The inconsistency and instability of Parkinson's disease motor subtypes.

INTRODUCTION: Tremor-dominant (TD), indeterminate/mixed (ID/M) and postural instability gait difficulty/akinetic-rigid (PIGD/AR) are commonly used subtypes to categorize Parkinson's disease (PD) patients based on their most prominent motor signs. Three different algorithms to determine these motor subtypes are used. Here, we examined if PD subtypes are consistent among algorithms and if subtype stability over time depends on the applied algorithm. METHODS: Using a large longitudinal PD database, we applied 3 published algorithms of PD motor subtype classification in two sets of analyses: 1) cross-sectional analysis in 1185 patients, determining the prevalence of subtypes in 5-year intervals of disease duration; 2) longitudinal analysis of 178 patients, comparing subtypes of individual patients at baseline (within 5 years of diagnosis) and at follow-up ≥ 5 years after baseline. RESULTS: Cross-sectionally, prevalence of subtypes varied widely among the 3 algorithms: 5-32% TD, 9-31% ID/M, and 59-75% PIGD/AR. For all 3 algorithms, cross-sectional analysis showed a marked decline of TD prevalence with disease duration and a corresponding increase in PIGD/AR prevalence, driven by increasing gait/balance scores over time. Longitudinally, only 15-36% of baseline TD patients were still categorized as TD at 6.2 ± 1.0 years of follow-up. In 15-39% of baseline TD patients, the subtype changed to ID/M, and 46-50% changed to PIGD/AR. This shift was observed using all 3 algorithms. CONCLUSION: PD motor subtypes determined by different established algorithms are inconsistent and unstable over time. Lack of subtype fidelity should be considered when interpreting biomarker-subtype correlation and highlights the need for better definition of PD subtypes.

Destroyers and other verses. Henry Head, the poet.

Henry Head's literary contributions have gone virtually unnoticed despite Lord Brain's contention that "Had Henry Head not adopted medicine as a profession, he might have been equally distinguished as a writer." During World War I, Head published war poems in several literary journals and in 1919 they were compiled into a volume entitled Destroyers and Other Verses. Prior to Destroyers, Head published two other volumes of poetry and, in 1922, he wrote an introduction to a collection of works by Thomas Hardy, compiled by his equally literate wife, Ruth. That the literary influence between the Heads was mutual is revealed by the many references to medicine and physicians in the novels of Ruth Head. This article presents the literary works of Henry and Ruth Head and describes this little known but important part of Sir Henry's career.

Wilson's disease. Development of neurological disease after beginning penicillamine therapy.

Patients with neurological symptoms and signs of Wilson's disease have been frequently noted to have a worsening of their condition after beginning chelation therapy with D-penicillamine. Presymptomatic patients, however, are not expected to develop neurological manifestations once appropriate therapy is begun. We describe a patient who was seen with hepatic disease and no neurological symptoms who became neurologically incapacitated soon after beginning penicillamine therapy. This case identifies an unexpected complication of penicillamine therapy that should be watched for in the presymptomatic patient who is beginning therapy.

Hereditary spastic paraplegia and hereditary ataxia, Part 2: A family demonstrating various phenotypic manifestations with the SCA3 genotype.

BACKGROUND: Clinical descriptions of the dominantly inherited ataxic motor syndromes in a 7-generation family of German origin were first reported in 1951. OBJECTIVE: To provide follow-up clinical, pathological, and genetic data for 9 patients in this family. DESIGN: Clinical histories and neurologic findings, gross and microscopic pathological features, and DNA analysis. RESULTS: Clinical presentations in this closely followed up portion of the family include fairly uniform ataxic and upper motor neuron symptoms. Nystagmus was a conspicuous and early sign, but generational anticipation was not evident. Although often present, amyotrophy was not a major source of disability. Major pathological degeneration was noted in the pons, spinal cord, and upper brainstem, where ubiquitin-immunoreactive intranuclear inclusion bodies were demonstrated. The diagnosis of Machado-Joseph disease (SCA3 [spinocerebellar ataxia type 3] genotype) was established from autopsy tissue in 1 patient and from blood specimens in 6 others. CONCLUSIONS: Clinical variation within this family and between this family and families with the SCA1 and SCA3 genotypes is so broad as to make the genetic diagnosis from clinical criteria alone practically impossible. The pathological definition of Machado-Joseph disease is more reliable, but some findings do overlap those of other genotypes. To our knowledge, the basis for the phenotypic variations in Machado-Joseph disease, genetic or otherwise, has not been established.

The use of alternative therapies by patients with Parkinson's disease.

OBJECTIVE: To determine the prevalence and spectrum of use of alternative therapy (AT) by patients with PD and to determine whether use of AT correlates with demographic, social, or disease-specific characteristics. METHODS: The authors administered a structured questionnaire, by interview, regarding the use of AT to 201 patients with PD. Demographic, social, and disease-specific characteristics were recorded for all patients. RESULTS: Eighty-one patients (40%) used at least one AT. Vitamins and herbs, massage, and acupuncture were most common. Users of AT were younger (p = 0.0021) and had a younger age at onset of PD (p = 0.0011) than nonusers of AT. There was no correlation with sex or race. Patients who used AT had a higher income (p = 0.038) and education level (p = 0.006) than did nonusers of AT. There was no association between the use of AT and the Hoehn and Yahr score, duration of PD, duration of treatment with levodopa, surgery for PD, and presence of fluctuations. CONCLUSIONS: The use of AT is common in patients with PD. The age at onset of PD is the most potent predictor of AT use. There is no association between the use of AT and the severity of PD. The widespread and largely unexamined use of AT for PD requires more attention. This should be directed at testing their safety and efficacy and improving physician and patient knowledge about the potential benefits, costs, limitations, and risks of AT.

PET imaging of the dopamine transporter in progressive supranuclear palsy and Parkinson's disease.

OBJECTIVE: To differentiate the patterns of dopamine transporter loss between idiopathic PD and progressive supranuclear palsy (PSP). METHODS: We used the radiotracer [11C]-WIN 35,428 and PET. Regional striatal dopamine transporter binding was measured in the caudate, anterior putamen, and posterior putamen of six patients with L-dopa-responsive stage 2 PD, six patients with PSP, and six age-comparable healthy controls. RESULTS: In patients with idiopathic PD, the most marked abnormality was observed in the posterior putamen (77% reduction), whereas transporter density in the anterior putamen (60% reduction) and the caudate (44% reduction) was less affected. Unlike the patients with PD, the PSP group showed a relatively uniform degree of involvement in the caudate (40% reduction), anterior putamen (47% reduction), and posterior putamen (51% reduction). When posterior putamen/caudate ratios were calculated, these values were significantly lower in patients with PD than they were in patients with PSP (p = 0.0008) and the control group (p < 0.0001). CONCLUSIONS: Patients with PD have a more pronounced loss of dopamine transporters in the posterior putamen due to a subdivisional involvement of nigrostriatal dopaminergic projections in idiopathic PD. This technique is useful in the determination of neurochemical changes underlying PD and PSP, thus differentiating between them.

Suppression of post-hypoxic and post-encephalitic myoclonus with levetiracetam.

Posthypoxic and postencephalitic myoclonus is often poorly controlled with current treatments. The authors successfully treated three patients with posthypoxic and postencephalitic myoclonus by using levetiracetam, a new antiepileptic drug. Levetiracetam appears to be a promising agent for treating action myoclonus caused by hypoxic and encephalitic brain injury-the degree of functional improvement may depend on the severity of associated motor dysfunction.

Patterns of bursting occurring in thalamic cells during parkinsonian tremor.

It has been proposed that parkinsonian tremor is produced either by the activity of an intrinsic thalamic pacemaker or by the oscillation of an unstable long loop reflex arc. The former (central) hypothesis proposes that overactivity of neurons in the internal segment of the globus pallidus inhibits or hyperpolarizes thalamic neurons. When hyperpolarized, thalamic cells oscillate with bursting of the type associated with low threshold calcium spikes (low threshold spike-bursts). Low threshold spike-bursts can be identified by particular patterns of interspike intervals within the burst. The alternative (peripheral) hypothesis proposes that tremor results from oscillation of a reflex arc transmitting activity from muscle stretch receptors to thalamus, motor cortex, and back to the stretched muscle. When the gain of this reflex is increased, the arc may become unstable and oscillate. Oscillations produced by peripheral inputs may produce an acceleration-deceleration pattern within the burst which results in sinusoidal modulation of a spike train if bursting is periodic. We have assessed these two hypotheses by studying the pattern of interspike intervals occurring within bursts recorded in patients with parkinsonian tremor. The spike trains were analysed for 118 cells located in the ventral nuclear group including ventralis intermedius (thalamic cerebellar relay nucleus, n=48) and ventralis oralis posterior (thalamic pallidal relay nucleus, n=39) of patients with parkinsonian tremor. Two cells recorded in ventralis intermedius of a sleeping patient with chronic pain showed bursting activity similar to the low threshold spike-bursts recorded in sleeping animals, suggesting a common mechanism for low threshold spike-bursts across species. Forty-two cells recorded in patients with parkinsonian tremor (ventralis intermedius, n=19; ventralis oralis posterior, n=12) were classified as tremor-related cells because their activity was characterized by both a concentration of power at tremor frequency and significant correlation with tremor. Eleven tremor-related cells, 10 located in ventralis intermedius or ventralis oralis posterior and most responding to sensory inputs, had an acceleration-deceleration pattern of intraburst firing. Only one cell, a tremor-related cell in ventralis intermedius, showed the pattern expected of presumed low threshold spike-bursts. Therefore, intraburst interspike interval patterns consistent with either the central or the peripheral hypothesis were recorded in the thalamus of patients with parkinsonian tremor. Twenty-one tremor-related cells (15 cells in ventralis intermedius or ventralis oralis posterior) had bursts with intraburst interspike intervals which were independent of position of the interspike interval within the burst. Therefore, the activity of the majority of cells was not consistent with either hypothesis, suggesting that another oscillatory process may contribute to parkinsonian tremor.

Adaptive Fourier modeling for quantification of tremor.

A new computational method for quantification of tremor, the weighted frequency Fourier linear combiner (WFLC), is presented. This technique rapidly determines the frequency and amplitude of tremor by adjusting its filter weights according to a gradient search method. It provides continual tracking of frequency and amplitude modulations over the course of a test. By quantifying time-varying characteristics, the WFLC assists in correctly interpreting the results of spectral analysis, particularly for recordings exhibiting multiple spectral peaks. It therefore supplements spectral analysis, providing a more accurate picture of tremor than spectral analysis alone. The method has been incorporated into a desktop tremor measurement system to provide clinically useful analysis of tremor recorded during handwriting and drawing using a digitizing tablet. Simulated data clearly demonstrate tracking of variations in frequency and amplitude. Clinical recordings then show specific examples of quantification of time-varying aspects of tremor.

Harvey Cushing's Guillain-Barré syndrome: an historical diagnosis.

Harvey Cushing developed an illness in the last months of World War I that made it impossible for him to operate and forced him to bed for over a month. The features of Cushing's malady included symmetrical weakness, numbness, and paresthesias of the hands and feet, areflexia, bilateral facial paresis, diplopia, and fever. Neither Cushing nor his physicians were able to make a diagnosis. John Fulton, Cushing's biographer, misdiagnosed the condition as a "vascular polyneuritis," and Harry Zimmerman, who performed Cushing's autopsy, incorrectly attributed his symptoms to occlusion of the abdominal aorta. Based on extensive notes in Cushing's war diary describing the illness, it is readily recognized today as Guillain-Barré syndrome.

Ocular motility in Parkinson's disease.

INTRODUCTION: Parkinson's disease is associated with multiple abnormalities of both the afferent and efferent visual systems. Blepharospasm, paucity of blinking, apraxia of lid opening, visual neglect, reduced vergence, reduced upgaze, and blurred vision are reported findings in these patients. The association of these findings with the disease, and their duration, severity, and treatment have not been systematically investigated. PATIENTS AND METHODS: Patients with Parkinson's disease were prospectively examined. An age-matched control group was recruited from accompanying family members and volunteers. Data recorded included presence of visual complaint, the severity of the Parkinson's disease by Hoehn and Yahr Stage (scale = 1 to 5), duration of disease, pharmacologic therapy, visual acuity, ocular motility, accommodation, convergence amplitudes, and the near point of convergence. RESULTS: Thirty-nine patients were entered into each group, each with 21 men and 18 women. The average patient had had the disease for 8.9 years with a severity index of 2.6. Asthenopia, upgaze deficiency, and convergence insufficiency were significantly more common in the patients with Parkinson's disease than in the controls. Mean geometric visual acuity was poorer in the Parkinson's patients (20/39 compared with 20/28); P < .001). DISCUSSION: Visual complaints were significantly more common in the Parkinson's patients than in the age-matched controls. The frequency of ocular abnormalities was not related to the duration of the disease. Increasing severity seemed to be correlated with the presence of convergence insufficiency and a decline in acuity.

What determines resilience in patients with Parkinson's disease?

OBJECTIVE: To investigate the relationship of resilience to disease severity, disability, quality of life (QoL) and non-motor symptoms in Parkinson's disease (PD). A secondary objective was to investigate whether resilience is distinct from other personality domains in PD. BACKGROUND: Resilience is the ability to reestablish emotional equilibrium in the face of adversity. It may play a pivotal role in disability and quality of life and has not been studied in PD. METHODS: 83 PD patients (Age 66.3 ± 10.6, Total Unified Parkinson's Disease Rating Scale (T-UPDRS) 36.9 ± 17.8) completed the Resilience Scale 15 (RS-15). Scales measuring disability, mental and physical health-related QoL, non-motor symptoms (depression, anxiety, somatization, apathy, fatigue), and personality domains were completed. Pearson's correlations were analyzed between these scales and the RS-15. RESULTS: Greater resilience correlated with less disability (r = -.30, p = .01), and better physical and mental QoL (r = .31, p < .01; r = .29, p = .01), but not with PD severity (T-UPDRS, r = -.17, p > .05). Among non-motor symptoms and personality domains, resilience strongly correlated with less apathy (r = -.66), less depression (r = -.49), and more optimism (r = .54, all p < .001). Moderate correlations were seen between more resilience, reduced fatigue (r = -.40) and anxiety (r = -.34; both p < .001). CONCLUSIONS: Resilience correlated with less disability and better QoL but not with PD severity. Resilience was also highly associated with both non-motor symptoms (less apathy, depression, fatigue) and a personality domain (more optimism). The role of resilience in helping patients adapt to living with symptoms of chronic disease may explain its lack of correlation with PD severity.

How accurate are bedside hearing tests?

The accuracy of five bedside hearing tests was evaluated in 107 consecutive adults, using pure-tone audiometry as the standard reference. Bedside tests had poor sensitivity (< or =0.60), relatively good specificity (> or =0.74), and variable positive predictive value (0.24 to 1.0) for detecting hearing loss. Sensitivity improved when bedside tests were combined with case history. The diagnostic utility of bedside tests routinely administered by neurologists to detect hearing loss in adults requires further study.

When do patients with Parkinson disease disclose their diagnosis?

The authors surveyed 101 patients with Parkinson disease (PD) about their experiences disclosing the diagnosis. Ninety percent disclosed early to family; more than 25% waited at least 1 year to disclose at work. The main concerns about disclosure were fear of reflecting negatively on themselves and fear of upsetting others. Patients who delayed disclosure were more likely male, younger, and employed. There is considerable variability among patients with PD in the time to disclose their diagnosis.

The dynias.

The "dynias" are a group of chronic, focal pain syndromes with a predilection for the orocervical and urogenital regions. They include glossodynia, carotidynia, vulvodynia, orchidynia, prostatodynia, coccygodynia, and proctodynia. In some cases, the dynias occur secondarily, but more often, despite an exhaustive evaluation, no etiology is found and in these remaining cases, the cause of the pain remains enigmatic. The controversy that surrounds this group of disorders, which ranges from questioning their existence to suggesting that they are purely psychosomatic, is counterbalanced by an extensive literature attesting to their organicity. The approach to the patient begins with acknowledging that the symptom is well described, searching for a secondary cause, and performing a careful psychologic assessment. Treatment is empirical and patients can often be helped with medications used to treat neuropathic pain, all the while providing psychologic support and exercising caution toward invasive and irreversible therapeutic procedures.

The menagerie of migraine.

Migraine is conventionally regarded as a specific type of headache with a small set of associated neurologic symptoms. Yet, the true scope and frequency of migrainous phenomena are much greater than is generally acknowledged. Six cases are presented to illustrate some of the diverse manifestations of migraine: (1) transient global amnesia, (2) persistent visual phenomena, (3) migraine and seizures, (4) vestibular dysfunction, (5) hearing loss, and (6) migraine masquerading as multiple sclerosis. These and other migraine-associated neurologic symptoms are discussed in relation to previous reports in the literature. Pitfalls in recognizing the diverse manifestations of migraine, which are often underdiagnosed or misdiagnosed, are reviewed. Whether or not the established diagnostic criteria for migraine are too strict, other factors contributing to failure to identify migraine when it causes nonclassic neurologic symptoms include: (1) the belief that these are rare, (2) lack of an objective measure for migraine, (3) inadequate attention to the positive diagnostic features of migraine in the absence of headache, (4) confusion regarding prior migraine history, and (5) dismissing the diagnosis because of reported failure of prior migraine treatment. Recognition of the diversity of migraine helps avoid unnecessary testing and opens the door to effective treatment.

Olanzapine for the treatment of psychosis in patients with Parkinson's disease and dementia.

Psychotic symptoms are a common complication in Parkinson's disease with dementia. The authors conducted an open-label 6-week trial of olanzapine preceded by a placebo lead-in in five subjects with Parkinson's disease, mild to moderately severe dementia, and psychosis. Four of the subjects terminated the trial early because of worsening motor function, sedation, or paranoia. There was no improvement in psychotic symptoms, and functional abilities declined significantly. Olanzapine appears to be poorly tolerated in patients with Parkinson's disease, psychotic symptoms, and dementia.