbances were the determinants of patient's QoL, while motor disturbances and depression were the predictors of the caregiver burden. Patient's disability and QoL as well as caregivers' burden should be taken into consideration while planning treatment strategy and the results of the present study show that the predictors of those treatment targets are different.

Factors affecting the quality of life in hemifacial spasm patients.

BACKGROUND AND PURPOSE: Hemifacial spasm (HFS), a movement disorder manifested by unilateral spasms of the muscles innervated by the facial nerve, interferes with social life in about 90% of patients, causing social isolation and depression and having a significant impact on the quality of life. The aim of the study was to assess factors affecting the quality of life in patients with HFS in respect of influence of the severity of depression symptoms and botulinum toxin type A (BTX-A) therapy. MATERIAL AND METHODS: Eighty-five out of 129 patients included in the HFS database of the Movement Disorders Outpatient Clinic, Department of Neurology, University Hospital, Cracow who fulfilled the inclusion criteria and had no exclusion criteria (suffering from concomitant movement disorders, other severe chronic diseases or cognitive impairment) were studied. Demographic and clinical data (age at onset, disease duration and accompanying symptoms) were collected. Severity of HFS was assessed by the five-point clinical scale and seven-point Clinical Global Impression scale. Quality of life was assessed with the HFS-36 questionnaire and severity of depressive symptoms was evaluated with the Beck Depression Inventory. HFS-36 was performed twice, before BTX-A injection and two weeks later. RESULTS: The mean global score of HFS-36 was 47 ± 31 (maximum: 140 pts). Decreased HFS-36 score resulted from divergent deterioration in all subscales included in the questionnaire. Independent risk factors of deterioration in HFS-36 were increased severity of HFS and depressive symptoms as well as accompanying trismus. The HFS-36 score depended on the number and type of accompanying symptoms as well. Botulinum toxin type A therapy led to a significant improvement of HFS-36, particularly high in patients with multiple (> 4) HFS-related symptoms. CONCLUSIONS: The HFS-36 score depends mostly on severity of HFS, depressive symptoms and occurrence of accompanying trismus. It improves after BTX-A treatment.