Prevalence and duration of non-motor symptoms in prodromal Parkinson's disease.

BACKGROUND AND PURPOSE: The prevalence and duration of non-motor symptoms (NMS) in prodromal Parkinson's disease (PD) has not been extensively studied. The aim of this study was to determine the prevalence and duration of prodromal NMS (pNMS) in a cohort of patients with recently diagnosed PD. METHODS: We evaluated the prevalence and duration of pNMS in patients with early PD (n = 154). NMS were screened for using the Non-Motor Symptom Questionnaire (NMSQuest). We subtracted the duration of the presence of each individual NMS reported from the duration of the earliest motor symptom. NMS whose duration preceded the duration of motor symptoms were considered a pNMS. Individual pNMS were then grouped into relevant pNMS clusters based on the NMSQuest domains. Motor subtypes were defined as tremor dominant, postural instability gait difficulty (PIGD) and indeterminate type according to the Movement Disorder Society Unified Parkinson's Disease Rating Scale revision. RESULTS: Prodromal NMS were experienced by 90.3% of patients with PD and the median number experienced was 4 (interquartile range, 2-7). A gender difference existed in the pNMS experienced, with males reporting more sexual dysfunction, forgetfulness and dream re-enactment, whereas females reported more unexplained weight change and anxiety. There was a significant association between any prodromal gastrointestinal symptoms [odds ratio (OR), 2.30; 95% confidence interval (CI), 1.08-4.89, P = 0.03] and urinary symptoms (OR, 2.54; 95% CI, 1.19-5.35, P = 0.016) and the PIGD phenotype. Further analysis revealed that total pNMS were not significantly associated with the PIGD phenotype (OR, 1.10; 95% CI, 0.99-1.21, P = 0.068). CONCLUSIONS: Prodromal NMS are common and a gender difference in pNMS experienced in prodromal PD may exist. The PIGD phenotype had a higher prevalence of prodromal gastrointestinal and urinary tract symptoms.

Cerebral glucose metabolism and cognition in newly diagnosed Parkinson's disease: ICICLE-PD study.

OBJECTIVE: To assess reductions of cerebral glucose metabolism in Parkinson's disease (PD) with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), and their associations with cognitive decline. METHODS: FDG-PET was performed on a cohort of 79 patients with newly diagnosed PD (mean disease duration 8 months) and 20 unrelated controls. PD participants were scanned while on their usual dopaminergic medication. Cognitive testing was performed at baseline, and after 18 months using the Cognitive Drug Research (CDR) and Cambridge Neuropsychological Test Automated Battery (CANTAB) computerised batteries, the Mini-Mental State Examination (MMSE), and the Montreal Cognitive Assessment (MoCA). We used statistical parametric mapping (SPM V.12) software to compare groups and investigate voxelwise correlations between FDG metabolism and cognitive score at baseline. Linear regression was used to evaluate how levels of cortical FDG metabolism were predictive of subsequent cognitive decline rated with the MMSE and MoCA. RESULTS: PD participants showed reduced glucose metabolism in the occipital and inferior parietal lobes relative to controls. Low performance on memory-based tasks was associated with reduced FDG metabolism in posterior parietal and temporal regions, while attentional performance was associated with more frontal deficits. Baseline parietal to cerebellum FDG metabolism ratios predicted MMSE (ß=0.38, p=0.001) and MoCA (ß=0.3, p=0.002) at 18 months controlling for baseline score. CONCLUSIONS: Reductions in cortical FDG metabolism were present in newly diagnosed PD, and correlated with performance on neuropsychological tests. A reduced baseline parietal metabolism is associated with risk of cognitive decline and may represent a potential biomarker for this state and the development of PD dementia.

Cognitive impairment in Parkinson's disease: impact on quality of life of carers.

BACKGROUND: The quality of life (QoL) of informal caregivers of people with Parkinson's disease (PD) (PwP) can be affected by the caring role. Because of cognitive symptoms and diminished activities of daily living, in addition to the management of motor symptoms, carers of PwP and cognitive impairment may experience increased levels of burden and poorer QoL compared with carers of PwP without cognitive impairment. This study aimed to investigate the impact of cognitive impairment in PD upon QoL of carers. METHODS: Approximately 36 months after diagnosis, 66 dyadic couples of PwP and carers completed assessments. PwP completed a schedule of neuropsychological assessments and QoL measures; carers of PwP completed demographic questionnaires and assessments of QoL. Factor scores of attention, memory/executive function and global cognition, as derived by principal component analysis, were used to evaluate cognitive domains. RESULTS: Hierarchical regression analysis found lower Montreal Cognitive Assessment was a significant independent predictor of poorer carer QoL, in addition to number of hours spent caregiving, carer depression and PD motor severity. Attentional deficits accounted for the largest proportion of variance of carer QoL. Carers of PwP and dementia (n = 9) had significantly poorer QoL scores compared with PwP and mild cognitive impairment (n = 18) or normal cognition (n = 39) carers (p < 0.01). CONCLUSIONS: Attentional deficits were the strongest predictor of carer QoL compared with other cognitive predictors. Carers for those with PD dementia reported the poorest QoL. Interventions such as respite or cognitive behavioural therapy to improve mood and self-efficacy in carers may improve carer QoL. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons, Ltd.

Progression of Neuropsychiatric Symptoms over Time in an Incident Parkinson's Disease Cohort (ICICLE-PD).

BACKGROUND: Cross-sectional studies have identified that the prevalence of neuropsychiatric symptoms (NPS) in Parkinson's disease (PD) ranges from 70-89%. However, there are few longitudinal studies determining the impact of NPS on quality of life (QoL) in PD patients and their caregivers. We seek to determine the progression of NPS in early PD. METHODS: Newly diagnosed idiopathic PD cases (n = 212) and age-matched controls (n = 99) were recruited into a longitudinal study. NPS were assessed using the Neuropsychiatric Inventory with Caregiver Distress scale (NPI-D). Further neuropsychological and clinical assessments were completed by participants, with reassessment at 18 and 36 months. Linear mixed-effects modelling determined factors associated with NPI-D and QoL over 36 months. RESULTS: Depression, anxiety, apathy and hallucinations were more frequent in PD than controls at all time points (p < 0.05). Higher motor severity at baseline was associated with worsening NPI-D scores over time (ß = 0.1, p < 0.05), but not cognition. A higher NPI total score was associated with poorer QoL at any time point (ß = 0.3, p < 0.001), but not changed in QoL scores. CONCLUSION: NPS are significantly associated with poorer QoL, even in early PD. Screening for NPS from diagnosis may allow efficient delivery of better support and treatment to patients and their families.

Head-up Tilt Table Testing: a state-of-the-art review.

Vasovagal syncope (VVS) is the commonest cause of syncope accounting for up to 60% of all cases. The head-up tilt-table test (HUTT) was first described as a diagnostic test for VVS in 1986 and is now in widespread use as a research and diagnostic tool. Vasovagal syncope was previously thought to be confined to younger patients but with the introduction of HUTT, it is now being diagnosed with greater frequency in the elderly. Research into the physiological changes in susceptible individuals during HUTT has greatly increased our understanding of the pathophysiological processes underlying VVS; in particular, the hypotensive response during VVS is associated with sympathetic withdrawal rather than bradycardia alone. Various provocation agents, including nitrates, isoprotenerol and lower body negative pressure have been described to improve the diagnostic yield of the HUTT. Glyceryl trinitrate is now routinely administered during HUTTs. Individuals with typical presentations and infrequent episodes do not require investigation with HUTT as history alone is often diagnostic. The head-up tilt-table test is, however, required with atypical features, seizure activity, occupational issues, and is more likely to be required in older patients. The practicalities of conducting the HUTT and limitations of HUTTs are also discussed.

Perinatal and maternal risk factors for autism spectrum disorders in New South Wales, Australia.

BACKGROUND: This study was commenced in 1999 with the aim of examining risk factors for autism using established population-based data for comparison. METHODS: Cases were ascertained using active surveillance and compared with birth data. RESULTS: Four risk factors were found to be significantly associated with autism using binary logistic regression analysis; being male [adjusted odds ratio (OR) 4.7, 95% confidence interval (CI) 3.2-7.0], being born prematurely (adjusted OR 2.2, 95% CI 1.5-3.5), having maternal age >/=35 years (adjusted OR 1.7, 95% CI 1.2-2.4) and having a mother born outside Australia (adjusted OR 1.4, 95% CI 1.0-1.9). For analysis completed for pregnancies, rather than live births, multiple birth was also a significant risk factor for one or more children of the pregnancy to be affected by autism (adjusted OR 2.5, 95% CI 1.1-5.5). There was a statistically significant trend towards increasing risk with increasing risk factor 'dose' for gestational age (P = 0.019), multiple birth (P = 0.016) and maternal age (P < 0.001). For mother's country of birth the group with the highest risk were children of mother's born in south-east or north-east Asia. There was a non-significant trend towards a higher proportion of children with developmental disability having risk factors. CONCLUSION: Replication of risk factors from previous studies and a significant risk factor 'dose' effect add to growing evidence that maternal and perinatal factors are low magnitude risk factors for autism. The association between developmental disability and autism risk factors warrants further examination.

Neurologic complications of bacterial endocarditis.

(1) Neurologic complications remain a significant problem in bacterial endocarditis. Of 218 patients with endocarditis, 84 (39%) had a neurologic complication and 58% of these 84 patients died. In contrast, the mortality rate was only 20% among those endocarditis patients without neurologic complications. (2) Of the neurologic complications, cerebral embolism is the most frequent and important. An embolic stroke occurred in 37 (17%) of our patients, with 30 of these patients dying. Emboli are important not only in terms of the direct morbidity and mortality they cause via cerebral infarction, but also because of their role in the causation of mycotic aneurysms, brain abscesses, and abnormal CSF formulae. (3) Cerebral emboli are particularly common in patients with mitral valve infection, and in patients with infection due to virulent organisms, particularly S. aureus and enteric gram-negative bacilli. (4) Mycotic aneurysms occur more frequently in the course of acute endocarditis rather than late in the course of subacute disease. Management of angiographically demonstrated mycotic aneurysms is dependent upon the presence or absence of hemorrhage, the anatomic location of the aneurysm, and the clinical course of the patient. Healing of mycotic aneurysms can occur during the course of effective antimicrobial therapy, thus obviating the need for neurosurgical intervention in all such patients. (5) Macroscopic brain abscess is a rare complication of bacterial endocarditis. Miliary microscopic abscesses are more common than larger abscesses, particularly in patients with acute disease and miliary infection in other organs of the body. (6) Focal seizures occur most commonly in endocarditis patients with acute embolic disease; generalized seizures are of diverse etiologies, with metabolic factors being most important. Penicillin neurotoxicity should be considered in patients with impaired renal function who are receiving high dose penicillin. (7) With the exception of hemorrhagic complications, lumbar puncture results tend to reflect the nature of the infecting organism rather than the nature of the neurologic complication. Endocarditis due to virulent organisms such as S. aureus is usually associated with a purulent CSF formula while nonvirulent organisms, such as viridans streptococci, susually have aseptic or normal CSF formulae.

Acute cerebellar infarction in the PICA territory.

Although old or recent infarcts of a cerebellar hemisphere in the territories of the posterior inferior (PICA), superior, or anterior inferior cerebellar arteries are commonplace autopsy findings, in no case have corresponding clinical symptoms been clearly identified. We have studied three cases, two clinocaopthologically and one clinicosurgically, in which an acute infarct involving only the cerebellum lay in the PICA territory distal to the branches to the medulla oblongata. The clinical manifestations consisted of rotatory dizziness intensified by motion, nausea, vomiting, imbalance, and nystagmus. In two cases, the clinical diagnosis had been a benign labyrinthine disorder. Recognition of a syndrome corresponding to cerebellar infarction in the PICA territory is important insofar as it assists in the differential diagnosis of dizziness. It becomes of crucial importance when cerebellar infarction is the prelude to cerebellar swelling and brain stem conpression leading to coma and death unless surgically relieved.

Controlled use of cranial computerized tomography.

This study attempts to assess the impact of computerized cranial tomography (CT) on clinical practice in a veterans hospital. A CT scan could be performed only if there existed a reasonable potential for the results to affect the patient's clinical course. We document many instances of how the 163 CT scans obtained during a one-year period aided patients. We quantitated one beneficial aspect by estimating the major neuroradiologic contrast procedures obviated by CT scan. Case-by-case review indicates 70 cerebral arteriograms and 58 pneumoencephalograms would have been performed had CT scanning not been available.

An evaluation of baclofen treatment for certain symptoms in patients with spinal cord lesions. A double-blind, cross-over study.

Baclofen (a gamma aminobutylic acid derivative) and a placebo were compared for their efficacy in relieving certain symptoms in patients with long-standing spinal cord lesions and "spinal spasticity." In a double-blind, cross-over clinical investigation, 22 patients with chronic spinal cord disease were studied. Baclofen regularly alleviated involuntary flexor or extensor spasms and increased resistance to passive movement of the legs but did not alter strength, gait, stretch reflexes, or clonus. Side effects were mild and transient. This study demonstrates that (1) baclofen is useful for the treatment of flexor spasms and (2) in evaluating a new mode of therapy, one must consider selectively the response of individual components of such global syndromes as "spasticity."

Broca aphasia: pathologic and clinical.

The speech disturbance resulting from infarction limited to the Broca area has been delineated; it differs from the speech disorder called Broca aphasia, which results from damage extending far outside the Broca area. Nor does Broca area infarction cause Broca aphasia. The lesions in 20 cases observed since 1972 were documented by autopsy, computerized tomography, or arteriogram; the autopsy records from the Massachusetts General hospital for the past 20 years and the published cases since 1820 were also reviewed. The findings suggest that infarction affecting the Broca area and its immediate environs, even deep into the brain, causes a mutism that is replaced by rapidly improving dyspraxic and effortful articulation, but that no significant distrubance in language function persists. The more complex syndrome traditionally referred to as Broca aphasia, including Broca's original case, is characterized by protracted mutism, verbal stereotypes, and agrammatism. It is associated with a considerably larger infarct which encompasses the operculum, including the Broca area, insula, and adjacent cerebrum, in the territory supplied by the upper division of the left middle cerebral artery.

The Harvard Cooperative Stroke Registry: a prospective registry.

Data from 694 patients hospitalized with stroke were entered in a prospective, computer-based registry. Three hundred and sixty-four patients (53 percent) were diagnosed as having thrombosis, 215 (31 percent)as having cerebral embolism 70 (10 percent) as having intracerebral hematoma, and 45 (6 percent) as having subarachnoid hemorrhage from aneurysm or arteriovenous malformations. The 364 patients diagnosed as having thrombosis were divided into 233 (34 percent of all 694 patients) whose thrombosis was thought to involve a large artery and 131 (19 percent) with lacunar infarction. Many of the findings in this study were comparable to those in previous registries based on postmortem data. New observations include the high incidence of lacunes and cerebral emboli, the absence of an identifiable cardiac origin in 37 percent of all emboli, a nonsudden onset in 21 percent of emboli, and the occurrence of vomiting at onset in 51 percent and the absence of headache at onset in 67 percent of hematomas.

Collagen and prostaglandin synthesis in force-stressed periodontal ligament in vitro.

A periodontal organ culture system capable of receiving orthodontic type forces was developed. Histological, radioautographical, collagen, and prostaglandin synthetic data demonstrated the vitality of the organ over a 24-hour period of culture. Significant increases in the proportion of type III collagen synthesized during periods of active stress were found, but no alterations in relative levels of prostaglandins synthesized during periods of force application were discernible.

Low-level, progestogen-releasing vaginal contraceptive devices.

Silicone rubber vaginal contraceptive devices of four different formulations, which release predetermined, controlled doses of three progestogens at four distinct levels, were designed and fabricated, and tested in 90-day clinical trials. Data obtained with 70 of the devices indicated that in vivo release rates (microgram/day +/- S.D.) for the formulations were: progesterone, 1400 +/- 30; norethindrone (two levels), 49.4 +/- 2.4, 196 +/- 21; d-norgestrel, 21.6 +/- 1.4. Clinical studies with these devices indicate that the women usually ovulate (with the exception of the high-dose norethindrone-releasing devices) while sperm penetration of the cervix was inhibited by all four fromulations, most consistently by the norgestrel-releasing devices.

PIP: 4 different formulations, which released predetermined, controlled doses of 3 progestogens at 4 distinct levels, were incorporated into newly designed and fabricated silicone rubber vaginal contraceptive devices. 90-day clinical trails tested in vivo release rates of 70 devices; the rates were: progesterone, 1400+ or -30 mcg/day; norethindrone (2 levels), 49.4+ or -2.4 and 196+ or -21 mcg/day; and d-norgestrel, 21.6+ or -1.4 mcg/day. Clinical studies with these devices indicated that the women usually ovulated (with the exception of the high-dose norethindrone-releasing device), whereas sperm penetration of the cervix was inhibited by all 4 formulations, most consistently by the norgestrel-releasing device. Data from a shelf-life study indicated that there were no significant differences between the amount of progestogen in freshly fabricated devices and that in devices stored at room temperature for 2 years.

Fabrication and testing of vaginal contraceptive devices designed for release of prespecified dose levels of steroids.

PIP: Polydimethylsiloxane (Silastic) intravaginal devices of 3 different designs were tested both in vivo and in vitro as delivery systems for d-norgestrel, norethindrone, and progesterone. The devices were toroids measuring 55.6 mm in diameter and 9.5 mm in cross-section. In vitro release rates were determined by placing the devices in a stirred stream of isotonic saline for 30-60 days, and certain others were tested following in vivo use. 78 devices used in clinical trials for an average 92.5 days formed the basis for in vivo data. In vitro relase rates at 10 days did not differ significantly from those at the end of testing, and they accorded closely with the in vivo release rates. 1 design problem encountered was the reduction in release rate once a certain portion of the dose had been expended.^ieng

Collaborative research and development on mifepristone in China to reduce unwanted pregnancies and recourse to abortion.

A program proposed and executed by The Concept Foundation and funded by the Rockefeller Foundation demonstrates the feasibility of using private/public-sector collaboration for making mifepristone widely available. The application of mifepristone to emergency, luteal phase and menstrual induction contraception is being assessed in clinical research programs conducted in accordance with international standards for good clinical research. Opportunities for introduction of mifepristone in developing countries are being pursued using mifepristone produced in China in accordance with international standards of good manufacturing practice.

Stroke prevention in non-rheumatic atrial fibrillation.

Warfarin can strikingly prevent stroke in patients with NRAF with or without a history of stroke or TIA. The target degree of anticoagulation is an INR between 2.0 and 3.0. Any degree of anticoagulation with less than an INR of 2.0 will not provide full protection, any greater anticoagulation is no more effective, and an INR greater than 4.0 increases the risk of hemorrhage. Patients 65 years or younger without any risk factor do no better with warfarin than with aspirin or placebo, and should not be anticoagulated. All older patients or those with risk factors but without contraindications gain significant stroke prevention with warfarin anticoagulation as recommended above.

Ethics and care for older people approaching the end of life -- symptoms, choices and dilemmas.

The provision of high quality care to older people with complex healthcare needs brings a unique set of clinical and ethical issues. This symposium explored a range of challenging topics which often confront clinicians. It aimed to increase knowledge of symptom control in complex conditions, improve confidence in decision-making regarding difficult ethical situations, and to provide a better understanding of how to organise and support end of life care both in the hospital and in the community.