What do patients with scans without evidence of dopaminergic deficit (SWEDD) have? New evidence and continuing controversies.

The term SWEDD (scans without evidence for dopaminergic deficit) refers to the absence, rather than the presence, of an imaging abnormality in patients clinically presumed to have Parkinson's disease (PD). However, such a term has since been widely used in the medical literature, even as a diagnostic label. While many authors have suggested that different disorders of PD lookalikes may account for a proportion of SWEDD cases, others have claimed that some of them may have a benign subtype of PD. Thus, there has been ensuing controversy and confusion and the use of this term continues without clarity of what it represents. We have systematically reviewed all the studies involving patients with SWEDD with the aim of shedding light on what these patients actually have. It becomes clear from this systematic review that while most 'SWEDD' cases are due to a clinical misdiagnosis of PD, there exists a small proportion of patients with SWEDD who may have PD on the basis of a positive levodopa response, clinical progression, imaging and/or genetic evidence. The latter challenge the seemingly incontrovertible relationship between dopaminergic tracer binding and the diagnosis of nigrostriatal parkinsonism, particularly PD. Patients with SWEDD are unlikely to reflect a single clinical entity and we suggest that the term SWEDD should be abandoned.

Development and validation of a carers quality-of-life questionnaire for parkinsonism (PQoL Carers).

PURPOSE: Atypical parkinsonism (AP) has a considerable impact on the lives not only of patients but also of their carers. The aim of this study was to develop an instrument for assessing the quality of life (QoL) of carers of patients with AP. METHODS: A 40-item pool was generated from in-depth interviews with carers of patients with AP, a thorough review of the existing literature and consultation with movement disorder experts. Item refinement and reduction was performed using the results of pilot testing and a survey in 282 carers of multiple system atrophy (MSA) patients and 226 carers of progressive supranuclear palsy (PSP) patients. A validation study, with responses of 243 carers of MSA and 187 carers of PSP patients, was undertaken to evaluate the psychometric properties of the final 26-item scale. RESULTS: The validation study results suggest that the scale is unidimensional and has high internal consistency (Cronbach's α = 0.96). The correlations of scale scores with patients' health status and QoL measures, such as PDQ-39 summary score and EQ-5D index (Spearman's ρ = 0.56 and -0.31, respectively, P < 0.001), as well as carers' measures, such as Caregiver Burden Inventory (CBI) total and EQ-5D index (Spearman's ρ = 0.85 and -0.39, respectively, P < 0.001), document the convergent and concurrent validity of the scale. ANOVA results support the discriminant validity of the scale, as evidenced by its capacity to differentiate between carers with varying levels of self-reported health. CONCLUSIONS: The 26-item Parkinsonism Carers QoL (PQoL Carer) is a concise instrument with adequate psychometric qualities that can be used for clinical and research purposes.

H-ABC syndrome and DYT4: Variable expressivity or pleiotropy of TUBB4 mutations?

Recently, mutations in the TUBB4A gene have been found to underlie hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) syndrome, a rare neurodegenerative disorder of infancy and childhood. TUBB4A mutations also have been described as causative of DYT4 ("hereditary whispering dysphonia"). However, in DYT4, brain imaging has been reported to be normal and, therefore, H-ABC syndrome and DYT4 have been construed to be different disorders, despite some phenotypic overlap. Hence, the question of whether these disorders reflect variable expressivity or pleiotropy of TUBB4A mutations has been raised. We report four unrelated patients with imaging findings either partially or totally consistent with H-ABC syndrome, who were found to have TUBB4A mutations. All four subjects had a relatively homogenous phenotype characterized by severe generalized dystonia with superimposed pyramidal and cerebellar signs, and also bulbar involvement leading to complete aphonia and swallowing difficulties, even though one of the cases had an intermediate phenotype between H-ABC syndrome and DYT4. Genetic analysis of the TUBB4A gene showed one previously described and two novel mutations (c.941C>T; p.Ala314Val and c.900G>T; p.Met300Ile) in the exon 4 of the gene. While expanding the genetic spectrum of H-ABC syndrome, we confirm its radiological heterogeneity and demonstrate that phenotypic overlap with DYT4. Moreover, reappraisal of previously reported cases would also argue against pleiotropy of TUBB4A mutations. We therefore suggest that H-ABC and DYT4 belong to a continuous phenotypic spectrum associated with TUBB4A mutations.

"Atypical" atypical parkinsonism: new genetic conditions presenting with features of progressive supranuclear palsy, corticobasal degeneration, or multiple system atrophy-a diagnostic guide.

Recently, a number of genetic parkinsonian conditions have been recognized that share some features with the clinical syndromes of progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA), the classic phenotypic templates of atypical parkinsonism. For example, patients with progranulin, dynactin, or ATP13A gene mutations may have vertical supranuclear gaze palsy. This has made differential diagnosis difficult for practitioners. In this review, our goal is to make clinicians aware of these genetic disorders and provide clinical clues and syndromic associations, as well as investigative features, that may help in diagnosing these disorders. The correct identification of these patients has important clinical, therapeutic, and research implications. © 2013 Movement Disorder Society.

Development and Validation of a Prognostic Model to Predict Overall Survival in Multiple System Atrophy.

Background: Multiple system atrophy (MSA) is a devastating disease characterized by a variable combination of motor and autonomic symptoms. Previous studies identified numerous clinical factors to be associated with shorter survival. Objective: To enable personalized patient counseling, we aimed at developing a risk model of survival based on baseline clinical symptoms. Methods: MSA patients referred to the Movement Disorders Unit in Innsbruck, Austria, between 1999 and 2016 were retrospectively analyzed. Kaplan-Meier curves and multivariate Cox regression analysis with least absolute shrinkage and selection operator penalty for variable selection were performed to identify prognostic factors. A nomogram was developed to estimate the 7 years overall survival probability. The performance of the predictive model was validated and calibrated internally using bootstrap resampling and externally using data from the prospective European MSA Study Group Natural History Study. Results: A total of 210 MSA patients were included in this analysis, of which 124 patients died. The median survival was 7 years. The following clinical variables were found to significantly affect overall survival and were included in the nomogram: age at symptom onset, falls within 3 years of onset, early autonomic failure including orthostatic hypotension and urogenital failure, and lacking levodopa response. The time-dependent area under curve for internal and external validation was >0.7 within the first 7 years of the disease course. The model was well calibrated showing good overlap between predicted and actual survival probability at 7 years. Conclusion: The nomogram is a simple tool to predict survival on an individual basis and may help to improve counseling and treatment of MSA patients.

The Unified Multiple System Atrophy Rating Scale: intrarater reliability.

BACKGROUND: The Unified Multiple System Atrophy Rating Scale (UMSARS) was developed to provide a surrogate measure of disease progression in multiple system atrophy. In the present study, the intrarater agreement of the motor examination part of the UMSARS was determined. METHODS: All patients were first examined face to face, while being video-recorded, by two senior and two junior investigators. The patients' videotaped examinations were reevaluated after 3 months. Intrarater reliability for each item was analyzed by kappa statistics. RESULTS: Overall weighted kappa (κ) values were at least substantial or excellent for all UMSARS motor examination items, except for ocular motor dysfunction, which showed only moderate intrarater agreement. Intrarater reliability was comparable between senior and junior raters, with all κ differences being ≤ 0.22. CONCLUSIONS: The motor examination part of the UMSARS was found to have satisfactory intrarater reliability in the present cohort.

Tremor--some controversial aspects.

The commonest cause of pathological tremor is essential tremor (ET). However, it has proved difficult to identify genetic mutations causing ET, particularly because other causes of tremor continue to be misdiagnosed as ET. Whether subjects with dystonia or Parkinson's disease (PD) carry an increased genetic risk of developing ET, or vice versa, is controversial. In addition, the notion of a separate disorder of benign tremulous parkinsonism (BTP) has been debated. This article gives a selective viewpoint on some areas of uncertainty and controversy in tremor.

Deep brain stimulation effects in dystonia: time course of electrophysiological changes in early treatment.

Deep brain stimulation to the internal globus pallidus is an effective treatment for primary dystonia. The optimal clinical effect often occurs only weeks to months after starting stimulation. To better understand the underlying electrophysiological changes in this period, we assessed longitudinally 2 pathophysiological markers of dystonia in patients prior to and in the early treatment period (1, 3, 6 months) after deep brain stimulation surgery. Transcranial magnetic stimulation was used to track changes in short-latency intracortical inhibition, a measure of excitability of GABA(A) -ergic corticocortical connections and long-term potentiation-like synaptic plasticity (as a response to paired associative stimulation). Deep brain stimulation remained on for the duration of the study. Prior to surgery, inhibition was reduced and plasticity increased in patients compared with healthy controls. Following surgery and commencement of deep brain stimulation, short-latency intracortical inhibition increased toward normal levels over the following months with the same monotonic time course as the patients' clinical benefit. In contrast, synaptic plasticity changed rapidly, following a nonmonotonic time course: it was absent early (1 month) after surgery, and then over the following months increased toward levels observed in healthy individuals. We postulate that before surgery preexisting high levels of plasticity form strong memories of dystonic movement patterns. When deep brain stimulation is turned on, it disrupts abnormal basal ganglia signals, resulting in the absent response to paired associative stimulation at 1 month. Clinical benefit is delayed because engrams of abnormal movement persist and take time to normalize. Our observations suggest that plasticity may be a driver of long-term therapeutic effects of deep brain stimulation in dystonia.

Graft-induced dyskinesias in Parkinson's disease: High striatal serotonin/dopamine transporter ratio.

Graft-induced dyskinesias are a serious complication after neural transplantation in Parkinson's disease. One patient with Parkinson's disease, treated with fetal grafts 14 years ago and deep brain stimulation 6 years ago, showed marked improvement of motor symptoms but continued to suffer from OFF-medication graft-induced dyskinesias. The patient received a series of clinical and imaging assessments. Positron emission tomography and single-photon emission computed tomography 14 years posttransplantation revealed an elevated serotonin/dopamine transporter ratio in the grafted striatum compatible with serotonergic hyperinnervation. Inhibition of serotonin neuron activity by systemic administration of a 5-HT(1A) agonist suppressed graft-induced dyskinesias. Our data provide further evidence that serotonergic neurons mediate graft-induced dyskinesias in Parkinson's disease. Achieving a normal striatal serotonin/dopamine transporter ratio following transplantation of fetal tissue or stem cells should be necessary to avoid the development of graft-induced dyskinesias.

IQGAP1 Is a Scaffold of the Core Proteins of the Hippo Pathway and Negatively Regulates the Pro-Apoptotic Signal Mediated by This Pathway.

The Hippo pathway regulates a complex signalling network which mediates several biological functions including cell proliferation, organ size and apoptosis. Several scaffold proteins regulate the crosstalk of the members of the pathway with other signalling pathways and play an important role in the diverse output controlled by this pathway. In this study we have identified the scaffold protein IQGAP1 as a novel interactor of the core kinases of the Hippo pathway, MST2 and LATS1. Our results indicate that IQGAP1 scaffolds MST2 and LATS1 supresses their kinase activity and YAP1-dependent transcription. Additionally, we show that IQGAP1 is a negative regulator of the non-canonical pro-apoptotic pathway and may enable the crosstalk between this pathway and the ERK and AKT signalling modules. Our data also show that bile acids regulate the IQGAP1-MST2-LATS1 signalling module in hepatocellular carcinoma cells, which could be necessary for the inhibition of MST2-dependent apoptosis and hepatocyte transformation.

Reckless generosity in Parkinson's disease.

There is an increasing awareness of impulsive-compulsive phenomena in patients treated for Parkinson's disease (PD). We describe another, potentially related phenomenon putatively associated with the use of dopamine agonists in 3 patients with PD, characterized by excessive and inappropriate philanthropy.

ATP13A2 mutations (PARK9) cause neurodegeneration with brain iron accumulation.

Kufor Rakeb disease (KRD, PARK9) is an autosomal recessive extrapyramidal-pyramidal syndrome with generalized brain atrophy due to ATP13A2 gene mutations. We report clinical details and investigational results focusing on radiological findings of a genetically-proven KRD case. Clinically, there was early onset levodopa-responsive dystonia-parkinsonism with pyramidal signs and eye movement abnormalities. Brain MRI revealed generalized atrophy and putaminal and caudate iron accumulation bilaterally. Our findings add KRD to the group of syndromes of neurodegeneration with brain iron accumulation (NBIA). KRD should be considered in patients with dystonia-parkinsonism with iron on brain imaging and we suggest classifying as NBIA type 3.

Nonmotor symptoms in Parkin gene-related parkinsonism.

The aim of the study was to explore the prevalence and differences of nonmotor symptoms (NMSs) in patients with young-onset Parkinson's disease (YOPD) with and without mutations in the Parkin gene and late-onset Parkinson's disease (LOPD). Twenty-seven patients with YOPD and 27 with LOPD, as well as 16 patients with homozygous or compound heterozygote Parkin mutations filled in the nonmotor symptoms questionnaire, a 30-item self-completed questionnaire that addresses various NMSs. Overall, NMSs were more prevalent in YOPD (12.07 +/- 3.9; P = 0.009) and LOPD (13.26 +/- 5.8; P = 0.001) compared with Parkin mutation carriers (7.38 +/- 4.2). Dribbling of saliva, vivid dreams, loss of smell, and urinary urgency were more prevalent in YOPD compared with Parkin mutation carriers. Only anxiety was more prevalent in the latter. Apart from anxiety, NMSs appear to be less prevalent in Parkin gene-related parkinsonism. Although these results need further study, the presented data might be helpful in the clinical recognition of specific phenotypes and genotypes in YOPD. The data are in keeping with a different pathological disease process in Parkin gene-related parkinsonism.

A comparison of depression, anxiety, and health status in patients with progressive supranuclear palsy and multiple system atrophy.

The objective of this study was to compare subjective health status and its correlates in progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). One hundred eighty-eight patients with PSP and 286 patients with MSA completed EQ-5D and Hospital Depression and Anxiety Scale. The impact on mobility, usual activities, and self-care was similarly high in both groups after similar duration. Fifty-six percent of PSP and 43% of MSA had probable depression, and 37% of both groups had probable anxiety. Patients with PSP had significantly higher depression scores, but groups did not differ in anxiety scores. Patients with MSA had significantly greater pain/discomfort than patients with PSP. The most important association with subjective health status was with depressive symptoms, which accounted for 38% and 29% of EQ-5D variance in patients with PSP and MSA, followed by disease severity and anxiety scores. We conclude that depressive symptoms were common in both disorders, but more severe in PSP. Anxiety symptoms affected 37% of patients in both groups and contributed to impaired subjective health status. Pain was more problematic in MSA than PSP.

Long-term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson's disease.

We report the 5 to 6 year follow-up of a multicenter study of bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) in advanced Parkinson's disease (PD) patients. Thirty-five STN patients and 16 GPi patients were assessed at 5 to 6 years after DBS surgery. Primary outcome measure was the stimulation effect on the motor Unified Parkinson's Disease Rating Scale (UPDRS) assessed with a prospective cross-over double-blind assessment without medications (stimulation was randomly switched on or off). Secondary outcomes were motor UPDRS changes with unblinded assessments in off- and on-medication states with and without stimulation, activities of daily living (ADL), anti-PD medications, and dyskinesias. In double-blind assessment, both STN and GPi DBS were significantly effective in improving the motor UPDRS scores (STN, P < 0.0001, 45.4%; GPi, P = 0.008, 20.0%) compared with off-stimulation, regardless of the sequence of stimulation. In open assessment, both STN- and GPi-DBS significantly improved the off-medication motor UPDRS when compared with before surgery (STN, P < 0.001, 50.5%; GPi, P = 0.002, 35.6%). Dyskinesias and ADL were significantly improved in both groups. Anti-PD medications were significantly reduced only in the STN group. Adverse events were more frequent in the STN group. These results confirm the long-term efficacy of STN and GPi DBS in advanced PD. Although the surgical targets were not randomized, there was a trend to a better outcome of motor signs in the STN-DBS patients and fewer adverse events in the GPi-DBS group.

A validation exercise on the new consensus criteria for multiple system atrophy.

The revised (new) consensus clinical diagnostic criteria for multiple system atrophy (MSA) were published in 2008. To validate these criteria, we utilized the same cohort that we reported previously, which included 59 patients with a clinical diagnosis of MSA that was confirmed neuropathologically in 51 of them at the Queen Square Brain Bank for Neurological Disorders. At the first clinic visit, sensitivity with new consensus possible category was higher, and PPV marginally higher, than for clinical diagnosis and old consensus possible category. New consensus probable category showed marginally higher sensitivity than, and the same PPV as, old consensus probable category. At the last clinic visit, new consensus possible category had exactly the same sensitivity and only marginally higher PPV compared with old consensus possible category. New consensus probable category showed the same sensitivity and PPV as old consensus probable category. Our data indicate that in this case material the new consensus criteria for possible MSA could improve diagnostic accuracy at first neurological evaluation compared with the old consensus criteria. Prospective clinicopathological validation studies of the new consensus criteria, particularly incorporating in vivo structural and functional imaging results, are required to extend the current findings.

Nigrostriatal dysfunction in homozygous and heterozygous parkin gene carriers: an 18F-dopa PET progression study.

Little is known about the rate of progression of striatal dysfunction in subjects with parkin-linked parkinsonism. Being a heterozygous parkin gene carrier may confer susceptibility to Parkinson's disease (PD). In a previous (18)F-dopa PET study, we reported that 69% of carriers of a single parkin mutation showed subclinical loss of putamen dopaminergic function. Using serial (18)F-dopa PET, the present longitudinal study addresses rates of progression of nigrostriatal dysfunction in both compound heterozygous (parkin-linked parkinsonism) and single heterozygous parkin gene carriers. Three symptomatic patients who were compound heterozygotes for parkin gene mutations and six asymptomatic heterozygous carriers were clinically assessed and had (18)F-dopa PET at baseline and again after 5 years. The patients with symptomatic parkin showed a mean 0.5% annual reduction in putamen (18)F-dopa uptake over 5 years while caudate (18)F-dopa uptake declined by a mean annual rate of 2 %. The asymptomatic heterozygote gene carriers showed a mean 0.56% annual reduction in putamen and 0.62 % annual reduction in caudate (18)F-dopa uptake. Neurological examination at both baseline and follow-up showed no evidence of parkinsonism. Loss of nigrostriatal dysfunction in parkin-linked parkinsonism occurs at a very slow rate compared to the 9-12% annual loss of putamen (18)F-dopa uptake reported for idiopathic PD. Although subclinical reductions of striatal (18)F-dopa uptake are common in carriers of a single parkin mutation their slow rate of progression suggests that few if any of these will develop clinical parkinsonism.

GLUT1 gene mutations cause sporadic paroxysmal exercise-induced dyskinesias.

Paroxysmal exercise-induced dyskinesias (PED) are involuntary intermittent movements triggered by prolonged physical exertion. Autosomal dominant inheritance may occur. Recently, mutations in the glucose transporter 1 (GLUT1) gene (chr. 1p35-p31.3) have been identified as a cause in some patients with autosomal dominant PED. Mutations in this gene have previously been associated with the GLUT1 deficiency syndrome. We performed mutational analysis in 10 patients with apparently sporadic PED. We identified two novel GLUT1 mutations, at least one likely to be de-novo, in two of our patients. Onset was in early childhood. One of our patients had a predating history of childhood absence epilepsy and a current history of hemiplegic migraine as well as a family history of migraine. The other patient had no other symptoms apart from PED. Brain MRI showed cerebellar atrophy in one case. Mutations in GLUT1 are one cause of apparently sporadic PED. The detection of this has important implications for treatment as ketogenic diet has been reported to be beneficial.

Quality of life in Parkinson's disease: the relative importance of the symptoms.

A body of literature now exists, which demonstrates that idiopathic Parkinson's disease (PD) has a major negative impact on quality of life (QoL), and that depression and cognitive impairment are among the main predictors of poor QoL in this disorder. Relatively little work has been done to assess the differential contribution of the specific symptoms of PD to QoL, which was the aim of this study. One hundred thirty patients with PD completed a booklet of questionnaires, which included the PDQ39 as a disease-specific measure of QoL, a symptom checklist, a mobility checklist, as well as patient ratings of disease stage and disability. The results indicated that the contribution of physical, medication-related, and cognitive/psychiatric symptoms to QoL can be significant. Sudden unpredictable on/off states, difficulty in dressing, difficulty in walking, falls, depression, and confusion were PD symptoms, which significantly influenced QoL scores. Among the mobility problems associated with PD, start hesitation, shuffling gait, freezing, festination, propulsion, and difficulty in turning had a significant effect on QoL scores. In addition to depression and anxiety, the major predictors of QoL were shuffling, difficulty turning, falls, difficulty in dressing, fatigue, confusion, autonomic disturbance particularly urinary incontinence, unpredictable on/off fluctuations, and sensory symptoms such as pain. The implications of these results for the medical management of PD are discussed.