The Profile and Evolution of Neuropsychiatric Symptoms in Multiple System Atrophy: Self- and Caregiver Report.

OBJECTIVE: Recent research shows that patients with multiple system atrophy (MSA) have significant cognitive and neuropsychiatric comorbidities that can color the clinical presentation of the disease and affect their quality of life. The aims of this study were to determine the neuropsychiatric profile in a cohort of patients with the parkinsonian type of MSA (MSA-P) and their dynamic changes over a 1-year follow-up period and to compare rates of neuropsychiatric symptoms (NPSs) reported by caregivers and the patients themselves. METHODS: Forty-seven patients were assessed at baseline; of these, 25 were assessed again after 1 year. NPS assessment tools included the Neuropsychiatric Inventory (NPI), the Beck Depression Inventory, the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, and the Apathy Evaluation Scale. RESULTS: The prevalence of NPSs in patients with MSA-P was very high, with depression, sleep disturbances, apathy, and anxiety being the most frequently occurring features. The evolution of NPSs was found to be independent of motor, autonomic, and cognitive symptoms. None of the scales measuring NPSs, including the NPI, were capable of detecting changes over the 1-year follow-up period. Although the overall prevalence of depression, apathy, and anxiety obtained from caregivers and the patients themselves was similar, reports from these two sources cannot be considered interchangeable. CONCLUSIONS: The progression of neuropsychiatric symptoms was not a subject of rapid change in MSA-P, in contrast to the observed motor, autonomic, and cognitive deterioration. These findings suggest the need to investigate the utility of available instruments in capturing the evolution of NPSs in MSA over time.

Tracking brain damage in progressive supranuclear palsy: a longitudinal MRI study.

OBJECTIVES: In this prospective, longitudinal, multiparametric MRI study, we investigated clinical as well as brain grey matter and white matter (WM) regional changes in patients with progressive supranuclear palsy-Richardson's syndrome (PSP-RS). METHODS: Twenty-one patients with PSP-RS were evaluated at baseline relative to 36 healthy controls and after a mean follow-up of 1.4 years with clinical rating scales, neuropsychological tests and MRI scans. RESULTS: Relative to controls, patients with PSP-RS showed at baseline a typical pattern of brain damage, including midbrain atrophy, frontal cortical thinning and widespread WM involvement of the main infratentorial and supratentorial tracts that exceeded cortical damage. Longitudinal study showed that PSP-RS exhibited no further changes in cortical thinning, which remained relatively focal, while midbrain atrophy and WM damage significantly progressed. Corpus callosum and frontal WM tract changes correlated with the progression of both disease severity and behavioural dysfunction. CONCLUSIONS: This study demonstrated the feasibility of carrying out longitudinal diffusion tensor MRI in patients with PSP-RS and its sensitivity to identifying the progression of pathology. Longitudinal midbrain volume loss and WM changes are associated with PSP disease course.

Use of the Neuropsychiatric Inventory to Characterize the Course of Neuropsychiatric Symptoms in Progressive Supranuclear Palsy.

The aim of this study was to determine the neuropsychiatric profile in a cohort of progressive supranucelar palsy (PSP) patients and their dynamic changes over a follow-up period of 1 year. A total of 59 patients were assessed at baseline, while 25 of them were accessible after 1 year of the follow-up. The most common symptoms were apathy and depression, which were also found to be, among other variables, the independent determinants of increased Neuropsychiatric Inventory (NPI) total score. Moreover, apathy deteriorated most profoundly over the follow-up period. The NPI seemed to be a sensitive measure of behavioral changes in PSP.

Brain Calcification and Movement Disorders.

Brain calcifications may be an incidental finding on neuroimaging in normal, particularly older individuals, but can also indicate numerous hereditary and nonhereditary syndromes, and metabolic, environmental, infectious, autoimmune, mitochondrial, traumatic, or toxic disorders. Bilateral calcifications most commonly affecting the basal ganglia may often be found in idiopathic cases, and a new term, primary familial brain calcification (PFBC), has been proposed that recognizes the genetic causes of the disorder and that calcifications occurred well beyond the basal ganglia. PFBC, usually inherited in an autosomal dominant fashion, is both an intrafamilial and an interfamilial heterogeneous disorder, clinically characterized by an insidious and progressive development of movement disorders, cognitive decline, and psychiatric symptoms, but also cerebellar ataxia, pyramidal signs, and sometimes isolated seizures and headaches/migraines. Heterozygous mutations in four genes (SLC20A2, PDGFRB, PDGFB, XPR1) have recently proved to be the causes of the autosomal dominant forms of PFBC, also suggesting disrupted phosphate homeostasis as "an underlying and converging" pathophysiological mechanism. However, to date, it is not possible to anticipate with acceptable certainty any of known genetic causes of PFBC on the basis of the type, severity, pattern of distribution, or combination of movement disorders (mainly parkinsonism, with or without tremor, but also dystonia, chorea, paroxysmal kinesigenic dyskinesia, orofacial dyskinesia, and gait and speech disorders).

Minimal change multiple system atrophy: an aggressive variant?

BACKGROUND: Glial cytoplasmic inclusions containing α-synuclein are the pathological hallmark of multiple system atrophy (MSA). Minimal change (MC-MSA) is an unusual MSA subtype with neuronal loss largely restricted to the substantia nigra and locus coeruleus. METHODS: Immunohistochemistry on selected brain regions and semiquantitative assessment were performed on six MC-MSA and eight MSA control cases. RESULTS: More neuronal cytoplasmic inclusions were seen in the caudate and substantia nigra in MC-MSA than in MSA controls (P = 0.002), without any statistical difference in glial cytoplasmic inclusion load in any region. Severe glial cytoplasmic inclusion load was found in the ventrolateral medulla (P = 1.0) and nucleus raphe obscurus (P = 0.4) in both groups. When compared with MSA controls, the three MC-MSA cases who had died of sudden unexpected death had an earlier age of onset (mean: 38 vs. 57.6 y, P = 0.02), a numerically shorter disease duration (mean: 5.3 vs. 8 y, P = 0.2) and a more rapid clinical progression with most of the clinical milestones reached within 3 y of presentation, suggesting an aggressive variant of MSA. Another three MC-MSA cases, who had died of unrelated concurrent diseases, had an age of onset (mean: 57.7 y) and temporal course similar to controls, had less severe neuronal loss and gliosis in the medial and dorsolateral substantia nigra subregions (P < 0.05) than in MSA controls, and could be considered as a unique group with interrupted pathological progression. Significant respiratory dysfunction and early orthostatic hypotension were observed in all MC-MSA cases. CONCLUSIONS: Our findings could suggest that α-synuclein-associated oligodendroglial pathology may lead to neuronal dysfunction sufficient to cause clinical symptoms before overt neuronal loss in MSA. © 2015 International Parkinson and Movement Disorder Society.

Zolpidem improves task-specific dystonia: A randomized clinical trial integrating exploratory transcranial magnetic stimulation and [18F] FDG-PET imaging.

BACKGROUND: Task-specific dystonia (TSFD) is a disabling movement disorder. Effective treatment options are currently limited. Zolpidem was reported to improve primary focal and generalized dystonia in a proportion of patients. The mechanisms underlying its therapeutic effects have not yet been investigated. METHODS: We conducted a randomized, double-blind, placebo-controlled, crossover trial of single-dose zolpidem in 24 patients with TSFD. Patients were clinically assessed using Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), Writers' Cramp Rating Scale (WCRS), and Visual Analogue Scale (VAS), before and after receiving placebo and zolpidem. Transcranial magnetic stimulation was conducted on placebo and zolpidem to compare corticospinal excitability - active and resting motor thresholds (AMT and RMT), resting and active input/output curves and intracortical excitability - cortical silent period (CSP), short-interval intracortical inhibition curve (SICI), long-interval intracortical inhibition (LICI) and intracortical facilitation (ICF). Eight patients underwent brain FDG-PET imaging on zolpidem and placebo. RESULTS: Zolpidem treatment improved TSFD. Zolpidem compared to placebo flattened rest and active input/output curves, reduced ICF and was associated with hypometabolism in the right cerebellum and hypermetabolism in the left inferior parietal lobule and left cingulum. Correlations were found between changes in dystonia severity on WCRS and changes in active input/output curve and in brain metabolism, respectively. Patients with lower RMT, and higher rest and active input/output curves exhibited better response to zolpidem compared to placebo. CONCLUSIONS: Zolpidem improved TSFD by reducing corticomotor output and influencing crucial nodes in higher-order sensory and motor networks.

Case report: Rapid-onset parkinsonism after a hornet sting.

Neurological manifestations with basal ganglia involvement following Hymenoptera stings are rare and clinically ill-defined conditions. We present a patient with acute parkinsonism non-responsive to levodopa, who developed striatal lesions after a hornet sting. We report his response to immunomodulatory treatment and subsequent clinical and brain magnetic resonance imaging (MRI) follow-up. We also searched the literature for patients with acute extrapyramidal syndromes following an insect sting. Fourteen cases have been published; 12 of them are reviewed here. The majority of cases presented with symmetric akinetic syndrome with axial rigidity and/or gait impairment. Six patients were treated with levodopa and only two of these had a modest response to therapy. Brain MRI/computed tomography scan revealed lesions of the basal ganglia, which resulted in fatal outcome in four patients, whereas only one achieved complete recovery. Clinicians should be aware of this rare but devastating cause of acute-onset parkinsonism and specific clinical presentation of this condition, and should consider prompt and prolonged immunomodulatory treatment to prevent irreversible basal ganglia damage.

Multiple system atrophy-parkinsonism with slow progression and prolonged survival: a diagnostic catch.

BACKGROUND: Multiple system atrophy (MSA) is a neurodegenerative disease leading to severe physical impairment, with a disease duration from onset to death of 6-9 years. METHODS: The clinical and neuropathological features of 4 MSA cases with disease duration of 15 years or more were analyzed. RESULTS: All patients presented with parkinsonism and had a mean latency of 11 years before the development of dysautonomia. Mean duration from onset of first symptoms to anterocollis, inspiratory stridor, and dysphagia was 9 years. Despite the limited levodopa response, all patients developed levodopa-induced dyskinesia. CONCLUSIONS: Late appearance of dysautonomia is a favorable prognostic factor in MSA-P. Greater awareness of this uncommon "benign" subgroup of MSA will improve diagnostic accuracy and help to more accurately inform treatment options.

Functional MRI connectivity of the primary motor cortex in functional dystonia patients.

BACKGROUND: Functional movement disorders include a wide spectrum of clinically documented movement disorders without an apparent organic substrate. OBJECTIVE: To explore the functional connectivity (FC) of the primary motor (M1) cortex in functional dystonia (FD) patients relative to healthy controls, with a focus on different clinical phenotypes. METHODS: Forty FD patients (12 fixed [FixFD]; 28 mobile [MobFD]) and 43 healthy controls (14 young FixFD-age-matched [yHC]; 29 old MobFD-age-matched [oHC]) underwent resting state fMRI. A seed-based FC analysis was performed using bilateral M1 as regions of interest. RESULTS: Compared to controls, FD patients showed reduced FC between left M1 and left dorsal anterior cingulate cortex, and between right M1 and left M1, premotor/supplementary motor area (SMA), dorsal posterior cingulate cortex (PCC), and bilateral precuneus. Relative to yHC, FixFD patients showed reduced FC between M1 and precuneus bilaterally. Compared to oHC, MobFD patients revealed reduced FC between right M1 and left M1, premotor/SMA, dorsal-PCC, bilateral primary sensory cortices and parieto-occipital areas, and increased FC of right M1 with right associative visual cortex and bilateral ventral-PCC. FixFD patients, relative to MobFD, showed lower FC between the right M1 and right associative visual area, and bilateral precuneus and ventral-PCC. CONCLUSIONS: This study suggests an altered brain FC of the motor circuit with areas involved in emotional processes and sense of agency in FD. FixFD patients showed FC abnormalities mainly in areas related to sense of agency, while MobFD in regions involved in sensorimotor functions (reduced FC) and emotional processing (increased FC).

Cognitive impairment and structural brain damage in multiple system atrophy-parkinsonian variant.

In this multiparametric, cross-sectional study, we aimed to investigate cognitive impairment and brain structural changes in patients with multiple system atrophy (MSA)-parkinsonian variant (MSA-p). Twenty-six MSA-p patients and 19 controls underwent clinical and neuropsychological evaluation and 1.5 T brain MRI scan. Cortical thickness measures and volumes of deep grey matter structures were obtained. A regression analysis correlated MRI metrics with clinical features in MSA-p patients. Almost 46% of MSA-p patients showed a mild cognitive impairment involving mainly attentive-executive and memory domains. Apathy and depression were found in half of MSA-p patients. MSA-p patients showed significant cortical thinning of fronto-temporal-parietal regions and atrophy of periaqueductal grey matter, left cerebellar hemisphere, left pallidum and bilateral putamen, compared to controls. Cortical thinning in temporal regions correlated with global cognitive status and memory impairment. Grey matter cerebellar atrophy correlated with motor deficits. MSA-p patients showed a multidomain cognitive impairment with a prominent cortical damage in anterior more than posterior brain regions and grey matter volume reduction in subcortical structures. Cortical and subcortical structural changes might lead to cognitive dysfunction in MSA-p.

Characteristics of two distinct clinical phenotypes of functional (psychogenic) dystonia: follow-up study.

BACKGROUND: The fixed dystonia phenotype was originally established as a prototype of functional dystonia. Nevertheless, in recent reports different functional dystonia phenotypes have been recognized with dystonic movement comprising phasic instead of tonic contraction. OBJECTIVES: To examine clinical characteristic in all patients with dystonia who fulfilled the criteria for functional movement disorders irrespective of phenotype in an attempt to determine parameters of clinical presentations that might impact the disease progression pattern and outcome. METHODS: Patients presented with dystonia features incompatible with organic disease without other features required for the diagnosis of functional movement disorders were analyzed and prospectively followed-up. The two-step cluster analysis was performed to obtain the subgroups of dystonia phenotypes. RESULTS: The two-step cluster analysis extracted two subgroup of patients. Patients of the first cluster (68.8%) presented with "mobile" dystonia (84.9%), of cranial/neck/trunk localization (90.9%), fluctuated clinical course (69.7%), with frequent additional movement or other functional neurological disorders (63.6%) during follow-up. In the second cluster (31.2%) all of the patients presented with "fixed" dystonia of extremities, and the clinical course was characterized by either the disease progression (60%), or continuous without improvement (26.7%), and rare occurrence of additional functional neurological disorders (13.3%). CONCLUSION: In terms of clinical and demographic features as well as pattern of disease progression there are two clinical phenotypes in patients with functional dystonia. Distinctive features of incongruence and inconstancy are characteristic for "mobile" functional dystonia subgroup of patients.

Factors associated with deterioration of health-related quality of life in multiple system atrophy: 1-year follow-up study.

The aim of this study was to identify the main contributors to the health-related quality of life (HRQoL) in multiple system atrophy with predominant parkinsonism (MSA-P) and to determine the usefulness of SF-36 in capturing the HRQoL changes over 1-year follow-up. A total of 45 MSA-P and 150 Parkinson's disease (PD) patients were studied. The hierarchical multiple regression analysis was conducted to identify predictors of the SF-36 total score. The magnitude of any change for the HRQoL over 1-year of follow-up, was calculated as an effect size. The average scores for each SF-36 domains, except for the bodily pain, were lower in MSA-P than in PD patients (p < 0.05). The most important predictors of HRQoL in MSA-P, were female gender, older age at onset, SCOPA-AUT score and UMSARS IV, which together with other selected clinical variables accounted for 84% of the variance in the total SF-36 score in the final model in hierarchical analyses. During the 1-year follow-up, the SF 36 was found capable of detecting changes in MSA-P. Our study provided some new insights into potential predictors of the HRQoL and its longitudinal changes in MSA-P, which should be considered when healthcare programs are developed.

Identification of novel variants in LRRK2 gene in patients with Parkinson's disease in Serbian population.

BACKGROUND: Mutations in LRRK2 (leucine-rich repeat kinase 2) are the most common cause of autosomal dominant Parkinson's disease (PD). Large international studies have revealed that pathogenic mutations are clustered in several exons coding for functional domains of LRRK2 protein, but the mutation frequency differs among populations. Systematic study of LRRK2 mutation prevalence and phenotype in Serbian population has not been performed. METHODS: Comprehensive mutation screening of selected exons of LRRK2 was performed in 486 Serbian PD patients. RESULTS: Previously reported mutations I1371V and G2019S were identified in a single patient each, and c.4536+3A>G substitution in two patients. G2019S is the most common, pathogenic mutation, while pathogenic roles for recurrent variants I1371V and c.4536+3A>G are not confirmed yet. Two novel variants S1508G and I1991V were discovered in 2 unrelated patients. These variants are considered as disease causing according to several software predictions, but additional segregation and functional analyses are required. CONCLUSIONS: Mutation frequency in our study (1.23%) was similar to other European populations, although the most common mutations were underestimated and novel variants were detected. In most cases, symptoms of LRRK2-PD are similar to sporadic PD, so estimation of frequency and penetrance of mutations in different populations is important for efficient genetic testing strategy and counseling.

Clinical outcomes of two main variants of progressive supranuclear palsy and multiple system atrophy: a prospective natural history study.

Progressive supranuclear palsy (PSP) and parkinsonian subtype of multiple system atrophy (MSA-P) are, after Parkinson's disease (PD), the most common forms of neurodegenerative parkinsonism. Clinical heterogeneity of PSP includes two main variants, Richardson syndrome (PSP-RS) and PSP-parkinsonism (PSP-P). Clinical differentiation between them may be impossible at least during the first 2 years of the disease. Little is known about the differences in natural course of PSP-RS and PSP-P and, therefore, in this study we prospectively followed the clinical outcomes of consecutive, pathologically unconfirmed patients with the clinical diagnoses of PSP-RS (51 patients), PSP-P (21 patients) and MSA-P (49 patients). Estimated mean survival time was 11.2 years for PSP-P, 6.8 years for PSP-RS, and 7.9 years for MSA-P, where a 5-year survival probabilities were 90, 66 and 78 %, respectively. More disabling course of PSP-RS compared to PSP-P was also highlighted through the higher number of milestones reached in the first 3 years of the disease, as well as in the trend to reach all clinical milestones earlier. We found that PSP-P variant had a more favorable course with longer survival, not only when compared to PSP-RS, but also when compared to another form of atypical parkinsonism, MSA-P.

Characteristic "Forcible" Geste Antagoniste in Oromandibular Dystonia Resulting From Pantothenate Kinase-Associated Neurodegeneration.

Geste antagonistes are usually considered typical of primary dystonia, although rarely they have been described in secondary/heredodegenerative dystonias. We have recently come across a particular geste antagoniste in 5 of 10 patients with pantothenate kinase-associated neurodegeneration (PKAN) who had prominent oromandibular involvement with severe jaw-opening dystonia. It consists of touching the chin with both hands characteristically clenched into a fist with flexion at the elbows. Because of the resemblance of this geste antagoniste with the praying-like posture of Mantis religiosa, we coined the term "mantis sign." Reviewing videos of PKAN cases in literature, including what is considered the first cinematic depiction of a case of this disorder, 3 additional cases with akin maneuvers were identified. In contrast, examining 205 videos of non-PKAN dystonic patients from our database for the presence of a similar maneuver was unrevealing. Thus, we consider the mantis sign to be quite typical of PKAN and propose it to be added as a clinical hint toward diagnosis.

[Superficial siderosis: case report and literature review].

INTRODUCTION: Superficial siderosis (SS) is caused by chronic subarachnoid bleeding and is characterized by free iron and hemosiderin deposition along the pial and subpial structures of central nervous system. SS leads to progressive and irreversible CNS damage. The most common causes of chronic subarachnoidal bleeding are tumors, head and spinal cord trauma, arteriovenous malformations and aneurysms. SS is characterized by clinical triad: sensorineural hearing loss, cerebellar ataxia and piramydal signs. Brain MR imaging is the investigation of choice for the diagnosis of SS.Typical findings include hypointensities seen on T2-weighted MR imaging around the brain, cerebellum, brain stem, spinal cord, VIII cranial nerve and atrophy of cerebellum and medulla. CASE OUTLINE: A 71-year-old female patient noticed hand tremor in the middle of the third decade of life, and later slowly progressive bilateral hearing loss. At the age of 64 she developed unsteady gate, hand clumsiness and dysarthria, to became incapable of independent walking and standing five years later. Clinical course and brain MRI findings were typical for SS, but additional investigation did not reveal the couse of subarahnoidal bleeding. CONCLUSION: SS represents a rare and under-recognized condition that must be considered in all patients with cerebellar syndrome of unknown cause. Early diagnosis of SS in some cases with identified cause of chronic bleeding allowes therapeutic interventions that may prevent further progression of the disease.

MM2 subtype of sporadic Creutzfeldt-Jakob disease may underlie the clinical presentation of progressive supranuclear palsy.

The classical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) is rapid progressive dementia often associated with myoclonus and ataxia followed by death in less than a year from diagnosis. The few patients in the literature who presented with parkinsonism and who were suspected to have progressive supranuclear palsy (PSP) all ran a malignant course and most of them died within 3 years of diagnosis. We screened the Queen Square Brain Bank database and, among 213 patients with a clinical diagnosis of PSP, we found ten patients with 3 years or less disease duration, including one patient with CJD pathology. We report this patient and review other similar cases from the literature. Ten additional cases with similar presentation were identified in the literature. The mean disease duration was 24.2 months. The classical clinical, radiological and laboratory findings for sCJD were absent in the majority of these cases. Clinical presentation of these patients consists of: early falls, prominent dementia, early vertical supranuclear gaze palsy and symmetric akinetic syndrome. In the patients who were subtyped at post-mortem, all four represented the MM2 subtype of sCJD. A rapidly progressive course of PSP with early falls, cognitive impairments and vertical supranuclear gaze palsy should raise suspicion of underlying sCJD pathology regardless of absence of supportive findings on ancillary tests. This case and the literature support the notion that biochemical properties of the prion protein can influence the clinical presentation of sCJD.

Mutation screening of the DYT6/THAP1 gene in Serbian patients with primary dystonia.

Primary dystonia (PrD) is characterized by sustained muscle contractions, causing twisting and repetitive movements and abnormal postures. Besides DYT1/TOR1A gene, DYT6/THAP1 gene is the second gene known to cause primary pure dystonia. We screened 281 Serbian primary dystonia patients and 106 neurologically healthy control individuals for the GAG deletion in TOR1A gene and for mutations in THAP1 gene by direct sequencing. Nine subjects were found to have the GAG deletion in TOR1A gene. Four coding mutations, including two novel mutations, were identified in the THAP1 gene in five unrelated patients. Two mutations were missense, one was nonsense, and one was 24 bp duplication. None of the coding mutations were seen in 106 control individuals. In addition, one novel nucleotide change in the 5'UTR region of THAP1 gene was detected in two unrelated patients. The mutation frequency of THAP1 gene in Serbian patients with primary dystonia was 1.8 %, similar to the mutation frequency in other populations. Most of the patients reported here with THAP1 mutations had the clinical features of predominantly laryngeal or oromandibular dystonia. Our data expand the genotypic spectrum of THAP1 and strengthen the association with upper body involvement, including the cranial and cervical regions that are usually spared in DYT1-PrD.

[Mitochondrial myopathy, encephalopathy, lactate acidosis with stroke-like episodes syndrome (MELAS): a case report].

INTRODUCTION: Mitochondrial encephalopathy, lactacidosis and stroke-like episodes (MELAS) represent a multisystemic dysfunction due to various mutations in mitochondrial DNA. Here we report a patient with genetically confirmed MELAS. CASE OUTLINE: A patient is presented whose clinical features involved short stature, easy tendency to fatigue, recurrent seizures, progressive cognitive decline, myopathy, sensorineural deafness, diabetes mellitus as well as stroke-like episodes. The major clinical feature of migraine type headache was not present. Neuroimaging studies revealed signs of ischemic infarctions localized in the posterior regions of the brain cortex. Electron microscopy of the skeletal muscle biopsy showed subsarcolemmal accumulation of a large number of mitochondria with paracristal inclusions in the skeletal muscle cells. The diagnosis of MELAS was definitively confirmed by the detection of a specific point mutation A to G at nucleotide position 3243 of mitochondrial DNA. CONCLUSION: When a relatively young patient without common risk factors for ischemic stroke presents with signs of occipitally localized brain infarctions accompanied with multisystemic dysfunction, MELAS syndrome, it is necessary to conduct investigations in order to diagnose the disease.