Distinct functional classes of PDGFRB pathogenic variants in primary familial brain calcification.

Platelet-derived growth factor receptor beta (PDGFRB) is one of the genes associated with primary familial brain calcification (PFBC), an inherited neurological disease (OMIM:173410). Genetic analysis of patients and families revealed at least 13 PDGFRB heterozygous missense variants, including two novel ones described in the present report. Limited experimental data published on five of these variants had suggested that they decrease the receptor activity. No functional information was available on the impact of variants located within the receptor extracellular domains. Here, we performed a comprehensive molecular analysis of PDGFRB variants linked to PFBC. Mutated receptors were transfected in various cell lines to monitor receptor expression, signaling, mitogenic activity and ligand binding. Four mutants caused a complete loss of tyrosine kinase activity in multiple assays. One of the novel variants, p.Pro154Ser, decreased the receptor expression and abolished binding of platelet-derived growth factor (PDGF-BB). Others showed a partial loss of function related to reduced expression or signaling. Combining clinical, genetic and molecular data, we consider nine variants as pathogenic or likely pathogenic, three as benign or likely benign and one as a variant of unknown significance. We discuss the possible relationship between the variant residual activity, incomplete penetrance, brain calcification and neurological symptoms. In conclusion, we identified distinct molecular mechanisms whereby PDGFRB variants may result in a receptor loss of function. This work will facilitate genetic counseling in PFBC.

From Dreams to Hallucinations: Jean Lhermitte's Contribution to the Study of Peduncular Hallucinosis and the Dissociation of States.

Jean Lhermitte (1877-1959) was one of the pioneers of behavioral neurology, including the field of hallucinations. This article focuses on his work concerning the relationship between hallucinations, sleep, and dreams. From 1910, Lhermitte became interested in sleep and its disorders, particularly narcolepsy and its accompanying symptoms. He also reported on sleep disorders and hallucinations occurring in people with lesions of the diencephalic region ("infundibular syndrome"), and later encephalitis lethargica. In 1922, he described a syndrome of complex, predominantly visual hallucinations in patients with vascular damage to the midbrain, known as peduncular hallucinosis. Twelve historical cases of peduncular hallucinosis, including 10 from Lhermitte, are reviewed. He gave a precise phenomenological description of peduncular hallucinosis, and put forward the hypothesis that the lesion disrupted the anatomy and connections of a center regulating wakefulness and sleep, thus enabling a dissociation of the mechanisms of dream and waking states. Although the pathophysiology of peduncular hallucinosis remains to this day partly obscure, the model of a limited subcortical lesion acting through complex mechanisms and ultimately involving the cortex remains valid. Lhermitte was also a pioneer in characterizing what contemporary sleep specialists call dissociation of states.

The prevalence and characteristics of hallucinations, delusions and minor phenomena in a non-demented population sample aged 60 years and over.

OBJECTIVE: Psychotic phenomena can occur in non-clinical subjects. The goals of this study were to assess the prevalence of delusions, hallucinations and minor 'psychotic' phenomena (visual illusions, feeling of presence and passage hallucinations) and to describe the characteristics of the latter in a non-clinical older population. METHODS: Three hundred and thirteen individuals aged 60 years and older, without cognitive deficits (according to mini-mental state examination scores) or patent psychotic disease, answered a structured questionnaire focusing on delusions, hallucinations and minor phenomena that they had experienced in the previous month. The study sample was stratified by age and gender according to French demographic characteristics. RESULTS: Twenty per cent of participants reported one or more psychotic phenomena. These subjects did not differ from those without psychotic symptoms as regards their age, mini-mental state examination scores or education. Minor phenomena were the most common (13%). Hallucinations, in any sensory modality, occurred in 9% of participants. No verbal auditory hallucinations or delusions were reported. The prevalence of minor phenomena increased with age and was associated with the use of psychoactive drugs. CONCLUSION: By extending the spectrum of psychotic symptoms to minor phenomena, we found that psychotic symptoms were common in a non-clinical older population. Whether the increasing prevalence of minor phenomena with age is due to prodromal neurodegenerative disease or to other factors remains to be investigated. Copyright © 2016 John Wiley & Sons, Ltd.

Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial.

BACKGROUND: Parkinson's disease is typically treated with oral dopamine replacement therapies; however, long-term treatment leads to motor complications and, occasionally, impulse control disorders caused by intermittent stimulation of dopamine receptors and off-target effects, respectively. We aimed to assess the safety, tolerability, and efficacy of bilateral, intrastriatal delivery of ProSavin, a lentiviral vector-based gene therapy aimed at restoring local and continuous dopamine production in patients with advanced Parkinson's disease. METHODS: We undertook a phase 1/2 open-label trial with 12-month follow-up at two study sites (France and UK) to assess the safety and efficacy of ProSavin after bilateral injection into the putamen of patients with Parkinson's disease. All patients were then enrolled in a separate open-label follow-up study of long-term safety. Three doses were assessed in separate cohorts: low dose (1·9×10(7) transducing units [TU]); mid dose (4·0×10(7) TU); and high dose (1×10(8) TU). Inclusion criteria were age 48-65 years, disease duration 5 years or longer, motor fluctuations, and 50% or higher motor response to oral dopaminergic therapy. The primary endpoints of the phase 1/2 study were the number and severity of adverse events associated with ProSavin and motor responses as assessed with Unified Parkinson's Disease Rating Scale (UPDRS) part III (off medication) scores, at 6 months after vector administration. Both trials are registered at ClinicalTrials.gov, NCT00627588 and NCT01856439. FINDINGS: 15 patients received ProSavin and were followed up (three at low dose, six mid dose, six high dose). During the first 12 months of follow-up, 54 drug-related adverse events were reported (51 mild, three moderate). Most common were increased on-medication dyskinesias (20 events, 11 patients) and on-off phenomena (12 events, nine patients). No serious adverse events related to the study drug or surgical procedure were reported. A significant improvement in mean UPDRS part III motor scores off medication was recorded in all patients at 6 months (mean score 38 [SD 9] vs 26 [8], n=15, p=0·0001) and 12 months (38 vs 27 [8]; n=15, p=0·0001) compared with baseline. INTERPRETATION: ProSavin was safe and well tolerated in patients with advanced Parkinson's disease. Improvement in motor behaviour was observed in all patients. FUNDING: Oxford BioMedica.

Volumetric changes and clinical trajectories in Parkinson's disease: a prospective multicentric study.

BACKGROUND: Longitudinal measures of structural brain changes using MRI in relation to clinical features and progression patterns in PD have been assessed in previous studies, but few were conducted in well-defined and large cohorts, including prospective clinical assessments of both motor and non-motor symptoms. OBJECTIVE: We aimed to identify brain volumetric changes characterizing PD patients, and determine whether regional brain volumetric characteristics at baseline can predict motor, psycho-behavioral and cognitive evolution at one year in a prospective cohort of PD patients. METHODS: In this multicentric 1 year longitudinal study, PD patients and healthy controls from the MPI-R2* cohort were assessed for demographical, clinical and brain volumetric characteristics. Distinct subgroups of PD patients according to motor, cognitive and psycho-behavioral evolution were identified at the end of follow-up. RESULTS: One hundred and fifty PD patients and 73 control subjects were included in our analysis. Over one year, there was no significant difference in volume variations between PD and control subjects, regardless of the brain region considered. However, we observed a reduction in posterior cingulate cortex volume at baseline in PD patients with motor deterioration at one year (p = 0.017). We also observed a bilateral reduction of the volume of the amygdala (p = 0.015 and p = 0.041) and hippocampus (p = 0.015 and p = 0.053) at baseline in patients with psycho-behavioral deterioration, regardless of age, dopaminergic treatment and center. CONCLUSION: Brain volumetric characteristics at baseline may predict clinical trajectories at 1 year in PD as posterior cingulate cortex atrophy was associated with motor decline, while amygdala and hippocampus atrophy were associated with psycho-behavioral decline.

Intrasubject subcortical quantitative referencing to boost MRI sensitivity to Parkinson's disease.

Several postmortem studies have shown iron accumulation in the substantia nigra of Parkinson's disease patients. Iron concentration can be estimated via MRI-R2∗ mapping. To assess the changes in R2∗ occurring in Parkinson's disease patients compared to controls, a multicentre transversal study was carried out on a large cohort of Parkinson's disease patients (n = 163) with matched controls (n = 82). In this study, 44 patients and 11 controls were removed due to motion artefacts, 21 patient and 6 controls to preserve matching. Thus, 98 patients and 65 age and sex-matched healthy subjects were selected with enough image quality. The study was conducted on patients with early to late stage Parkinson's disease. The images were acquired at 3Tesla in 12 clinical centres. R2∗ values were measured in subcortical regions of interest (substantia nigra, red nucleus, striatum, globus pallidus externus and globus pallidus internus) contralateral (dominant side) and ipsilateral (non dominant side) to the most clinically affected hemibody. As the observed inter-subject R2∗ variability was significantly higher than the disease effect, an original strategy (intrasubject subcortical quantitative referencing, ISQR) was developed using the measurement of R2∗ in the red nucleus as an intra-subject reference. R2∗ values significantly increased in Parkinson's disease patients when compared with controls; in the substantia nigra (SN) in the dominant side (D) and in the non dominant side (ND), respectively (PSN_D and PSN_ND < 0.0001). After stratification into four subgroups according to the disease duration, no significant R2∗ difference was found in all regions of interest when comparing Parkinson's disease subgroups. By applying our ISQR strategy, R2(ISQR)∗ values significantly increased in the substantia nigra (PSN_D and PSN_ND < 0.0001) when comparing all Parkinson's disease patients to controls. R2(ISQR)∗ values in the substantia nigra significantly increased with the disease duration (PSN_D = 0.01; PSN_ND = 0.03) as well as the severity of the disease (Hoehn & Yahr scale <2 and ≥ 2, PSN_D = 0.02). Additionally, correlations between R2(ISQR)∗ and clinical features, mainly related to the severity of the disease, were found. Our results support the use of ISQR to reduce variations not directly related to Parkinson's disease, supporting the concept that ISQR strategy is useful for the evaluation of Parkinson's disease.

Feeling of presence in Parkinson's disease.

BACKGROUND: A feeling of presence (FP), that is, the vivid sensation that somebody (distinct from oneself) is present nearby, is commonly reported by patients with Parkinson's disease (PD), but its phenomenology has not been described precisely. The objective of this study was to provide a detailed description of FP in PD and to discuss its possible mechanisms. PATIENTS AND METHODS: The authors studied 52 non-demented PD patients reporting FP in the preceding month (38 consecutive outpatients and 14 inpatients). FP characteristics were recorded with a structured questionnaire. The outpatients with FP were compared with 78 consecutive outpatients without FP. RESULTS: About half the patients said they recognised the 'identity' of the presence. More than 75% of patients said the FP were not distressing, were short-lasting, were felt beside and/or behind the patient, and occurred while indoors; most patients checked for a real presence, but their insight was generally preserved. In 31% of cases, the patients had an unformed visual hallucination simultaneously with the FP. A higher daily levodopa-equivalent dose and the presence of visual illusions or hallucinations were independently associated with FP. DISCUSSION: Although FP is not a sensory perception, projection of the sensation into the extrapersonal space, along with the frequent co-occurrence of elementary visual hallucinations and the strong association with visual hallucinations or illusions, supports its hallucinatory nature. FP may be viewed as a 'social' hallucination, involving an area or network specifically activated when a living being is present, independently of any perceptual clue.

A reappraisal of long-latency abdominal muscle reflexes in patients with propriospinal myoclonus.

BACKGROUND: We report 3 patients with typical clinical and electrophysiological characteristics of propriospinal myoclonus propagating from a thoracic spine generator. METHODS: In these patients, the pattern of recruitment of long-latency electromyographic reflexes in abdominal muscles was studied in response to various stimuli. RESULTS: Abdominal reflex latency varied from 60 to 140 ms depending on stimulus location. Latency increased from magnetic stimulation of the thoracic spine to electrical stimulation of the supraorbital nerve, electrical stimulation of the median nerve, and magnetic stimulation of the motor cortex. CONCLUSIONS: Long-latency abdominal reflex jerks are probably controlled by the brain stem to propriospinal system projections in patients with propriospinal myoclonus. The stereotyped pattern of recruitment of these reflexes could be of clinical utility to differentiate organic propriospinal myoclonus from psychogenic or mimicked jerks.

The changing face of Parkinson's disease-associated psychosis: a cross-sectional study based on the new NINDS-NIMH criteria.

New criteria for Parkinson's disease-associated psychosis (PDAP) were recently proposed by a NINDS-NIMH working group. We assessed 116 consecutive unselected outpatients with PD for the existence of psychotic symptoms during the previous month, using a structured questionnaire covering the whole spectrum of PDAP symptoms. Hallucinations occurred in 42% of the patients (visual: 16%; nonvisual: 35%), delusions in 4%, and minor symptoms in 45% (sense of presence, visual illusions, or passage hallucinations). The prevalence of PDAP was 43% when the usual definition was used (hallucinations and/or delusions) and 60% when the NINDS-NIHM criteria were used. Correlations between PDAP and patient characteristics varied with the definition of PDAP. These findings suggest that the epidemiology of PDAP should be re-evaluated with the new criteria. Minor symptoms and nonvisual hallucinations are an important part of the PDAP spectrum, which has commonly been restricted to visual hallucinations and delusions.

[Psychological and behavioural disorders in Parkinson's disease]. / Troubles psychiques et comportementaux de la maladie de Parkinson.

Psychological and behavioral disorders associated with Parkinson's disease can have a major impact on patients' and caregivers' quality of life. Depression, anxiety, psychotic symptoms (e.g hallucinations), apathy and impulse-control disorders raise questions as to the respective roles of premorbid vulnerability, disease-related factors, and drug adverse effects. These disorders are often difficult to manage, and there is an unmet need for controlled trials in this field.

Scales to assess psychosis in Parkinson's disease: Critique and recommendations.

Psychotic symptoms are a frequent occurrence in Parkinson's disease (PD), affecting up to 50% of patients. The Movement Disorder Society established a Task Force on Rating Scales in PD, and this critique applies to published, peer-reviewed rating psychosis scales used in PD psychosis studies. Twelve psychosis scales/questionnaires were reviewed. None of the reviewed scales adequately captured the entire phenomenology of PD psychosis. While the Task Force has labeled some scales as "recommended" or "suggested" based on the fulfilling-defined criteria, none of the current scales contained all the basic content, mechanistic and psychometric properties needed to capture PD psychotic phenomena and to measure clinical response over time. Different scales may be better for some settings versus others. Since one scale may not be able to serve all needs, a scale used to measure clinical response and change over time [such as the Clinical Global Impression Scale (CGIS)] may need to be combined with another scale better at cataloging specific features [such as the Neuropsychiatric Inventory (NPI) or Schedule for Assessment of Positive Symptoms (SAPS)]. At the present time, for clinical trials on PD psychosis assessing new treatments, the following are recommended primary outcome scales: NPI (for the cognitively impaired PD population or when a caregiver is required), SAPS, Positive and Negative Syndrome Scale (PANSS), or Brief Psychiatric Rating Scale (BPRS) (for the cognitively intact PD population or when the patient is the sole informant). The CGIS is suggested as a secondary outcome scale to measure change and response to treatment over time.

Psychosis in Parkinson's disease: phenomenology, frequency, risk factors, and current understanding of pathophysiologic mechanisms.

Psychosis in Parkinson's disease refers to a combination of hallucinations and delusions occurring with a clear sensorium and a chronic course. Hallucinations may involve several sensory modalities. Complex visual hallucinations are the most common type. "Minor" hallucinatory phenomena are frequently present and include visual illusions, passage hallucinations, and sense of presence. Insight may be lost in patients with cognitive impairment. Delusions of a paranoid type are more rare than hallucinations. Both hallucinations and delusions are more frequent in Parkinson's disease patients with dementia. Pathogenesis involves complex and probably multifactorial mechanisms, including pharmacologic (dopaminergic treatment and others) and disease-related factors.

Outcome of bilateral subthalamic nucleus stimulation in the treatment of Parkinson's disease: correlation with intra-operative multi-unit recordings but not with the type of anaesthesia.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) gained general acceptance in the treatment of Parkinson's disease (PD). OBJECTIVE: To study the clinical outcome and the predicting factors of efficacy of chronic STN stimulation, while DBS electrodes were implanted under local or general anaesthesia with intra-operative electrophysiological guidance based on multi-unit recordings. METHODS: We included a large single-centre cohort of 54 patients with advanced PD (mean age: 59 years; disease duration: 14 years). Clinical evaluation was performed by the Unified Parkinson's Disease Rating Scale (UPDRS) before and 1 year after surgical placement of DBS electrodes. RESULTS: In the on-stimulation and off-medication condition, the UPDRS part III score was reduced by 56% compared to the off-stimulation condition or pre-operative off-drug score. In the on-stimulation and on-medication condition, this score was reduced by 73%. The severity of motor fluctuations and dyskinesia (UPDRS part IV) and the activities of daily living (UPDRS part II) were reduced by 65 and 80%, respectively, in the on-stimulation/on-medication condition compared to the pre-operative baseline. The daily dose of antiparkinsonian treatment was diminished by 72%. Among the various pre- and intra-operative data, the most important predictive factor for clinical efficacy of STN stimulation was the length of hyperactivity along the best track observed in intra-operative multi-unit recordings. Other predictive factors included age, disease duration and pre-operative levodopa responsiveness or baseline off-drug values of the Hoehn and Yahr and UPDRS part III scores. In contrast, the type of anaesthesia (local vs. general) did not significantly influence the clinical outcome. CONCLUSION: The present results are in the average of previously published results, but they have been obtained from a large single-centre cohort of patients with important reductions in the daily dose of antiparkinsonian drugs. This study confirmed the efficacy of the STN-DBS technique and emphasized the value of an original intra-operative electrophysiological approach based on multi-unit and not single-unit quantified recordings. This method allows DBS electrode implantation to be safely performed under general anaesthesia without lessening the rate of efficacy of the procedure.

[Psychotic symptoms in Parkinson's disease]. / Les troubles psychotiques de la maladie de Parkinson.

About one third of patients with Parkinson's disease (PD) experience hallucinations, mostly of a complex visual type, less often auditory or tactile. Minor hallucinatory phenomena, including sense of presence, passage hallucinations and visual illusions are frequent. Hallucinations primarily occur in a context of clear sensorium in patients with longstanding PD. They are more frequent in the evening or during the night. Insight in the hallucinatory nature of the phenomenon may be retained, partial, fluctuating, or abolished. An altered insight is common when cognitive impairment is present, and may be associated with delusions and (or) delusional misidentifications. Pharmacological factors such as dopaminergic treatment clearly trigger or increase the occurence of hallucinations in PD. However, in the recent years, emphasis has been made on disease-related factors including cognitive impairment, diurnal somnolence, visual disorders (either contrast and color discrimination impairment due to PD, or coincident ocular disorders), long duration of PD, late onset, severe axial impairment and autonomic dysfunction. The pathophysiology of hallucinations of PD is poorly understood but is likely to be multifactorial. The first steps of the treatment consist in giving information and reassurance to the patient and his/her caregiver, re-evaluating the antiparkinsonian treatment and associated medications, and evaluating the patient for mood disorder, visual impairment, and cognitive impairment. Cholinesterase inhibitors, when prescribed for associated cognitive impairment, may be beneficial on hallucinations. In the more severe forms, clozapine has been proved to be safe and effective.

[Relationships between weight loss and circulating cytokines in patients with Alzheimer's disease]. / Amaigrissement et cytokines circulantes chez des patients souffrant d'une maladie d'Alzheimer.

106 consecutive patients with Alzheimer's disease living in the community were examined in a memory clinic from a neurological department. They were screened for weight loss over the last 2 years. Age, duration of the disease, behavioral disorders, mini mental status examination, body mass index were recorded. Tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), interleukin 6 (IL-6) and interleukin 2 (IL-2) blood levels were measured. Weight loss was reported in 42.5% of the patients. TNFalpha levels were significantly higher in these patients (18.8 versus 15.8 pg/mL; p=0.04) than in patients without weight loss. Weight loss was also associated with a lower MMSE score (16.9 versus 19.3; p=0.03), current pacing (20% versus 1.6%; p=0.002), and hallucinations (20.0% versus 3.3%; p=0.008). The levels of the other cytokines did not differ between the patients with and without weight loss. Our findings suggest an association between high levels of circulating TNFalpha and unexplained weight loss in Alzheimer's disease.

Brain (18)F-FDG, (18)F-Florbetaben PET/CT, (123)I-FP-CIT SPECT and Cardiac (123)I-MIBG Imaging for Diagnosis of a "Cerebral Type" of Lewy Body Disease.

A 67-year-old man was referred for fluctuating neuropsychiatric symptoms, featuring depression, delirious episodes, recurrent visual hallucinations and catatonic syndrome associated with cognitive decline. No parkinsonism was found clinically even under neuroleptic treatment. (18)F-FDG PET/CT showed hypometabolism in the posterior associative cortex including the occipital cortex, suggesting Lewy body dementia, but (123)I-FP-CIT SPECT was normal and cardiac (123)I-MIBG imaging showed no signs of sympathetic denervation. Alzheimer's disease was excluded by a normal (18)F-florbetaben PET/CT. This report suggests a rare case of α-synucleinopathy without brainstem involvement, referred to as "cerebral type" of Lewy body disease.

[Management of psychiatric complications of Parkinson's disease]. / Prise en charge des troubles psychiques dans la maladie de Parkinson.

Psychic disturbances are frequently present in patients with Parkinson's disease. They increase the disability and handicap, contribute to poor quality of life and often make the treatment of motor symptoms more difficult. Cognitive impairment may be restricted to subtle changes on neuropsychological testing, but the evolution towards a dementia appears more frequent than previously thought. Depression, anxiety and hallucinations are common but may be underestimated. During recent years, new psychiatric aspects have been described such as apathy and the so-called syndrome of dopamine dysregulation.

Clinical routine use of dopamine transporter imaging in 516 consecutive patients.

[(123)I]-FP-CIT is a single photon emission computed tomography (SPECT) ligand showing in vivo the loss of dopaminergic terminals in the brain and is now available in the market. Despite several systematic studies in clinically inconclusive cases, the use of such imaging in clinical routine is scarcely reported. We analyzed 516 files of subjects with movement disorders who were consecutively examined using [(123)I]-FP-CIT scan and determined whether the use of imaging was appropriate and if it improved clinical diagnosis or care of the patient. In addition, we determined if appropriate use was related to subspecialties in Neurology, e.g., movement disorders' specialists vs. general neurologists, and if appropriate use was increasing over time. Among the 516 scans, 18% were in agreement with the license, 62% were classified as appropriate and 37% were considered inappropriate. A change of management was obvious in 60% of patients, but in 92% of those with an appropriate request vs. 13% of patients with an inappropriate request. Movement disorders' specialists had more appropriate requests than other practitioners. Eventually, comparing the first 100 vs. the last 100 quantified SPECT, performed more than 2.5 years apart, we found no difference for the appropriateness of the examination. The use of [(123)I]-FP-CIT imaging in clinical routine does not fit a restrictive license. An inappropriate use is seen in nearly 40% of cases, which reduces the real cost-effectiveness of the technique suggesting a need for continuing medical education on the topic.

Vascular parkinsonism.

The concept of vascular parkinsonism (VP) has been highly controversial since the initial paper by Critchley in 1929. This review tentatively delineates the extent of the spectrum of VP. Much confusion has arisen owing to the lack of clear definitions of parkinsonism, "atypical parkinsonism" and "pseudoparkinsonism", which we here attempt to define. Confusion has also arisen because incidental vascular lesions occurring in true idiopathic Parkinson's disease (IPD) are up to 10 times more common than parkinsonism due to cerebrovascular disease. VP is clinically heterogeneous. Most often VP is atypical and can be separated from IPD, on the basis of the presence of additional focal signs, and the absence of typical resting tremor in the upper limbs, of true akinesia (i. e.: with decrement and fatiguing of alternating movements), and of definite benefit from levodopa. Exceptionally, VP may mimic IPD or other degenerative diseases such as progressive supranuclear palsy or corticobasal degeneration. The lesions responsible for VP are mostly basal ganglia lacunes and/or subcortical white matter vasculopathy of the "Binswanger" type. Rarely, a single striatal infarct, striatal cribriform cavities or ischaemic changes in the substantia nigra have been described. Vascular "pseudo-parkinsonism" refers to isolated gait disorders called "lower body parkinsonism", "frontal-type gait disorders" or "gait ignition failure" that are reminiscent of, but distinct from, that found in IPD. The pathophysiology of VP is poorly understood. Why some patients develop parkinsonism and others do not, despite the same apparent lesion load, remains a mystery.