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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Anal sphincter dysfunction in Parkinson's disease.

Striated anal sphincter function was studied electrophysiologically and radiologically in six patients with Parkinson's disease and chronic constipation. In five cases, there was paradoxic anal sphincter muscle contraction during simulated defecation straining resembling anismus-type pelvic outlet obstruction. Radiologic studies showed functional improvement of the defecatory mechanism following the administration of the dopamine receptor agonist apomorphine in four patients. Dysfunction of the striated anal sphincter musculature may be a significant cause of constipation in some parkinsonian patients, occurring as part of the generalized extrapyramidal motor disorder.

Dietary factors in the management of Parkinson's disease.

Oral administration of L-dopa is currently the most effective way to treat the cerebral dopamine deficiency which causes Parkinson's disease. Unfortunately, many patients with advanced Parkinson's disease develop an unstable pattern of response to L-dopa because of fluctuating delivery of the drug to the brain. Diet contributes to this problem through its adverse effects on L-dopa pharmacokinetics. This article reviews dietary strategies to improve responsiveness to pharmaceutical L-dopa treatment and the potential use of food as a source of L-dopa. Nutritional factors concerning weight loss and energy balance in Parkinson's disease are also discussed. A set of dietary guidelines is developed to assist clinical nutritionists and neurologists in the practical management of patients with Parkinson's disease.

A double-blind, controlled study of high-dose L-deprenyl in the treatment of Parkinson's disease.

The conventional dose of deprenyl used in Parkinson's disease is 10 mg/day, having been established by in vitro platelet studies and clinical evaluation. Twelve patients with Parkinson's disease on treatment with L-dopa who showed evidence of wearing-off effects or motor oscillation were studied in a double-blind, placebo-controlled, crossover trial to compare conventional doses of deprenyl with higher doses (up to 40 mg/day) and placebo. We did not find higher doses of deprenyl to be superior to conventional doses and in 17% of cases treatment had to be withdrawn because of side effects.

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.

Response to L-dopa and evolution of motor fluctuations in the early phase of treatment of Parkinson's disease.

Twenty patients with Parkinson's disease were studied during the early phase of L-dopa treatment to clarify the development and progression of Parkinsonian motor fluctuations. Two patients had developed symptomatic motor fluctuations of moderate severity and another 3 had mild fluctuations. Both the initial response to L-dopa and the amplitude of response to a L-dopa test dose after a mean follow up period of 30 months were significantly greater for the fluctuating patients compared with those without fluctuation (p < 0.05). Although severe motor fluctuations do not usually develop until a number of years of L-dopa treatment have elapsed, this study shows that motor fluctuations can be detected quite early in the disease course and tend to appear in those patients who respond best to L-dopa.

A clinical study of convulsive syncope.

An analysis of the clinical features of patients having evidence of a syncopal onset to convulsive episodes is reported. The range of convulsive phenomena was quite wide and did not appear to differentiate the syndrome from primary epilepsy in terms of seizure morphology, occurrence of incontinence or pattern of post-ictal recovery. It is therefore suggested that the premonitory and precipitating features are more specific in the diagnosis of convulsive syncope. Skin pallor was often reported during attacks. Although EEG abnormalities were seen in some cases, the follow-up results indicate a low incidence of unprovoked convulsions in patients with this condition without anticonvulsant treatment.

Intermittent subcutaneous apomorphine injection treatment for parkinsonian motor oscillations.

Eight patients with severe Parkinsonian motor oscillations have been treated with the dopamine receptor agonist apomorphine by intermittent subcutaneous self-injection as an adjunct to oral anti-Parkinsonian medication. The dopamine receptor antagonist domperidone was also given by mouth to prevent nausea. Six patients remain on chronic treatment (mean period 6.5 months) with improved control of motor function in each case. Four have had major enhancement of their quality of life. Benefits of this treatment stem from the training of patients to use intelligent behaviour to administer a promptly acting and effective pharmacological agent, thereby exercising a degree of direct control over previously unpredictable variations in motor performance.

Impairment of consciousness in migraine.

A series is reported of 25 subjects with migraine, whose attacks on some occasions involved impairment of consciousness. The disorder did not necessarily involve younger people, or occur early in the course of the malady.