The Various Ways in Which Birds Blink.

There has, to date, been no systematic study of the various ways in which birds blink. Digital video recordings were made, and studied using still frames, of 524 bird species, mainly in zoos but also in the wild. Videos on 106 species from various sites on the internet were studied, some of which we had also videoed, giving a total of 591 (out of a possible 10,000) species from all 43 orders and 125 (out of a possible 249) families. Digital video recordings were also made of 15 (out of a possible 24) species of crocodile. Three types of blink were observed in birds: (1) Nictitating membrane blinks were rapid and brief (phasic) and occurred mainly on head movement. (2) Upper lid blinks were seen in parrots, owls, pigeons and some others. These were also rapid and brief and accompanied nictitating membrane blinks. (3) Lower lid blinks were slow and sustained (tonic) and occurred with drowsiness and preening. Nictitating membrane blinks and lower lid blinks were seen in crocodiles but not upper lid blinks. Globe retraction, where the eyeball is pulled into the orbit of the skull during a blink, was seen in crocodiles but not birds. Phasic blinks remove debris and moisten the cornea, essential for allowing oxygen to diffuse into the cornea, which has no blood supply. Tonic blinks are probably mainly protective. The orders of birds which have upper lid blinking are not closely related and this feature is probably the result of convergent evolution.

The origin of blinking in both mudskippers and tetrapods is linked to life on land.

Blinking, the transient occlusion of the eye by one or more membranes, serves several functions including wetting, protecting, and cleaning the eye. This behavior is seen in nearly all living tetrapods and absent in other extant sarcopterygian lineages suggesting that it might have arisen during the water-to-land transition. Unfortunately, our understanding of the origin of blinking has been limited by a lack of known anatomical correlates of the behavior in the fossil record and a paucity of comparative functional studies. To understand how and why blinking originates, we leverage mudskippers (Oxudercinae), a clade of amphibious fishes that have convergently evolved blinking. Using microcomputed tomography and histology, we analyzed two mudskipper species, Periophthalmus barbarus and Periophthalmodon septemradiatus, and compared them to the fully aquatic round goby, Neogobius melanostomus. Study of gross anatomy and epithelial microstructure shows that mudskippers have not evolved novel musculature or glands to blink. Behavioral analyses show the blinks of mudskippers are functionally convergent with those of tetrapods: P. barbarus blinks more often under high-evaporation conditions to wet the eye, a blink reflex protects the eye from physical insult, and a single blink can fully clean the cornea of particulates. Thus, eye retraction in concert with a passive occlusal membrane can achieve functions associated with life on land. Osteological correlates of eye retraction are present in the earliest limbed vertebrates, suggesting blinking capability. In both mudskippers and tetrapods, therefore, the origin of this multifunctional innovation is likely explained by selection for increasingly terrestrial lifestyles.

Phenotypic insights into ADCY5-associated disease.

BACKGROUND: Adenylyl cyclase 5 (ADCY5) mutations is associated with heterogenous syndromes: familial dyskinesia and facial myokymia; paroxysmal chorea and dystonia; autosomal-dominant chorea and dystonia; and benign hereditary chorea. We provide detailed clinical data on 7 patients from six new kindreds with mutations in the ADCY5 gene, in order to expand and define the phenotypic spectrum of ADCY5 mutations. METHODS: In 5 of the 7 patients, followed over a period of 9 to 32 years, ADCY5 was sequenced by Sanger sequencing. The other 2 unrelated patients participated in studies for undiagnosed pediatric hyperkinetic movement disorders and underwent whole-exome sequencing. RESULTS: Five patients had the previously reported p.R418W ADCY5 mutation; we also identified two novel mutations at p.R418G and p.R418Q. All patients presented with motor milestone delay, infantile-onset action-induced generalized choreoathetosis, dystonia, or myoclonus, with episodic exacerbations during drowsiness being a characteristic feature. Axial hypotonia, impaired upward saccades, and intellectual disability were variable features. The p.R418G and p.R418Q mutation patients had a milder phenotype. Six of seven patients had mild functional gain with clonazepam or clobazam. One patient had bilateral globus pallidal DBS at the age of 33 with marked reduction in dyskinesia, which resulted in mild functional improvement. CONCLUSION: We further delineate the clinical features of ADCY5 gene mutations and illustrate its wide phenotypic expression. We describe mild improvement after treatment with clonazepam, clobazam, and bilateral pallidal DBS. ADCY5-associated dyskinesia may be under-recognized, and its diagnosis has important prognostic, genetic, and therapeutic implications. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Dysexecutive behaviour following deep brain lesions--a different type of disconnection syndrome?

The suppression of automatic prepotent behaviour in favour of more successful, more 'appropriate' behaviour is the primary function of the frontal lobe. Five frontal-subcortical circuits connect the frontal lobe to the basal ganglia and the thalamus. We report 17 patients with small lesions in the downstream structures of the frontal-subcortical circuits displaying severe dysexecutive behaviour. Positron emission tomography (PET) demonstrated hypometabolism of the frontal lobe in some of these patients. The literature on frontal lobe dysfunction after lesions in the basal ganglia and thalamus is discussed and the semiology of frontal lobe dysfunction in relation to the frontal-subcortical circuits is highlighted. Derived from our findings we suggest a disconnection syndrome of the frontal lobe caused by lesions in the downstream structures of the frontal-subcortical circuits.

The use of Fogs' test to assess associated movements in Parkinsonism, dystonia, and controls.

The Fogs' test elicits non-homologous associated movements which reflect underlying pathology or immaturity of the CNS, but has not been thoroughly studied. We filmed participants performing a modified Fogs' test and developed a reliable scoring system for the associated movements. We assessed scores in healthy controls of all ages and compared scores in dystonia and parkinsonism to age similar controls. Associated movements were marked in children, lessened as they matured into adults, and then increased in old age. Associated movements were marked in dystonia but not in parkinsonism. Our scoring system showed robust inter- and intra-rater reliability. The Fogs' test is a reliable addition to the clinical examination that can be used to screen for both normal and abnormal neurological status. We suggest a potential neural pathway via cervical-lumbosacral connections within the spinal cord which are modulated by propriospinal and cerebral input.

Clinical and physiological assessments for elucidating falls risk in Parkinson's disease.

The study aims were to devise (1) a fall risk screen for people with PD using routine clinical measures and (2) an explanatory (physiological) fall risk assessment for guiding fall prevention interventions. One hundred thirteen people with PD (age 66 +/- 95% CI 1.6 years) underwent clinical assessments and quantitative tests of sway, gait, strength, reaction time, and lower limb sensation. Participants were then followed up for 12 months to determine fall incidence. In the follow-up year, 51 participants (45%) fell one or more times whereas 62 participants (55%) did not fall. Multivariate analyses of routine clinical measures revealed that a fall in the past year, abnormal axial posture, cognitive impairment, and freezing of gait were independent risk factors for falls and predicted 38/51 fallers (75%) and 45/62 non-fallers (73%). A multivariate model combining clinical and physiological measures that elucidate the pathophysiology of falls identified abnormal posture, freezing of gait, frontal impairment, poor leaning balance, and leg weakness as independent risk factors. This model correctly classified 39/51 fallers (77%) and 51/62 non-fallers (82%). Patients with PD at risk of falls can be identified accurately with routine clinical assessments and quantitative physiological tests. Many of the risk factors identified are amenable to targeted intervention.

The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years.

After 20 years follow-up of newly diagnosed patients with Parkinson's disease (PD), 100 of 136 (74%) have died. The mortality rate fell in the first 3 years of treatment, then rose compared to the general population, the standardized mortality ratio from 15 to 20 years reaching 3.1. Drug induced dyskinesia and end of dose failure were experienced by most patients, but the main current problems relate to the non-levodopa responsive features of the disease. Dementia is present in 83% of 20-year survivors. Dementia correlates with increasing age and probably reflects an interplay of multiple pathologies. Seventeen people with dementia had postmortems. Eight had diffuse Lewy bodies as the only cause of dementia, while others had mixed neuropathology. Only one person lives independently and 48% are in nursing homes. Excessive daytime sleepiness is noted in 70%, falls have occurred in 87%, freezing in 81%, fractures in 35%, symptomatic postural hypotension in 48%, urinary incontinence in 71%, moderate dysarthria in 81%, choking in 48%, and hallucinations in 74%. The challenge is to understand the cellular mechanisms underlying the diverse features of advanced PD that go far beyond a lack of dopamine.

Carotid stenting and cerebral hyperperfusion syndrome.

We present a patient who became hemiparetic and drowsy 30 min after insertion of a carotid artery stent for severe (>80%) asymptomatic left common carotid artery stenosis. A carotid angiogram at this time showed widely patent vessels. Non-contrast head computed tomography showed a diffuse increase in signal intensity in the distribution of the left middle cerebral artery. Repeat computed tomography 8 days later showed no evidence of cerebral infarction or haemorrhage. The patient's arm remained weak for several months. A diagnosis of cerebral hyperperfusion syndrome was made. The features of this unusual cause of stroke are reviewed.

Evidence for L-dopa incorporation into cell proteins in patients treated with levodopa.

Levodopa (L-dopa) is the most widely used agent for the symptomatic relief of Parkinson's disease. There is concern that chronic L-dopa treatment may be detrimental, with some studies suggesting that L-dopa may be neurotoxic. A potentially important mechanism whereby L-dopa may exert neurotoxic effects has been overlooked: that of the incorporation of L-dopa into proteins by protein synthesis. L-Dopa competes with tyrosine as a substrate in protein synthesis in vitro. We provide evidence that L-dopa can also be incorporated into proteins in vivo. Blood from L-dopa-treated and -non-treated patients was separated into protein, erythrocyte and lymphocyte fractions and levels of protein-incorporated dopa quantified by HPLC. Levels of protein-incorporated dopa were significantly increased in lymphocyte cell proteins from L-dopa-treated patients. This has not arisen from oxidative pathways as there was no evidence of oxidative damage to proteins. In addition, there was no increase in protein-incorporated dopa in erythrocytes, which are not actively synthesizing proteins. We suggest that protein-incorporated dopa could also be generated in the CNS. The accumulation of protein-incorporated dopa in cells is associated with oxidative stress and impaired function and could contribute to some of the problems associated with long-term L-dopa treatment.

Comparison of motor, cognitive, and behavioral features in progressive supranuclear palsy and Parkinson's disease.

Major clinical features and global measures were systematically evaluated and compared in progressive supranuclear palsy (PSP) and Parkinson's disease (PD). In addition to gaze palsy and early postural instability in PSP, absence of levodopa-induced dyskinesia, frontalis muscle overactivity, primitive reflexes, visuospatial impairment, and substantial frontal behavioral disturbances differentiated almost all patients with this disorder from PD. For PSP, behavioral changes related to severity of general disability, thereby challenging previous models of relationships between behavior, motor, and cognitive disturbance for this disorder.

A matter of motion or an emotional matter? Management of depression in Parkinson's disease.

Depression is one of the most frequent comorbidities occurring in Parkinson's disease, affecting up to 50% of patients. Depression is associated with severe negative symptoms and has been shown to contribute to an increased rate of decline of both cognitive and motor function, profoundly impacting on the patient's quality of life. The symptoms of depression overlap with the motor features of Parkinson's disease, making detection difficult. Moreover, the lack of specialized screening tools means that depression remains undiagnosed and untreated in a high percentage of patients. However, depression in Parkinson's disease, when identified early, can be effectively treated with a variety of antidepressant medications, improving quality of life and preserving daily function. The focus of this review is to provide an overview of current knowledge regarding depression in Parkinson's disease, followed by a practical discussion addressing the issues of the detection, diagnosis and treatment.

Sydney Multicenter Study of Parkinson's disease: non-L-dopa-responsive problems dominate at 15 years.

One-third of the 149 people recruited 15 to 18 years ago in the Sydney Multicenter Study of Parkinson's disease have survived. The original study compared low-dose levodopa with low-dose bromocriptine. We now report the problems experienced by people who survive 15 years from diagnosis. The standardized mortality ratio is significantly elevated at 1.86 and is not significantly different between treatment arms. Falls occur in 81% of patients, and 23% sustained fractures. Cognitive decline is present in 84%, and 48% fulfill the criteria for dementia. Hallucinations and depression are experienced by 50%. Choking has occurred in 50%, symptomatic postural hypotension in 35%, and urinary incontinence in 41%. No patient is still employed, and 40% of patients live in aged care facilities. Although approximately 95% have experienced L-dopa-induced dyskinesia/dystonia and end of dose failure of medication, in the majority, these symptoms are not disabling. Dyskinesia and dystonia were delayed by early use of bromocriptine, but end-of-dose failure appeared at a similar time once L-dopa was added. The rate of disease progression is similar in both arms of the study. We conclude that the most disabling long-term problems of Parkinson's disease relate to the emergence of symptoms that are not improved by L-dopa. Neuroprotective interventions in Parkinson's disease should be judged by their ability to improve non-L-dopa-responsive aspects of the disease, rather than just by their capacity to delay the introduction of L-dopa or reduce its associated side effects.

Movement disorder emergencies.

Movement disorders may present acutely, and failure to recognize and exclude important differential diagnoses can result in significant morbidity or mortality. Unfortunately, much of the literature pertaining to this topic is scattered and not easily accessible. This review aims to address this deficit. Movement disorder emergencies are discussed according to their most likely mode of presentation. Diagnostic considerations and early management principles are reviewed, along with appropriate pathophysiology where relevant.

Athetosis II: the syndrome of mild athetoid cerebral palsy.

We describe 8 patients who presented with continuous, irregular movements occurring independently in individual fingers and, in some cases, toes, in the setting of mild dystonia present since early childhood and not associated with major disability. The finger movements varied from low-amplitude quivering or wriggling to larger amplitude movements in the plane of abduction-adduction as well as flexion-extension; they were asymmetrical but not unilateral. Quivering or working of the facial muscles was seen in 5 patients. Most patients reported worsening of the movements over the years, but there was no other evidence of a progressive neurological disease. We classify the movement disorder as athetosis as described by Hammond and Shaw and the syndrome as mild athetoid cerebral palsy.

Dopa-responsive parkinsonism secondary to right temporal lobe haemorrahage.

A 46-year-old man developed a symmetrical parkinsonian syndrome 7 weeks after large right temporal intracerebral haemorrhage resulting from a ruptured arteriovenous malformation. His signs included bradykinesia, rigidity, start hesitation, and poor postural reflexes, without a resting tremor. He also had signs of a Parinaud's syndrome. Computed tomography and magnetic resonance imaging of the brain demonstrated changes in the right temporal lobe associated with the haemorrhage but no abnormality of the basal ganglia or midbrain. Levodopa therapy produced a dramatic improvement within a few days of commencement. We postulate that the parkinsonism resulted from midbrain compression secondary to transtentorial herniation. Although parkinsonism is a rare complication of lobar intracerebral haemorrhage, it is important to recognise as it may be potentially treatable.

Loss of reflex inhibition following muscle tendon stimulation in essential tremor.

Electrical stimulation of human upper limb muscle tendons produces a reflex inhibition (I(1)) in the same muscles. This inhibition is reduced in Parkinson's disease (PD), prompting a similar study of essential tremor (ET). In essential tremor, two of eight subjects had no discernible inhibition, even following supramaximal stimulation (< 80 mA) of the tendons from extensor digitorum communis and extensor pollicis brevis. In the remaining six subjects, the mean thresholds for I(1) in these muscles were increased by 270 and 320%, respectively, relative to controls. The maximal amplitude of the inhibition was significantly reduced in the ET group, as was the following excitation (E(1)). The latency and duration of I(1) were not different in ET subjects and controls. The maximal duration of I(1) was correlated with tremor frequency in individuals, and tendon stimulation was effective in initiating ongoing tremor cycles. These results disclose a peripheral reflex abnormality in ET that is mediated by tendon afferents and can be linked to the coexistent tremor. The response in ET was distinguished from that in PD by its different time-course and by failure of the response to appear in the antagonist muscle. The abnormality may prove a useful marker for ET, which currently lacks a definitive pathological or neurophysiological marker to support objective clinical diagnosis.