Normalized Mutual Information of phonetic sound to distinguish the speech of Parkinson's disease.

This study has investigated the use of inter-personnel mutual information computed from the phonetic sound recordings to differentiate between Parkinson's disease (PD) and control subjects. The normalized mutual information (NMI) denotes the amount of information shared between the voice recordings of people within the same group: PD and Control. The hypothesis of this study was that within group NMI will be significantly different when compared with inter- group NMI. For each phonetic sound, the NMI was computed for every pairing of recordings for both the PD and control groups. Pearson correlation coefficient analysis was used to determine the association of NMI with clinical parameters including Unified Parkinson's Disease Rating Scale (UPDRS), Montreal cognitive assessment (MoCA) and disease duration. ANOVA test for the three phonetic sounds of control and PD subjects showed that there is significant difference between the intra-group mean NMI for the two groups (p <; 0.003) and also showed significant association with the UPDRS motor examination score, MoCA and disease duration.

James Parkinson's Chimera: syndrome or disease?

It is 200 years since James Parkinson published An Essay on the Shaking Palsy. While his monograph continues to be acclaimed for its precedence and clarity of description, what is often overlooked is the originality of Parkinson's ideas. Here we show that he appreciated the weakness of the systematic 18th century nosologies, which presupposed that medical species, the building blocks of these Linnaean taxonomic schemes, were as distinct as plant and animal species; and that Parkinson made a conceptual leap about combinations of clinical phenomena in recurring patterns, now recognised to be one of the germs of neurological thinking about syndromes. The Essay's written style underpins another aspect of significance to contemporary neurological practice - an inherent intellectual humility. In this commemorative year we locate the continuing importance of the related notions of syndrome and disease in successive frameworks of knowledge about the shaking palsy. Syndrome and disease are interpreted as dual character concepts, one clinically-based and the other restricted to pathophysiological causation. They both remain fundamental to understanding Parkinson's syndrome-disease today.

E. Graeme Robertson--dynamics in fluid and light.

An eponymous lecture at the Australian and New Zealand Association of Neurologists Annual Scientific Meeting commemorates E. Graeme Robertson (1903-75), and some neurologists will know that particular Australian practices in clinical neurology, so far as they exist, have origins in his career. This is a historical article on the literary record of a man who had his own sense of history--an affinity with the past as well as an awareness of future generations of readers. He wrote authoritative texts on pneumoencephalography before new technology made it obsolete, and he produced a series of books on decorative architectural cast iron in Australian cities. A talent for visual interpretation seems to have drawn him to both of these topics; a common theme is contrast between light and dark, which is expatiated in images and in clear, well-written prose in his publications. We review his medical writings, including some largely forgotten principles of cerebrospinal fluid physics that he discovered when researching pneumoencephalography. We also explore his obsession with cast iron--its architectural historical significance, his techniques for photographing it, and some of the ways that it related to his life's work as a clinical neurologist.

A clinico-pathological study of subtypes in Parkinson's disease.

We have carried out a systematic review of the case files of 242 donors with pathologically verified Parkinson's disease at the Queen Square Brain Bank for Neurological Disorders in an attempt to corroborate the data-driven subtype classification proposed by Lewis and colleagues (Heterogeneity of Parkinson's disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry 2005; 76: 343-8). Cases were segregated into earlier disease onset (25%), tremor dominant (31%), non-tremor dominant (36%) and rapid disease progression without dementia (8%) subgroups. We found a strong association between a non-tremor dominant disease pattern and cognitive disability. The earlier disease onset group had the longest duration to death, and greatest delay to the onset of falls and cognitive decline. Patients with a tremor dominant disease pattern did not live significantly longer than non-tremor dominant patients and showed no difference in mean time to onset of falls and hallucinations. Rapid disease progression was associated with older age, early depression and early midline motor symptoms, and in 70% of the cases, tremulous onset. The non-tremor dominant subgroup had a significantly higher mean pathological grading of cortical Lewy bodies than all other groupings (P < 0.05) and more cortical amyloid-beta plaque load and cerebral amyloid angiopathy than early disease onset and tremor dominant groups (P = 0.047). An analysis of cases with pathologically defined neocortical Lewy body disease confirmed the link between bradykinetic onset, cognitive decline and Lewy body deposition in the neocortex. Although neuropathological examination failed to distinguish the other subtypes, the classification scheme was supported by an analysis of clinical data that were independent of the basic subgroup definitions.

Clinical outcomes of progressive supranuclear palsy and multiple system atrophy.

Prognostic predictors have not been defined for progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). Subtypes of both disorders have been proposed on the basis of early clinical features. We performed a retrospective chart review to investigate the natural history of pathologically confirmed cases of PSP and MSA. Survival data and several clinically relevant milestones, namely: frequent falling, cognitive disability, unintelligible speech, severe dysphagia, dependence on wheelchair for mobility, the use of urinary catheters and placement in residential care were determined. On the basis of early symptoms, we subdivided cases with PSP into 'Richardson's syndrome' (RS) and 'PSP-parkinsonism' (PSP-P). Cases of MSA were subdivided according to the presence or absence of early autonomic failure. Sixty-nine (62.7%) of the 110 PSP cases were classified as RS and 29 (26.4%) as PSP-P. Of the 83 cases of MSA, 42 (53.2%) had autonomic failure within 2 years of disease onset. Patients with PSP had an older age of onset (P < 0.001), but similar disease duration to those with MSA. Patients with PSP reached their first clinical milestone earlier than patients with MSA (P < 0.001). Regular falls (P < 0.001), unintelligible speech (P = 0.04) and cognitive impairment (P = 0.03) also occurred earlier in PSP than in MSA. In PSP an RS phenotype, male gender, older age of onset and a short interval from disease onset to reaching the first clinical milestone were all independent predictors of shorter disease duration to death. Patients with RS also reached clinical milestones after a shorter interval from disease onset, compared to patients with PSP-P. In MSA early autonomic failure, female gender, older age of onset, a short interval from disease onset to reaching the first clinical milestone and not being admitted to residential care were independent factors predicting shorter disease duration until death. The time to the first clinical milestone is a useful prognostic predictor for survival. We confirm that RS had a less favourable course than PSP-P, and that early autonomic failure in MSA is associated with shorter survival.

The Lhermitte phenomenon: variant forms and their significance.

Typical Lhermitte phenomenon (tingling sensations moving down the limbs or trunk on neck flexion) is a sign of intrinsic spinal cord pathology, most commonly cervical spinal cord demyelination. The phenomenon has several variant forms, and each has a different pathological significance. A delayed typical Lhermitte phenomenon can follow contusion of the spinal cord from neck trauma. Reverse Lhermitte phenomenon induced by neck extension is usually produced by extrinsic compression of the cervical spinal cord. Upward moving paraesthesia with neck flexion (inverse Lhermitte phenomenon) is relatively rare, and can be a sign of myelopathy from nitrous oxide inhalation.

John Ruskin's relapsing encephalopathy.

John Ruskin (1819-1900) is chiefly remembered for his works on painting and architecture, and for his powerful and original prose style. In middle age, he suffered recurring episodes of delirium with visual hallucinations and delusions. At about the same time, his writing developed a disjointed polemical character, with cryptic and intemperate elements that disorientated some readers. The nature of Ruskin's 'madness' is a key to understanding his later writing career but the psychiatric explanations given by many of his literary biographers seem unsatisfactory. Ruskin left numerous clues about the illness in his diaries, correspondence and publications. It is likely that he had a relapsing-progressive neurological disorder with neuropsychiatric manifestations. It could have been a fluctuating metabolic or immunological encephalopathy, but the diagnosis that best fits the time course of his illness and the prior history of mood disorder and of migraine with aura is Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Whatever the pathology, its first effects on frontal lobe function may have actually enhanced Ruskin's creative energy for a long time before stepwise cognitive impairment degraded his ability to write.

Patterns of levodopa response in Parkinson's disease: a clinico-pathological study.

Patients with Parkinson's disease who develop disabling levodopa-induced motor fluctuations have a stronger therapeutic response than those who experience a more modest but stable response. A difference in the histopathological lesion between the two groups might be responsible. Case records from 97 patients with pathologically proven Parkinson's disease were reviewed to determine the pattern of levodopa response. Pathological findings for fluctuating and non-fluctuating cases were compared. Patients with motor fluctuations had a younger age of onset and longer disease course (P < 0.001), although mean age at death was almost the same. Four milestones of advanced disease (frequent falls, visual hallucinations, cognitive disability and need for residential care) occurred at a similar time from death in each group; this interval was not proportionate to the disease duration. There were no significant differences in the severity or distribution of Lewy body or other pathologies. Irrespective of the pattern of levodopa response, patients reach a common pathological endpoint at a similar age, and the duration and manifestations of end-stage disease are alike. A non-linear or exponential time relationship may govern the late clinical and pathological progression of Parkinson's disease.

Two cases of Cryptococcus meningitis presenting as leukoencephalopathy prior to amphotericin therapy.

We report two patients with cryptococcal meningitis and combined immunodeficiency with unusual magnetic resonance imaging findings of gadolinium-enhancing white matter lesions, quite different from cryptococcomas and seen prior to anti-fungal treatment. The lesions resembled demyelinating plaques and resolved. In one patient, biopsy of the lesion revealed cryptococci, non-specific inflammatory changes and occasional small perivascular lymphocyte collections, but not demyelination. Leukoencephalopathy, previously rarely observed in Cryptococcal meningitis, was thought to be the sequelae of amphotericin toxicity. Our cases demonstrate cryptococcal meningitis may present with leukoencephalopathy, possibly as an immune response to the organism.

Sporadic encephalitis lethargica.

Three women (aged 21-36 years) developed acute illnesses that were similar to epidemic encephalitis lethargica. Each presented with a neuropsychiatric disturbance that was succeeded by pyrexia, a fluctuating conscious state and involuntary movements including oculogyria. Cerebrospinal fluid examination showed a predominantly lymphocytic pleocytosis (64-120x10(6) cells/L) and oligoclonal bands were detected in two cases. Two patients died, while the third made a gradual recovery. Post-mortem examination in the two fatal cases showed changes of lymphocytic meningitis and focal diencephalic lymphocytic infiltration, although these changes were mild relative to the effects of the clinical illness. The diagnosis of sporadic encephalitis lethargica relies on identifying shared clinical features with the past epidemic disease plus circumstantial evidence of immunological activity from laboratory investigations and some tests of exclusion of other disorders.

Staying on the surface.

Every neurologist needs to develop an effective technique to diagnose and manage non-organic disorders, although there are different ways to go about it. The complex relationship that exists between functional and organic illness is an inescapable theme in daily neurological practice. Usually, it is better to read these case stories by examining their surface detail rather than to try to understand their psychological depth.

Looking for clues.

At certain moments in clinical practice, one can seem to possess the powers of a Sherlock Holmes to search out clues and deduce the diagnosis. Many neurologists are aware of links between the workings of detective fiction and the methods of problem-solving in neurological cases. One similarity concerns the professional counterpart of the conventional detective story, the single case report.

Reading a story.

Case delineation in clinical medicine is the technique of creating a narrative that allows the appropriate scientific knowledge to be brought to bear. Neurologists get to be good at this type of story reading and telling from dealing with clinical stories which are relatively long and complicated. These skills are evident whenever working neurologists gather to discuss case material, or when studying their written clinical communications. The purpose of the article is to analyze this aspect of everyday neurological practice by looking at some of the general principles of story telling and appreciation.

Evolution of motor fluctuations in Parkinson's disease: a longitudinal study over 6 years.

A prospective longitudinal 6-year study of 34 patients with Parkinson's disease from the time of initiation of drug treatment explored changes in the motor response to L-dopa over the early to mid disease course. Motor fluctuations developed in 41% after a mean L-dopa treatment interval of 25 months and dyskinesia developed in 53% after a mean of 15 months' treatment. Patients who developed fluctuations had a significantly better response to L-dopa than nonfluctuators. Nonfluctuators also had significantly greater "midline" motor disability affecting cranial and truncal muscles and gait. The development of motor fluctuations may simply reflect a retained capacity to respond to L-dopa as endogenous dopaminergic neurotransmission declines with progressive nigral cell loss. Many patients who show no sign of motor fluctuation 5 or 6 years into the disease course have a relatively blunted response to L-dopa. The proportion of such cases seems to correspond to the percentage that have coexisting striatal pathologic changes in postmortem studies.

Pharmacokinetic and clinical evaluation of liquid L-dopa/carbidopa in Parkinson's disease.

The aim of the study was to assess the pharmacokinetic properties and clinical effectiveness of L-dopa/carbidopa solution treatment in patients with parkinsonian motor fluctuations. No significant difference in maximal L-dopa concentration, time to peak L-dopa concentration and area under curve was found in single dose studies which compared equivalent tablet and solution L-dopa/carbidopa doses in 9 patients. Seven out of 10 patients treated with hourly doses of liquid L-dopa/carbidopa were improved after switching from conventional tablet medication. Less 'off' time per day and less 'off' phase disability were the usual benefits. Six of these patients maintained this improvement and continued on long-term liquid medication. The benefits of this treatment do not relate to improved L-dopa delivery to the bloodstream. The ability of patients to fractionate the treatment into small, frequent doses which can be used more flexibly than tablets appears to confer the main advantages of liquid L-dopa/carbidopa in the management of parkinsonian motor fluctuations.

An aquatic toxicological evaluation of fenthion in the context of finch control in South Africa.

Queletox, containing fenthion as active ingredient, is the avicide formulation used in South Africa to control red-billed finches (Quelea quelea). Control measures involve night spraying of roosting areas with a light aircraft. Since roosting areas often include reedbeds along riversides and on islands, proper control is difficult without exposing the aquatic environment to some risk of contamination. This study tested the acute effects of fenthion, in association with the queletox formulation, on the cladocerans Daphnia pulex and Ceriodaphnia dubia and the fish species Poecilia reticulata, Tilapia rendalli, Cyprinus carpio, and Oreochromis mossambicus. The chronic effects of fenthion on D. pulex were evaluated in a 14-day reproduction test. Mean 48-hr LC50 values estimated for D. pulex and C. dubia were 1.30 and 1.72 micrograms liter-1 respectively. For the fish estimated 96-hr LC50 values were as follows: 2.12 (P. reticulata), 2.53 (C. carpio), 2.92 (T. rendalli) and 1.71 micrograms liter-1 (O. mossambicus). In the chronic test reproduction of the exposed population was stimulated at the lowest two fenthion concentrations (0.1 and 0.6 ng liter-1), while a reproductive impairment was recorded at concentrations varying from 1 to 10 ng liter-1. Concentrations of fenthion measured in dams after spraying are given to indicate the levels of contamination that may occur. QSAR was used to estimate the toxicity of some fenthion metabolites. The results of this study reveal that fenthion, at the concentrations occurring in the environment after aerial spraying, can have marked effects on the survival and reproduction of D. pulex for long periods after spraying.

Motor response to levodopa in patients with parkinsonian motor fluctuations: a follow-up study over three years.

To clarify the way in which the clinical response to levodopa changes with the progression of Parkinson's disease, a longitudinal study was performed to quantify motor response characteristics to single doses of levodopa by mouth over three years in 23 patients with fluctuating motor function. A significant increase in motor disability in "on" (time of peak motor improvement) and "off" (before levodopa dose) phases occurred and "on" phase dyskinesia increased by 24%, though the amplitude of motor response was conserved. There was no evidence of progressive loss of response of certain motor deficits affecting axial muscles and gait. The mean duration of motor response decreased by 17%. Both shortening of response duration and increase in "off" phase disability contribute to the development of motor fluctuations. A short response time to the levodopa test dose was not an invariable finding in patients with severe fluctuations, whereas all had large response amplitudes and high "off" phase disability scores. Patients who have developed motor fluctuations may continue to respond to dopaminergic treatment until late in the disease course, despite the unstable nature of their responses.