Health at the writing desk of John Ruskin: a study of handwriting and illness.

Though John Ruskin (1819-1900) is remembered principally for his work as a theorist, art critic and historian of visual culture, he wrote exhaustively about his health in his correspondence and diaries. Ruskin was prone to recurring depressive and hypochondriacal feelings in his youth and adulthood. In 1871, at the age of 52 years, he developed an illness with relapsing psychiatric and neurological features. He had a series of attacks of brain disturbance, and a deterioration of his mental faculties affected his writing for years before curtailing his career a decade before he died. Previous writers have suggested he had a psychiatric malady, perhaps schizophrenia or schizoaffective disorder. But the more obvious conclusion from a close medical reading of Ruskin's descriptions of his illness is he had some sort of 'organic' brain illness. This paper aims to give insight into the relationship between Ruskin's state of well-being and the features of his writing through a palaeographical study of his letters and diary entries. We examine the handwriting for physical traces of Ruskin's major brain illness, guided by the historical narrative of the illness. We also examine Ruskin's recording of his experiences for what they reveal about the failure of his health and its impact on his work. Ruskin's handwriting does not have clear-cut pathological features before around 1885, though suggestions of subtle writing deficits were present as early as 1876. After 1887, Ruskin's handwriting shows fixed pathological signs-tremor, disturbed letter formation and features that reflect a slow and laborious process of writing. These observations are more than could be explained by normal ageing, and suggest the presence of a neurological deficit affecting writing control. Our findings are consistent with conclusions that we drew from the historical record-that John Ruskin had an organic neurological disorder with cognitive, behavioural, psychiatric and motor effects.

A New Evolutionary Algorithm-Based Home Monitoring Device for Parkinson's Dyskinesia.

Parkinson's disease (PD) is a neurodegenerative movement disorder. Although there is no cure, symptomatic treatments are available and can significantly improve quality of life. The motor, or movement, features of PD are caused by reduced production of the neurotransmitter dopamine. Dopamine deficiency is most often treated using dopamine replacement therapy. However, this therapy can itself lead to further motor abnormalities referred to as dyskinesia. Dyskinesia consists of involuntary jerking movements and muscle spasms, which can often be violent. To minimise dyskinesia, it is necessary to accurately titrate the amount of medication given and monitor a patient's movements. In this paper, we describe a new home monitoring device that allows dyskinesia to be measured as a patient goes about their daily activities, providing information that can assist clinicians when making changes to medication regimens. The device uses a predictive model of dyskinesia that was trained by an evolutionary algorithm, and achieves AUC>0.9 when discriminating clinically significant dyskinesia.

Study of levodopa response in Parkinson's disease: Observations on rates of motor progression.

INTRODUCTION: It is important to understand how the rate of motor progression in PD relates to dopaminergic treatment. METHODS: The methods for this study comprised prospective defined off state measurements of the levodopa response at 3-year intervals over a mean 13.3-year period in 34 patients enrolled before treatment initiation. RESULTS: Despite worsening of on and off scores, the magnitude of the l-dopa short-duration response is maintained as the disease progresses. A linear mixed-effects regression analysis of off phase motor scores showed a yearly deterioration of 2.3% of the maximum disability score. Greater motor disability at the commencement of treatment was an independent predictor of faster progression. Demented patients had worse motor function than those without dementia (P = 0.02), and motor deficit appeared to accelerate toward the end of the disease course in patients who had died. CONCLUSIONS: These observations should inform clinical trial design for drugs with possible neuroprotective properties.

Deep learning of Parkinson's movement from video, without human-defined measures.

BACKGROUND: The core clinical sign of Parkinson's disease (PD) is bradykinesia, for which a standard test is finger tapping: the clinician observes a person repetitively tap finger and thumb together. That requires an expert eye, a scarce resource, and even experts show variability and inaccuracy. Existing applications of technology to finger tapping reduce the tapping signal to one-dimensional measures, with researcher-defined features derived from those measures. OBJECTIVES: (1) To apply a deep learning neural network directly to video of finger tapping, without human-defined measures/features, and determine classification accuracy for idiopathic PD versus controls. (2) To visualise the features learned by the model. METHODS: 152 smartphone videos of 10s finger tapping were collected from 40 people with PD and 37 controls. We down-sampled pixel dimensions and videos were split into 1 s clips. A 3D convolutional neural network was trained on these clips. RESULTS: For discriminating PD from controls, our model showed training accuracy 0.91, and test accuracy 0.69, with test precision 0.73, test recall 0.76 and test AUROC 0.76. We also report class activation maps for the five most predictive features. These show the spatial and temporal sections of video upon which the network focuses attention to make a prediction, including an apparent dropping thumb movement distinct for the PD group. CONCLUSIONS: A deep learning neural network can be applied directly to standard video of finger tapping, to distinguish PD from controls, without a requirement to extract a one-dimensional signal from the video, or pre-define tapping features.

Longitudinal study of levodopa in Parkinson's disease: effects of the advanced disease phase.

Thirty-four patients have been studied from the time of initiation of pharmacological treatment in a long-term prospective study of levodopa effects and disease progression in Parkinson's disease. Objective motor scoring of the response to levodopa in defined off states was performed every 3 years. The mean time from the initiation of levodopa treatment to the most recent measurements was 18.2 years. Of 8 patients who are still alive, only 3 had none of the features of the advanced disease phase (dementia, hallucinations, frequent falling). Off-phase motor function worsened at a yearly rate of 1.9% of the maximum disability score, although the plots of the serial scores showed that the magnitude of the levodopa response is well preserved. There was little difference in the rate of progression between patients with tremor-dominant and non-tremor-dominant motor subtypes. Those who developed dementia had more rapid deterioration of motor scores, with significantly worse off-phase (P = .008) and on-phase (P = .03) motor function. A graph of serial scores of patients who have died, aligned for time of death, showed an upward curving trend of motor disability in the last 5 years of the disease course. Its advanced phase may reveal that Parkinson's disease has an exponential pattern of progression.

Palliative care for Parkinson's disease: a summary of the evidence and future directions.

BACKGROUND: Parkinson's disease is a common, life-limiting, neurodegenerative condition. Despite calls for improved access to palliative care for people with Parkinson's disease, services have been slow in developing. Obstacles include poor understanding and recognition of palliative care needs, the role for specialist palliative care services and an agreed structure for sustainable palliative care provision. AIM: To summarise the evidence base for palliative care in Parkinson's disease, linking current understanding with implications for clinical practice and identifying areas for future research. WHAT IS KNOWN: Convention recognises a final 'palliative phase' in Parkinson's disease, while qualitative studies suggest the presence of palliative care need in Parkinson's disease from diagnosis. Clinical tools to quantify palliative symptom burden exist and have helped to identify targets for intervention. Dementia is highly prevalent and influences many aspects of palliative care in Parkinson's disease, with particular implications for end-of-life care and advance care planning. IMPLICATIONS FOR CLINICAL PRACTICE: The 'palliative phase' represents a poor entry point for consideration of palliative care need in Parkinson's disease. An alternative, integrated model of care, promoting collaboration between specialist palliative and neurological services, is discussed, along with some specific palliative interventions. WHAT IS UNKNOWN: Limited evidence exists regarding timing of palliative interventions, triggers for specialist referral and management of terminal care. IMPLICATIONS FOR FUTURE RESEARCH: Research examining access to palliative care and management of terminal symptoms will assist development of sustainable, integrated palliative care services for Parkinson's disease.

Parkinsonian Hand or Clinician's Eye? Finger Tap Bradykinesia Interrater Reliability for 21 Movement Disorder Experts.

BACKGROUND: Bradykinesia is considered the fundamental motor feature of Parkinson's disease (PD). It is central to diagnosis, monitoring, and research outcomes. However, as a clinical sign determined purely by visual judgement, the reliability of humans to detect and measure bradykinesia remains unclear. OBJECTIVE: To establish interrater reliability for expert neurologists assessing bradykinesia during the finger tapping test, without cues from additional examination or history. METHODS: 21 movement disorder neurologists rated finger tapping bradykinesia, by Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Modified Bradykinesia Rating Scale (MBRS), in 133 videos of hands: 73 from 39 people with idiopathic PD, 60 from 30 healthy controls. Each neurologist rated 30 randomly-selected videos. 19 neurologists were also asked to judge whether the hand was PD or control. We calculated intraclass correlation coefficients (ICC) for absolute agreement and consistency of MDS-UPDRS ratings, using standard linear and cumulative linked mixed models. RESULTS: There was only moderate agreement for finger tapping MDS-UPDRS between neurologists, ICC 0.53 (standard linear model) and 0.65 (cumulative linked mixed model). Among control videos, 53% were rated > 0 by MDS-UPDRS, and 24% were rated as bradykinesia by MBRS subscore combination. Neurologists correctly identified PD/control status in 70% of videos, without strictly following bradykinesia presence/absence. CONCLUSION: Even experts show considerable disagreement about the level of bradykinesia on finger tapping, and frequently see bradykinesia in the hands of those without neurological disease. Bradykinesia is to some extent a phenomenon in the eye of the clinician rather than simply the hand of the person with PD.

Does serum neurofilament light help predict accelerated cognitive ageing in unimpaired older adults?

Introduction: Neurofilament light (NfL) is a blood biomarker of neurodegeneration. While serum NfL levels have been demonstrated to increase with normal ageing, the relationship between serum NfL levels and normal age-related changes in cognitive functions is less well understood. Methods: The current study investigated whether cross-sectional serum NfL levels measured by single molecule array technology (Simoa®) mediated the effect of age on cognition, measured by a battery of neuropsychological tests administered biannually for 8 years, in a cohort of 174 unimpaired older adults (≥50 years) from the Tasmanian Healthy Brain Project. Mediation analysis was conducted using latent variables representing cognitive test performance on three cognitive domains - episodic memory, executive function, and language (vocabulary, comprehension, naming). Cognitive test scores for the three domains were estimated for each participant, coincident with blood collection in 2018 using linear Bayesian hierarchical models. Results: Higher serum NfL levels were significantly positively associated with age (p < 0.001 for all domains). Cognitive test scores were significantly negatively associated with age across the domains of executive function (p < 0.001), episodic memory (p < 0.001) and language (p < 0.05). However, serum NfL levels did not significantly mediate the relationship between age and cognitive test scores across any of the domains. Discussion: This study adds to the literature on the relationship between serum NfL levels and cognition in unimpaired older adults and suggests that serum NfL is not a pre-clinical biomarker of ensuing cognitive decline in unimpaired older adults.

Sex-Specific Protective Effects of Cognitive Reserve on Age-Related Cognitive Decline: A 5-Year Prospective Cohort Study.

BACKGROUND AND OBJECTIVES: Females have a higher age-adjusted incidence of Alzheimer disease than males but the reasons for this remain unclear. One proposed contributing factor is that, historically, females had less access to education and, therefore, may accumulate less cognitive reserve. However, educational attainment is confounded by IQ, which in itself is a component of cognitive reserve and does not differ between sexes. Steeper age-related cognitive declines are associated with increased risk of dementia. We, therefore, evaluated the moderating effects of 2 proxies for cognitive reserve, education and IQ, on the steepness of age-related declining cognitive trajectories in unimpaired older males and females. METHODS: The Tasmanian Healthy Brain Project, a long-term cohort study, recruited healthy Australians aged 50-80 years without cognitive impairment. Baseline cognitive reserve was measured using educational history and IQ, measured by the Wechsler Test of Adult Reading, Full Scale Predicted IQ (WTAR-FSIQ). Cognitive trajectories for language, executive function, and episodic and working memory over 5 years were extracted from neuropsychological assessments. The adjusted effects of education, estimated IQ, and APOE allelic variant on cognitive trajectories were compared between males and females. RESULTS: Five hundred sixty-two individuals (mean [SD] age 60 [6.7] years; 68% male; 33% APOE ε4+) were followed up over 5 years with 1,924 assessments and 24,946 cognitive test scores (annualized attrition rate 6.6% per year). Estimated IQ correlated with years of education (p < 0.001). Estimated IQ interacted with sex to moderate age-related cognitive trajectories (p = 0.03; adjusted for education); lower IQ males experienced steeper declining trajectories than higher IQ males, but lower IQ females had similar steepness of declining trajectories to higher IQ females. Education was not associated with rate of cognitive decline (p = 0.67; adjusted for WTAR-FSIQ). There were no significant differences in age-related cognitive trajectories between APOE genotypes in either sex. DISCUSSION: IQ, a measure of cognitive reserve, predicted the steepness of declining cognitive trajectories in males only. Education did not explain as much variation in cognitive trajectories as IQ. Our findings do not support the hypothesis that historical sex disparities in access to education contribute to the higher female incidence of Alzheimer disease.

To the emergency room and back again: Circular healthcare pathways for acute functional neurological disorders.

BACKGROUND AND OBJECTIVES: Studies of Functional Neurological Disorders (FND) are usually outpatient-based. To inform service development, we aimed to describe patient pathways through healthcare events, and factors affecting risk of emergency department (ED) reattendance, for people presenting acutely with FND. METHODS: Acute neurology/stroke teams at a UK city hospital were contacted regularly over 8 months to log FND referrals. Electronic documentation was then reviewed for hospital healthcare events over the preceding 8 years. Patient pathways through healthcare events over time were mapped, and mixed effects logistic regression was performed for risk of ED reattendance within 1 year. RESULTS: In 8 months, 212 patients presented acutely with an initial referral suggesting FND. 20% had subsequent alternative diagnoses, but 162 patients were classified from documentation review as possible (17%), probable (28%) or definite (55%) FND. In the preceding 8 years, these 162 patients had 563 ED attendances and 1693 inpatient nights with functional symptoms, but only 26% were referred for psychological therapy, only 66% had a documented diagnosis, and care pathways looped around ED. Three better practice pathway steps were each associated with lower risk of subsequent ED reattendance: documented FND diagnosis (OR = 0.32, p = 0.004), referral to clinical psychology (OR = 0.35, p = 0.04) and outpatient neurology follow-up (OR = 0.25, p < 0.001). CONCLUSION: People that present acutely to a UK city hospital with FND tend to follow looping pathways through hospital healthcare events, centred around ED, with low rates of documented diagnosis and referral for psychological therapy. When better practice occurs, it is associated with lower risk of ED reattendance.

A randomized, double-blind, placebo-controlled trial of levetiracetam for dyskinesia in Parkinson's disease.

BACKGROUND: This randomized double blind, placebo-controlled crossover study investigated the antidyskinetic effects of levetiracetam in Parkinson's disease. METHODS: Sixteen participants with levodopa-induced dyskinesia were enrolled. Hourly videotaped dyskinesia assessments scored by the Goetz method and hourly Unified Parkinson's Disease Rating Scale motor subscale scoring were conducted on 1 day at the end of each treatment period. RESULTS: Dyskinesia was slightly less on placebo (P = .26). Patient diary records also showed less dyskinesia on placebo (P = .10). Parkinsonism was a little worse on levetiracetam, at borderline statistical significance (P = .05). CONCLUSIONS: Levetiracetam was well tolerated at doses up to 2000 mg per day, but we did not detect any antidyskinetic properties.

A practical guide to the differential diagnosis of tremor.

Tremor is, by definition, a rhythmic oscillation of a body part. It is the most prevalent movement disorder in clinical medicine, so doctors working in many specialities and in general practice can expect to encounter it. Most tremors can be classified on the basis of four observable clinical characteristics: anatomical pattern; the relative prominence of the tremor at rest, on maintaining a posture, and with action; tremor frequency; and tremor amplitude. A resting tremor suggests Parkinson's disease, and the diagnosis then depends on a judgement about whether the patient has other signs of parkinsonism. The most common causes of postural tremor are physiological tremor, essential tremor and drug-induced tremor. The differential diagnosis may also include dystonic tremor and psychogenic tremor, while metabolic tremor caused by thyrotoxicosis should be considered in any recent-onset postural tremor. Wilson's disease and fragile X-associated tremor/ataxia syndrome are rarer conditions that may present with tremor and are very important to identify. There is a small but genuine diagnostic grey zone between Parkinson's disease and more benign tremor disorders such as essential tremor and dystonic tremor, in which resting and postural tremor coexist with mild or equivocal non-tremor parkinsonian signs. The authors review clinical features and investigational techniques that may help to discriminate this group of hard-to-classify tremors.

Accuracy of Smartphone Video for Contactless Measurement of Hand Tremor Frequency.

BACKGROUND: Computer vision can measure movement from video without the time and access limitations of hospital accelerometry/electromyography or the requirement to hold or strap a smartphone accelerometer. OBJECTIVE: To compare computer vision measurement of hand tremor frequency from smartphone video with a gold standard measure accelerometer. METHODS: A total of 37 smartphone videos of hands, at rest and in posture, were recorded from 15 participants with tremor diagnoses (9 Parkinson's disease, 5 essential tremor, 1 functional tremor). Video pixel movement was measured using the computing technique of optical flow, with contemporaneous accelerometer recording. Fast Fourier transform and Bland-Altman analysis were applied. Tremor amplitude was scored by 2 clinicians. RESULTS: Bland-Altman analysis of dominant tremor frequency from smartphone video compared with accelerometer showed excellent agreement: 95% limits of agreement -0.38 Hz to +0.35 Hz. In 36 of 37 videos (97%), there was <0.5 Hz difference between computer vision and accelerometer measurement. There was no significant correlation between the level of agreement and tremor amplitude. CONCLUSION: The study suggests a potential new, contactless point-and-press measure of tremor frequency within standard clinical settings, research studies, or telemedicine.

Significant cognitive decline in Parkinson's disease exacerbates the reliance on visual feedback during upper limb reaches.

While upper limb reaches are often made in a feed-forward manner, visual feedback during the movement can be used to guide the reaching hand towards a target. In Parkinson's disease (PD), there is evidence that the utilisation of this visual feedback is increased. However, it is unclear if this is due solely to the characteristic slowness of movements in PD providing more opportunity for incorporating visual feedback to modify reach trajectories, or whether it is due to cognitive decline impacting (feed-forward) movement planning ability. To investigate this, we compared reaction times and movement times of reaches to a target in groups of PD patients with normal cognition (PD-NC), mild cognitive impairment (PD-MCI) or dementia (PD-D), to that of controls with normal cognition (CON-NC) or mild cognitive impairment (CON-MCI). Reaches were undertaken with full visual feedback (at a 'natural' and 'fast-as-possible' pace); with reduced visual feedback of the reaching limb to an illuminated target; and without any visual feedback to a remembered target with eyes closed. The PD-D group exhibited slower reaction times than all other groups across conditions, indicative of less efficient movement planning. When reaching to a remembered target with eyes closed, all PD groups exhibited slower movement times relative to their natural pace with full visual feedback. Crucially, this relative slowing was most pronounced for the PD-D group, compared to the PD-MCI and PD-NC groups, suggesting that substantial cognitive decline in PD exacerbates dependence on visual feedback during upper limb reaches.

Management of Secondary Poor Response to Botulinum Toxin in Cervical Dystonia: A Multicenter Audit.

BACKGROUND: Botulinum toxin A (BoNT-A) is an effective treatment for cervical dystonia. Nevertheless, up to 30% to 40% patients discontinue treatment, often because of poor response. The British Neurotoxin Network (BNN) recently published guidelines on the management of poor response to BoNT-A in cervical dystonia, but adherence to these guidelines has not yet been assessed. OBJECTIVES: To assess adherence to and usefulness of BNN guidelines in clinical practice. METHODS: We undertook a retrospective medical notes audit of adherence to the BNN guidelines in 3 United Kingdom tertiary neurosciences centers. RESULTS: Of 76 patients identified with poor response, 42 (55%) had a suboptimal response and, following BNN recommendations, 25 of them (60%) responded to adjustments in BoNT dose, muscle selection or injection technique. Of the remaining 34 (45%) patients with no BoNT response, 20 (59%) were tested for immune resistance, 8 (40%) of whom showed resistance. Fourteen (18%) of all patients were switched to BoNT-B, and 27 (36%) were referred for deep brain stimulation surgery. In those not immune to BoNT-A, clinical improvement was seen in 5 (41%) after adjusting their dose and injection technique. CONCLUSION: Our audit shows that optimizing BoNT dose or injection strategy largely led to improvements in those with suboptimal response and in those reporting no response without resistance. It would be helpful to standardize investigations of potential resistance in those with no therapeutic response.

Seeing the unseen: Could Eulerian video magnification aid clinician detection of subclinical Parkinson's tremor?

INTRODUCTION: Eulerian magnification amplifies very small movements in video, revealing otherwise invisible motion. This raises the possibility that it could enable clinician visualisation of subclinical tremor using a standard camera. We tested whether Eulerian magnification of apparently atremulous hands reveals a Parkinsonian tremor more frequently in Parkinson's than in controls. METHOD: We applied Eulerian magnification to smartphone video of 48 hands that appeared atremulous during recording (22 hands from 11 control participants, 26 hands from 17 idiopathic Parkinson's participants). Videos were rated for Parkinsonian tremor appearance (yes/no) before and after Eulerian magnification by three movement disorder specialist neurologists. RESULTS: The proportion of hands correctly classified as Parkinsonian or not by clinicians was significantly higher after Eulerian magnification (OR = 2.67; CI = [1.39, 5.17]; p < 0.003). Parkinsonian-appearance tremors were seen after magnification in a number of control hands, but the proportion was greater in the Parkinson's hands. CONCLUSION: Eulerian magnification slightly improves clinician ability to identify apparently atremulous hands as Parkinsonian. This suggests that some of the apparent tremor revealed may be subclinical Parkinson's (pathological) tremor, and Eulerian magnification may represent a first step towards contactless visualisation of such tremor. However, the technique also reveals apparent tremor in control hands. Therefore, our method needs additional elaboration and would not be of direct clinical use in its current iteration.

The discerning eye of computer vision: Can it measure Parkinson's finger tap bradykinesia?

OBJECTIVE: The worldwide prevalence of Parkinson's disease is increasing. There is urgent need for new tools to objectively measure the condition. Existing methods to record the cardinal motor feature of the condition, bradykinesia, using wearable sensors or smartphone apps have not reached large-scale, routine use. We evaluate new computer vision (artificial intelligence) technology, DeepLabCut, as a contactless method to quantify measures related to Parkinson's bradykinesia from smartphone videos of finger tapping. METHODS: Standard smartphone video recordings of 133 hands performing finger tapping (39 idiopathic Parkinson's patients and 30 controls) were tracked on a frame-by-frame basis with DeepLabCut. Objective computer measures of tapping speed, amplitude and rhythm were correlated with clinical ratings made by 22 movement disorder neurologists using the Modified Bradykinesia Rating Scale (MBRS) and Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). RESULTS: DeepLabCut reliably tracked and measured finger tapping in standard smartphone video. Computer measures correlated well with clinical ratings of bradykinesia (Spearman coefficients): -0.74 speed, 0.66 amplitude, -0.65 rhythm for MBRS; -0.56 speed, 0.61 amplitude, -0.50 rhythm for MDS-UPDRS; -0.69 combined for MDS-UPDRS. All p < .001. CONCLUSION: New computer vision software, DeepLabCut, can quantify three measures related to Parkinson's bradykinesia from smartphone videos of finger tapping. Objective 'contactless' measures of standard clinical examinations were not previously possible with wearable sensors (accelerometers, gyroscopes, infrared markers). DeepLabCut requires only conventional video recording of clinical examination and is entirely 'contactless'. This next generation technology holds potential for Parkinson's and other neurological disorders with altered movements.

Longitudinal study of the levodopa motor response in Parkinson's disease: relationship between cognitive decline and motor function.

In this prospective study of 34 patients with Parkinson's disease (PD), measurements of the short duration levodopa motor response have been performed every 3 years in defined off states. The mean time from initiation of levodopa treatment was 14.8 years, and 17 patients survived to the latest assessment stage. Off phase motor function worsened at a yearly rate of 2.2% of the maximum disability score. The magnitude of the levodopa response is well preserved as the disease progresses, and patients who developed motor fluctuations maintained better on phase motor function than nonfluctuators (P = 0.01). Ten patients, of whom 5 survive, developed dementia. There was no difference in pretreatment disability or initial levodopa response between demented and nondemented subjects. However, dementia was associated with worse on and off motor disability scores after 11 and 14 years (P < 0.001), and a smaller levodopa response magnitude after 14 years (P = 0.008). The plot of sequential scores shows the association between cognitive decline and accelerating increase in motor disability. This suggests that the advanced phase of PD, when Lewy body pathology involves the cerebral cortex, progresses in an exponential rather than linear fashion.