An evaluation of istradefylline treatment on Parkinsonian motor and cognitive deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque models.

Istradefylline (KW-6002), an adenosine A2A receptor antagonist, is used adjunct with optimal doses of L-3,4-dihydroxyphenylalanine (l-DOPA) to extend on-time in Parkinson's disease (PD) patients experiencing motor fluctuations. Clinical application of istradefylline for the management of other l-DOPA-induced complications, both motor and non-motor related (i.e. dyskinesia and cognitive impairments), remains to be determined. In this study, acute effects of istradefylline (60-100 mg/kg) alone, or with optimal and sub-optimal doses of l-DOPA, were evaluated in two monkey models of PD (i) the gold-standard 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque model of parkinsonian and dyskinetic motor symptoms and (ii) the chronic low dose (CLD) MPTP-treated macaque model of cognitive (working memory and attentional) deficits. Behavioural analyses in l-DOPA-primed MPTP-treated macaques showed that istradefylline alone specifically alleviated postural deficits. When combined with an optimal l-DOPA treatment dose, istradefylline increased on-time, enhanced therapeutic effects on bradykinesia and locomotion, but exacerbated dyskinesia. Istradefylline treatment at specific doses with sub-optimal l-DOPA specifically alleviated bradykinesia. Cognitive assessments in CLD MPTP-treated macaques showed that the attentional and working memory deficits caused by l-DOPA were lowered after istradefylline administration. Taken together, these data support a broader clinical use of istradefylline as an adjunct treatment in PD, where specific treatment combinations can be utilised to manage various l-DOPA-induced complications, which importantly, maintain a desired anti-parkinsonian response.

A longitudinal study of motor subtypes in delirium: frequency and stability during episodes.

OBJECTIVE: Motor-defined subtypes are a promising means of identifying clinically relevant patient subgroups but little is known about their course and stability during a delirium episode. METHODS: We assessed 100 consecutive adult palliative care patients with DSM-IV delirium twice weekly during their episodes using the Delirium Motor Subtype Scale (DMSS), Delirium Rating Scale-Revised-98 (DRS-R98) and Cognitive Test for Delirium (CTD). DMSS subtypes were assigned for each assessment and analysed for stability within patients during episodes. RESULTS: Across all assessments (n=303; mean 3 per patient, range 2-9), subtype occurrence was hypoactive (35%), mixed (26%), hyperactive (15%) and no subtype (24%). "No subtype" was associated with significantly lower DRS-R98 severity scores, of which 80% were subsyndromal, whereas mixed subtype assessments were the most impaired on the DRS-R98 and CTD. Subtypes were stable within delirium episodes in 62% of patients: 29% hypoactive, 18% mixed, 10% hyperactive and 6% no-subtype. The DRS-R98 noncognitive subscale scores differed across groups whereas cognitive subscale scores did not (p<0.001). CONCLUSIONS: We conclude that motor subtypes occur in nearly all patients with full syndromal delirium and are often stable during an episode. Subtypes exhibited comparable levels of cognitive impairment but differed in non-cognitive symptoms, supporting the importance of cognitive testing to detect delirium in less overt cases.

Retrospective chart review of catatonia in child and adolescent psychiatric patients.

OBJECTIVE: Identify the frequency of catatonia among at-risk children and adolescents receiving psychiatric treatment. METHOD: Subjects were children and adolescents (<18 years), who had received psychiatric treatment at a University Hospital during 2004-2009, and were diagnosed with disorders with known risk for catatonia or displayed symptoms suggestive of catatonia. Approval was obtained from the Investigational Review Board (IRB). The first 101 (n = 101) subjects were selected among 570 subjects identified by psychiatric diagnoses: any pervasive developmental disorder, psychosis-NOS (Not Otherwise Specified), intermittent explosive disorder, mental retardation, catatonia and neuroleptic malignant syndrome. Subjects met study-defined criteria for catatonia, if they had three or more of the following symptoms: unexplained agitation/excitement, disturbed or unusual movements, reduced movements, repetitive or stereotyped movements, or reduced or loss of speech. RESULTS: Eighteen (17.8%) subjects, among a group suspected to be at a higher risk for catatonia, met the study-defined criteria for this syndrome. However, only two subjects had been diagnosed by their treatment providers. Higher rates of intellectual disability and aggression were found among the group that met study-criteria. CONCLUSION: We concluded that catatonia is under recognized and undertreated among children and adolescents receiving psychiatric treatment.

Puncture of a lumbar intervertebral disc induces changes in spontaneous pain behavior: an experimental study in rats.

STUDY DESIGN: Changes in spontaneous behavior was studied in rats after a controlled puncture of a lumbar intervertebral disc. OBJECTIVE: To study if puncture of a lumbar disc would induce recordable changes in spontaneous pain behavior. SUMMARY OF BACKGROUND DATA: Anular tears are common and may be found both in patients with low back pain and in asymptomatic patients. It has been suggested that anular injury may relate to low back pain either by stimulation of local sensory receptors in the posterior part of the anulus fibrosus or by ingrowth of newly formed nerve fibers into the deeper parts of the disc. The objective of the study was to analyze if a controlled puncture of a lumbar intervertebral disc might induce recordable changes in spontaneous behavior of rats. METHODS: After anesthesia, the L4-L5 disc was punctured in 10 rats. Ten other rats received sham surgery. Spontaneous behavior was assessed at days 1, 3, 7, 14, and 21 after surgery. RESULTS: Statistically significant differences in behavior were seen at all days analyzed. Most consistent were increases in "grooming" and in "wet-dog shakes." CONCLUSION: Puncture of a lumbar intervertebral disc in the rat produces changes in spontaneous behavior mainly seen as increased "grooming" and "wet-dog shakes," 2 behaviors that have been suggested to indicate stress and pain.

Globus pallidus stimulation improves both motor and nonmotor aspects of quality of life in advanced Parkinson's disease.

Our purpose was to measure the change in quality of life (QoL) following deep brain stimulation of the globus pallidus interna (GPi-DBS) in advanced Parkinson 's disease (PD), and identifies any associations with changes in motor features of the disease. Eleven patients (age range 54-69 years, 2 women) underwent GPi-DBS (4 unilateral, 7 bilateral). Outcome measures included assessment of PD-specific QoL (mean 8 months postsurgery) using the PDQ-39 questionnaire, and standard motor assessments. Off-period UPDRS III motor scores fell by (43 +/- 8)% (mean +/- SEM). Dyskinesia severity was reduced on the abnormal involuntary movement scale by (80 +/- 3)% and UPDRS IVa by (58 +/- 8)%. QoL as assessed by the PDQ39SI improved by (30 +/- 5)%, with significant improvements in mobility, activities of daily living, bodily discomfort, emotional wellbeing, communication, and cognitions subscales. Bilateral and unilateral groups demonstrated equivalent PDQ39SI improvement. QoL improvement was highly correlated with dyskinesia reduction but not reduction in UPDRS score or age at surgery. GPi-DBS markedly improves QoL in advanced PD. The impacts are broad and improve QoL domains not directly affected by the motor symptoms of the disease. Reduced dyskinesia plays a major role in the improvement of QoL in GPi-DBS treated patients.