The Thermodynamic Consequences of Parkinson's Disease.

Several lines of evidence point to a pervasive disturbance of energy balance in Parkinson's disease (PD). Weight loss, common and multifactorial, is the most observable sign of this. Bradykinesia may be best understood as an underinvestment of energy in voluntary movement. This accords with rodent experiments that emphasise the importance of dopamine in allocating motor energy expenditure. Oxygen consumption studies in PD suggest that, when activities are standardised for work performed, these inappropriate energy thrift settings are actually wasteful. That the dopaminergic deficit of PD creates a problem with energy efficiency highlights the role played by the basal ganglia, and by dopamine, in thermodynamic governance. This involves more than balancing energy, since living things maintain their internal order by controlling transformations of energy, resisting probabilistic trends to more random states. This review will also look at recent research in PD on the analysis of entropy-an information theory metric of predictability in a message-in recordings from the basal ganglia. Close relationships between energy and information converge around the concept of entropy. This is especially relevant to the motor system, which regulates energy exchange with the outside world through its flow of information. The malignant syndrome in PD, a counterpart of neuroleptic malignant syndrome, demonstrates how much thermodynamic disruption can result from breakdown of motor signalling in an extreme hypodopaminergic state. The macroenergetic disturbances of PD are consistent with a unifying hypothesis of dopamine's neurotransmitter actions-to adapt energy expenditure to prevailing economic circumstances.

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.

Propensity for seizure-related cortical laminar necrosis in hepatic encephalopathy.

•Hepatic encephalopathy may predispose to seizure-related cortical laminar necrosis.•Elevated ammonia levels potentially compound the excitotoxic effects of epilepsy.•Early identification and treatment of seizures in liver disease could be protective.

Inferring the long duration response to levodopa in Parkinson's disease.

INTRODUCTION: The long duration response to levodopa in Parkinson's disease outlasts drug elimination by days to weeks. Though a substantive part of anti-parkinsonian motor benefit, it cannot easily be observed. OBJECTIVES: To infer the magnitude of the long duration response during the first decade of Parkinson's disease and identify factors that influence it. METHODS: Serial practically defined off scores of 24 patients from a longitudinal study of levodopa short duration response were used to establish their rate of motor progression. A line of notional untreated disability (as if drug treatment had never been given) with the same progression gradient was the basis for calculation of the long duration response. Predictors of mean long duration response amplitude were identified using a multiple linear regression model. RESULTS: Over a mean treatment period of 16.6 ±â€¯4.4 years, annual increase in motor disability was 2.3% of the maximum score. The long duration response composed 49% of total levodopa response during the first decade of treatment, and this proportion was significantly higher soon after commencing levodopa (p = 0.001). Higher pre-treatment motor score (r = 0.60) and lower MMSE (r = 0.60) were the main predictors of a larger long duration response. There was little correlation between long and short duration responses. CONCLUSIONS: Long duration responses contribute almost half of the total levodopa benefit during the first decade of treatment. An appreciation of both long and short duration components of drug symptomatic effects is important in clinical trial design to investigate possible neuroprotective treatments.

Depression and psychosis in ADCY5-related dyskinesia-part of the phenotypic spectrum?

This report details prominent neuropsychiatric features in one family with an ADCY5 gene mutation. ADCY5 mutations cause a variable motor phenotype, though most cases have some core involuntary movement features. The psychiatric aspects of the disorder have not been emphasised in previous publications. We discuss possible pathogenesis.

A History of Dystonia: Ancient to Modern.

Before 1911, when Hermann Oppenheim introduced the term dystonia, this movement disorder lacked a unifying descriptor. While words like epilepsy, apoplexy, and palsy have had their meanings since antiquity, references to dystonia are much harder to identify in historical documents. Torticollis is an exception, although there is difficulty distinguishing dystonic torticollis from congenital muscular torticollis. There are, nevertheless, possible representations of dystonia in literature and visual art from the pre-modern world. Eighteenth century systematic nosologists such as Linnaeus, de Sauvages, and Cullen had attempted to classify some spasmodic conditions, including torticollis. But only after Charcot's contributions to clinical neuroscience were the various forms of generalized and focal dystonia clearly delineated. They were categorized as névroses: Charcot's term for conditions without an identifiable neuroanatomical cause. For a time thereafter, psychoanalytic models of dystonia based on Freud's ideas about unconscious conflicts transduced into physical symptoms were ascendant, although there was always a dissenting "organic" school. With the rise of subspecialization in movement disorders during the 1970s, the pendulum swung strongly back toward organic causation. David Marsden's clinical and electrophysiological research on the adult-onset focal dystonias was particularly important in establishing a physical basis for these disorders. We are still in a period of "living history" of dystonia, with much yet to be understood about pathophysiology. Rigidly dualistic models have crumbled in the face of evidence of electrophysiological and psychopathological overlap between organic and functional dystonia. More flexible biopsychosocial frameworks may address the demand for new diagnostic and therapeutic rationales.

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.

Ten year clinical experience with stroke and cerebral vasculitis.

Angiitis of the central nervous system (CNS) is difficult to diagnose but potentially fatal. When stroke occurs in a younger individual or is associated with multiple infarcts on imaging, clinicians must decide how far to pursue a possible diagnosis of vasculitis. The aim of this study is to establish the prevalence of primary and secondary cerebral angiitis among patients presenting with stroke. Hospital attendances over a 10year period were surveyed by searching for diagnostic codes and key words specific for cerebral vasculitis/angiitis. Case notes were reviewed by the authors using two sets of criteria for angiitis of the CNS. Thirty-two patients were initially considered likely to have cerebral angiitis by treating physicians. Thirteen had been admitted to hospital with stroke. During this period, there were 7475 admissions for ischaemic and haemorrhagic stroke. Six patients had a final diagnosis of vasculitic stroke but only one had definite CNS angiitis with a first presentation as ischaemic stroke (0.02%). Most patients who did have cerebral vasculitis developed multifocal or subacute neurological deficits, or already had an immunological disorder known to be associated with secondary CNS angiitis. Of 19 patients given an alternative final diagnosis, the most common were atherosclerotic/embolic cerebrovascular disease (n=9) and reversible cerebral vasoconstriction syndrome (n=7). Stroke is rarely the first manifestation of cerebral vasculitis. Our findings suggest that routine screening for angiitis in stroke patients may not be warranted.

Reflections: Neurology and The Humanities. The case of the locked house. The finished mystery.

After the death in 2012 of Dr. Robert Joynt, who served Neurology® as CPC Section Editor, an unfinished manuscript was found on his computer. It would have been his sixth Sherlock Holmes pastiche. Intrigued by the story but deflated at the lack of an ending, the editors published the case in the September 10, 2013, issue of Neurology and requested that readers finish it. A panel of editors reviewed over 30 submissions and the top 4 were posted online and on the iPad. Readers voted online, on the iPad, and during the 2014 American Academy of Neurology Annual Meeting in Philadelphia. The winning coauthors are Peter A. Kempster, from Melbourne, and Andrew J. Lees, from London. The runners-up are Anonymous (ending 1), Gerald Honch (ending 2), and Clifton Gooch (ending 4). The editors thank all participants and voters. The rule on page 662 indicates where the winning ending begins.

Neurology and detective writing.

When searching for clues to reach a diagnosis, neurologists often empathise with the detective who is trying to solve a case. The premise of this article is that detective stories have been part of the fabric of neurology ever since the time that it evolved into a discrete medical speciality. We will examine how this form of narrative has found expression in detective mystery fiction and popular science publications created by 20th century neurologist physician-writers. We will also investigate the power of the neurologist's alter ego, Sherlock Holmes: his relationship to founders of clinical neuroscience such as Jean-Martin Charcot, William Gowers and Sigmund Freud, and his influences on neurological practice and its literary traditions.

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.

Neuropathological findings in benign tremulous parkinsonism.

Benign tremulous parkinsonism, a tremor dominant syndrome with a relatively slow rate of deterioration, is recognized by clinicians although its pathological basis is not well understood. A systematic review of Queen Square Brain Bank donors was carried out to determine the natural history and pathology of individuals who had tremor dominant parkinsonism with mild non-tremor components and minimal gait disability for at least 8 years. We identified 16 cases of pathologically proved benign tremulous Parkinson's disease (PD); another 5 individuals conformed to the definition but did not have the pathology of PD. Patients with verified benign tremulous PD had less severe neuronal loss in the substantia nigra than controls (χ(2): P = .003). Twelve of these had been correctly diagnosed with PD at their first neurological evaluation, whereas the other 4 were originally thought to have another tremor disorder. The only consistent distinguishing feature of the 5 pathologically disproved cases, who may have had either essential tremor with associated rest tremor or dystonic tremor, was a failure to develop unequivocal bradykinesia within a decade of onset of tremor at rest. Our findings support the existence of a distinct subgroup of benign tremulous PD. The slower rate of clinical progression correlates with less severe nigral cell loss at postmortem, although many of these patients transgress the benign tremulous parkinsonism definition by the final third of their disease course and develop the common features of advanced PD.

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.

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.

Relationships between age and late progression of Parkinson's disease: a clinico-pathological study.

To investigate the relationships between age, the advanced clinical stages of Parkinson's disease and neuropathology, we surveyed 129 case records from donors with pathologically proven Parkinson's disease at the Queen Square Brain Bank for Neurological Disorders. Cases were separated into five groups according to age at death, thus comparing patients who reached the advanced stage of the disease at different ages. Four milestones of advanced disease (frequent falls, visual hallucinations, dementia and need for residential care) occurred at a similar time from death in each group. There were no significant differences in disease duration across these age groupings, nor were there differences in the severity and distribution of Lewy body and other pathologies. The milestones of dementia (P < 0.0005) and visual hallucinations (P = 0.02) as well as the accumulation of multiple milestones (P < 0.0005) were associated with high cortical Lewy body scores. Demented cases also had significantly more Alzheimer neurofibrillary and amyloid-beta plaque pathology. Correlation analysis showed that the time intervals between disease onset and recording of milestones were strongly influenced by age at onset (P < 0.0001) and by total disease duration (P < 0.0001). The advanced disease phase plays out in a similar fashion at whatever age it occurs, with a common pathological endpoint. The clinico-pathological comparisons for the final stage of Parkinson's disease do support a staging system based on the rostral extent and severity of Lewy body pathology, although other pathologies may play a synergistic role in causing cognitive disability. The chief effects of age on the rate of progression are seen over the early-middle part of the disease. An exponential curve for clinical progression provides the best explanation for these observations about age and the disease course.

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.

A new look at James Parkinson's Essay on the Shaking Palsy.

James Parkinson's Essay on the Shaking Palsy, published in 1817, represents a landmark in the development of writing about neurologic disorders. Parkinson was an astute clinician-investigator, and his wide scientific interests and ideas on social advancement in many ways typified the spirit of the Age of Enlightenment. Our commentary on the text of his essay identifies important sources of its originality: the particular way in which Parkinson collected and categorized clinical material, his use of a field neurology method to identify affected individuals, and his skills as a narrative writer. Although the essay belongs to an older tradition of disease classification, it also anticipates the modern neurologist's reliance on accurate clinical description and natural history in establishing a diagnosis.