Novel insights into cerebral palsy.

Cerebral palsy (CP) is a neurodevelopmental disorder characterized by abnormalities of muscle tone, movement and motor skills, and is attributed to injury to the developing brain. CP affects about 1 in 500 neonates. CP shows clinical features which evolve with age, and these may over time lead to deterioration of motor function although the lesion to the developing brain is non-progressive. The underlying causes for CP remain unclear. Based on recent research we are able to give a physiological explanation on the appearance and development of the condition. The damage to the central nervous system causes a change in collagen structure, with a higher level of deposition of collagen around the muscles, increasing throughout life. Assuming this premise is correct, the question is, will it by any treatment be possible to delay or prevent this collagen accumulation in the CP muscles, thereby giving CP patients a better prognosis in the future.

Risk of Multiple System Atrophy and the Use of Anti-Inflammatory Drugs: A Danish Register-Based Case-Control Study.

INTRODUCTION: Multiple system atrophy (MSA) is a rare rapidly progressive atypical Parkinson disorder presenting clinically with parkinsonism and/or a cerebellar syndrome in combination with dysautonomia. Severe neuroinflammation develops along with hallmark neuropathological changes, and as in Parkinson's disease, intake of anti-inflammatory medication has been hypothesized to be protective for development of disease. We aimed to investigate if use of non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin, or statins were associated with a reduced risk of MSA. METHODS: We performed a register-based case-control study in MSA (n = 155) cases and population controls (n= 7,750) matched on age, gender, and place of residency by risk-set sampling. Pharmacological exposure prior to diagnosis was assessed in 2 categories (user vs. nonuser, cumulated dose in tertiles [T1-T3]). In an unconditional logistic regression model, adjusted for age, gender, residency, and chronic obstructive pulmonary disease (COPD), we estimated ORs and 95% CIs. RESULTS: Data suggested a trend towards non-aspirin NSAID use to be associated with a decreased risk of MSA (OR 0.72 [95% CI 0.49-1.06]) compared to nonusers, decreasing dose-dependently (T2 OR 0.77 [95% CI 0.43-1.38]; T3 OR 0.55 [95% CI 0.29-1.06]). However, data were based on small numbers. Use of statins and low-dose aspirin was not associated with a decreased risk of MSA. Results were lagged 5 years from index date to address reverse causation. CONCLUSION: A trend toward use of non-aspirin NSAID and an associated reduced risk of MSA was observed in this study. However, our analyses had limited statistical precision, and further studies including larger sample sizes and longer exposure periods are needed.

Clinical Features in a Danish Population-Based Cohort of Probable Multiple System Atrophy Patients.

BACKGROUND: Multiple system atrophy (MSA) is a rare, sporadic and progressive neurodegenerative disorder. We aimed to describe the clinical features of Danish probable MSA patients, evaluate their initial response to dopaminergic therapy and examine mortality. METHODS: From the Danish National Patient Registry, we identified 782 patients diagnosed with conditions potentially compatible with probable MSA (International Classification of Diseases, version 10 (ICD-10) codes G23.2, G23.8 and G23.9) during 1994-2009. Through medical record review, we narrowed our sample to 115 patients who fulfilled the criteria for probable MSA. We recorded clinical features, examined differences by MSA subtype and used Kaplan-Meier survival analysis to examine mortality. RESULTS: The mean age at onset of patients with probable MSA was 60.2 years (range 36-75 years) and mean time to wheelchair dependency was 4.7 years (range 0-15 years). One-third of patients experienced a transient improvement in motor symptoms with use of levodopa. Median survival from disease onset was 6.9 years (range 1-16 years, 95% CI 6.3-7.5) with no apparent variation according to gender or subtype. CONCLUSIONS: Our nationwide approach corroborated that MSA is associated with diverse and grave symptoms, only limited response to levodopa, and poor prognosis.

Probing cellular health at the muscle level-Multi-frequency bioimpedance in Parkinson's disease.

Bioimpedance (mfBIA) non-invasively assesses cellular muscle health. Our aim was to explore whether mfBIA captures abnormal cellular muscle health in patients with Parkinson's Disease (PD) and how such changes are modulated with the use of Parkinson's medication. In patients with PD (n = 20) mfBIA measurements were made of biceps brachii, triceps, and extensor carpi radialis longus muscles of the more affected arm whilst at rest, using a mobile mfBIA device (IMPEDIMED, Australia). mfBIA and assessment of motor symptoms were performed in a pragmatic off-medication state, as well as one and 3 h after oral intake of 200 mg levodopa. Age and sex-matched healthy subjects (HC; n = 20) served as controls. PD and HC mfBIA parameters were compared by applying an unpaired two-tailed adjusted t-test and ANOVA with Tukey's correction for multiple comparisons (p ≤ 0.05). The PD group consisted of 13 men (71 ± 17 years) and 7 women (65 ± 7 years). Independent of medication, internal (Ri ) and external resistance (Re ) were found to be significantly higher, and membrane capacitance (Mc) significantly lower, in m.biceps brachii in PD subjects compared to HC. Center frequency (fc) was significantly higher in m.biceps brachii of PD subjects in the "medication-off" state. There was no difference between PD and HC in mfBIA parameters in the measured extensor muscles. The upper limb flexor muscle shows a difference in mfBIA parameters in PD compared to HC. mfBIA may be useful in the diagnosis and assessment of PD patients and is objective, non-invasive, reliable, and easy to use.

Risk for Parkinson's disease among patients with osteoarthritis: a Danish cohort study.

It has been suggested that use of nonsteroidal anti-inflammatory drugs (NSAID) protects against Parkinson's disease, although the results are not consistent. We investigated the risk for Parkinson's disease in patients with osteoarthritis, who are typically intensive users of NSAID. By using the files of the National Danish Hospital Register for the period 1977-2006, we identified a cohort of 134,176 patients with osteoarthritis severe enough to have required subsequent hip or knee implant surgery. The number of first hospital contacts for Parkinson's disease among cohort members in 1986-2007 was compared with that expected from the age-, gender- and period-specific hospital contact rates of the general Danish population, and standardized incidence ratios (SIRs) and associated 95% confidence intervals (CIs) were derived. Cohort members were also linked to the Danish Cancer Register to estimate the SIRs for colorectal and lung cancer. We observed a slightly increased risk for Parkinson's disease among patients with osteoarthritis and subsequent implant surgery (SIR, 1.07; 95% CI, 0.99-1.16). Decreased SIRs were found for both colorectal cancer (0.92; 95% CI, 0.88-0.97), consistent with a high prevalence of NSAID use among cohort members, and lung cancer (0.77; 95% CI, 0.73-0.80), indicating a lower prevalence of smoking than usual. Our results do not support the hypothesis that patients with prolonged use of NSAID and other analgesics are at reduced risk for Parkinson's disease. A possible lower smoking prevalence among patients with osteoarthritis might explain the slightly increased risk for Parkinson's disease.

Duodopa pump treatment in patients with advanced Parkinson's disease.

INTRODUCTION: Patients with advanced Parkinson's disease (PD) often develop motor complications including fluctuations and involuntary movements (dyskinesias). In Denmark, treatment has comprised Deep Brain Stimulation (DBS) since the late 1990s, and as from 2002 use of a subcutaneous apomorphine pump. Monotherapy with continuous intestinal levodopa infusion to the duodenum (Duodopa) was introduced in 2004. MATERIAL AND METHODS: A total of 14 PD patients were assessed for Duodopa pump therapy in the 2004-2008 period. After an initial test week, 12 of the patients had a permanent percutaneous endoscopic gastrostomy (PEG) tube inserted containing a smaller intestinal tube terminating in the duodenum. Before and after treatment initiation, we evaluated the patients using clinical rating scales and video recordings. RESULTS: Objectively, all 12 patients experienced a significant reduction in fluctuations and dyskinesias while achieving a better gait function. Three patients received Duodopa as 24-hour treatment with good effect on severe nocturnal dystonic pain. One patient suffered a severe complication (peritonitis). CONCLUSION: Duodopa has a symptom-relieving and stabilizing effect without side effects, but entails a risk of surgical complications (peritonitis).

[Lewy body dementias].

Dementia with Lewy bodies and Parkinson disease dementia share the same pathophysiology. Together they are called Lewy body dementias and are the second most common type of dementia. Lewy body dementias receive little attention, and patients are often misdiagnosed, leading to less than ideal management. In this article, diagnostic criteria combined with imaging and other biomarkers as well as current treatment recommendations are summarized, and some of the challenges for the future are outlined. Refinement of diagnosis and clarification of the pathogenesis are required in search for disease-modifying treatments.

Increased Motor Activity During REM Sleep Is Linked with Dopamine Function in Idiopathic REM Sleep Behavior Disorder and Parkinson Disease.

STUDY OBJECTIVES: Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by impaired motor inhibition during REM sleep, and dream-enacting behavior. RBD is especially associated with α-synucleinopathies, such as Parkinson disease (PD). Follow-up studies have shown that patients with idiopathic RBD (iRBD) have an increased risk of developing an α-synucleinopathy in later life. Although abundant studies have shown that degeneration of the nigrostriatal dopaminergic system is associated with daytime motor function in Parkinson disease, only few studies have investigated the relation between this system and electromyographic (EMG) activity during sleep. The objective of this study was to investigate the relationship between the nigrostriatal dopamine system and muscle activity during sleep in iRBD and PD. METHODS: 10 iRBD patients, 10 PD patients with PD, 10 PD patients without RBD, and 10 healthy controls were included and assessed with (123)I-N-omega-fluoropropyl-2-beta-carboxymethoxy-3beta-(4-iodophenyl) nortropane ((123)I-FP-CIT) Single-photon emission computed tomography (SPECT) scanning ((123)I-FP-CIT SPECT), neurological examination, and polysomnography. RESULTS: iRBD patients and PD patients with RBD had increased EMG-activity compared to healthy controls. (123)I-FP-CIT uptake in the putamen-region was highest in controls, followed by iRBD patients, and lowest in PD patients. In iRBD patients, EMG-activity in the mentalis muscle was correlated to (123)I-FP-CIT uptake in the putamen. In PD patients, EMG-activity was correlated to anti-Parkinson medication. CONCLUSIONS: Our results support the hypothesis that increased EMG-activity during REM sleep is at least partly linked to the nigrostriatal dopamine system in iRBD, and with dopamine function in PD.

Prepulse inhibition is associated with attention, processing speed, and 123I-FP-CIT SPECT in Parkinson's disease.

BACKGROUND: Prepulse inhibition is a measure of sensorimotor gating, which reflects the ability to filter or 'gate' irrelevant information. Prepulse inhibition is dramatically altered in basal ganglia disorders associated with dysfunction in the midbrain dopaminergic system, and corresponding cognitive information processing deficits such as slowed processing speed. Parkinson's disease is characterised by the degeneration of the midbrain dopaminergic system and is associated with cognitive dysfunction, including slowed information processing. Although sensorimotor processes in Parkinson's disease have been extensively studied in relation to motor function, less is known about the potential role of sensorimotor processes in cognitive function. OBJECTIVE: We investigated the relationship between prepulse inhibition, cognition and nigrostriatal dysfunction, as measured with 123I-FP-CIT-SPECT scanning, in patients with Parkinson's disease. METHODS: 38 Parkinson patients were assessed with prepulse inhibition, neuropsychological tests, and neurological investigation. A subset of these patients underwent 123I-FP-CIT-SPECT scanning. RESULTS: Patients with a higher level of prepulse inhibition performed better on cognitive measures tapping attention and processing speed than patients with a lower level of prepulse inhibition. Furthermore, there were significant correlations between prepulse inhibition and 123I-FP-CIT uptake in the striatum. CONCLUSIONS: Our results suggest that the level of prepulse inhibition is related to the efficiency of information processing in Parkinson's disease, and to the density of dopamine transporters in the striatum.

Sensorimotor gating deficits in multiple system atrophy: comparison with Parkinson's disease and idiopathic REM sleep behavior disorder.

BACKGROUND: Prepulse inhibition (PPI) of the auditory blink reflex is a measure of sensorimotor gating, which reflects an organism's ability to filter out irrelevant sensory information. PPI has never been studied in patients with multiple system atrophy (MSA), although sensorimotor deficits are frequently associated with synucleinopathies. We investigated whether alterations in PPI were more pronounced in MSA compared with Parkinson's disease (PD), idiopathic rapid eye movement sleep behavior disorder (iRBD) and healthy controls. METHODS: 10 patients with MSA, 12 patients with iRBD, 40 patients with PD, and 20 healthy controls completed the study. A passive acoustic prepulse inhibition paradigm was applied with prepulses 5 dB and 15 dB above background noise at 30-, 60-, 120- and 300-ms intervals. RESULTS: Non-parametric analyses showed that MSA patients had significantly lower prepulse inhibition, as measured with max-amplitude, than PD patients and iRBD patients on the 60 ms-85 dB and 120 ms-85 dB inter-stimulus intervals. The same relation was found when using area under the curve. No differences were found between groups for the 30 ms-85 dB and 300 ms-85 dB. Furthermore, blink reflex characteristics such as habituation did not differ between patients and controls. CONCLUSIONS: The present study showed that sensorimotor gating, as measured with PPI, is markedly reduced in MSA. This may be due to the pronounced severity of striatal and brainstem dysfunction, as well as the degeneration of other structures related to the PPI modulating pathways in MSA. PPI may be a non-invasive neurophysiological measure that can aid in the differential diagnosis between PD and MSA.

The health-related, social, and economic consequences of parkinsonism: a controlled national study.

Parkinson's disease (PD) and atypical parkinsonism (AP) cause a significant socioeconomic burden, but there is insufficient information about the total disease burden at a national level. Thus, the goal of this study was to estimate the excess direct and indirect costs of PD and AP in a national sample. Using records from the Danish National Patient Registry (1997-2007), 13,400 PD and 647 AP patients were identified and compared with, respectively, 53,600 and 2,588 control cases randomly selected with respect to age, gender, civil status, and geographic location. Direct costs including frequencies of primary and sector contacts and procedures, and medication from primary and secondary sectors were obtained from the Danish Ministry of Health, the Danish Medicines Agency, and the National Health Security. Indirect costs, which included labor supply and social transfer payments, were based on income data derived from the Coherent Social Statistics. Patients with PD and AP had significantly higher rates of health-related contact and medication use and a higher socioeconomic cost. Furthermore, they had very low employment rates, and those in employment had a lower income level than employed control subjects. The annual mean excess health-related cost was 6,500 ($8,975/£5,543) and 9,771 ($13,491/£8,332) for each patient with PD and AP, respectively. In addition, the patients with PD and AP received an annual mean excess social transfer income of 324 (£276/$447) and 844 (£719/$1,165), respectively. The employment- and health-related consequences could be identified up to 8 years before the first diagnosis and increased with disease advancement. PD and AP have major socioeconomic consequences for patients and society. The health effects are present for up to more than 8 years before a diagnosis of PD/AP.

[Lewy body dementia]. / Lewy body-demens.

Newer estimations indicate a considerable increase in the number of elderly people with dementia and Lewy body dementia (DLB) in Denmark. Simultaneously, the prescription of antipsychotics to elderly patients remains very high in Denmark. This report reflects on the importance of keeping DLB in mind when physicians encounter elderly demented patients with visual hallucinations, fluctuations and parkinsonism, as 50% of patients with DLB have severe sensitivity to antipsychotics. With new clinical criteria including SPECT of dopaminergic transporters, diagnosis has become sufficiently accurate to differentiate between the two diagnoses.

Risk of Parkinson's disease after hospital contact for head injury: population based case-control study.

OBJECTIVE: To determine whether a hospital contact for a head injury increases the risk of subsequently developing Parkinson's disease. DESIGN: Population based case-control study. SETTING: Denmark. PARTICIPANTS: 13 695 patients with a primary diagnosis of Parkinson's disease in the Danish national hospital register during 1986-2006, each matched on age and sex to five population controls selected at random from inhabitants in Denmark alive at the date of the patient's diagnosis (n=68 445). MAIN OUTCOME MEASURES: Hospital contacts for head injuries ascertained from hospital register; frequency of history of head injury. RESULTS: An overall 50% increase in prevalence of hospital contacts for head injury was seen before the first registration of Parkinson's disease in this population (odds ratio 1.5, 95% confidence interval 1.4 to 1.7). The observed association was, however, due almost entirely to injuries that occurred during the three months before the first record of Parkinson's disease (odds ratio 8.0, 5.6 to 11.6), and no association was found between the two events when they occurred 10 or more years apart (1.1, 0.9 to 1.3). CONCLUSIONS: The steeply increased frequency of hospital contacts for a head injury during the months preceding the date at which Parkinson's disease was first recorded is a consequence of the evolving movement disorder rather than its cause.