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.

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.

Single-neuron analysis of human thalamus in patients with intention tremor and other clinical signs of cerebellar disease.

Tremor that occurs as a result of a cerebellar lesion, cerebellar tremor, is characteristically an intention tremor. Thalamic activity may be related to cerebellar tremor because transmission of some cerebellar efferent signals occurs via the thalamus and cortex to the periphery. We have now studied thalamic neuronal activity in a cerebellar relay nucleus (ventral intermediate-Vim) and a pallidal relay nucleus (ventralis oral posterior-Vop) during thalamotomy in patients with intention tremor and other clinical signs of cerebellar disease (tremor patients). The activity of single neurons and the simultaneous electromyographic (EMG) activity of the contralateral upper extremity in tremor patients performing a pointing task were analyzed by spectral cross-correlation analysis. EMG spectra during intention tremor often showed peaks of activity in the tremor-frequency range (1.9-5.8 Hz). There were significant differences in thalamic neuronal activity between tremor patients and controls. Neurons in Vim and Vop had significantly lower firing rates in tremor patients than in patients undergoing thalamic surgery for pain (pain controls). Other studies have shown that inputs to Vim from the cerebellum are transmitted through excitatory connections. Therefore the present results suggest that tremor in these tremor patients is associated with deafferentation of the thalamus from cerebellar efferent pathways. The thalamic X EMG cross-correlation functions were studied for cells located in Vim and Vop. Neuronal and EMG activity were as likely to be significantly correlated for cells in Vim as for those in Vop. Cells in Vim were more likely to have a phase lag relative to EMG than were cells in Vop. In monkeys, cells in the cerebellar relay nucleus of the thalamus, corresponding to Vim, are reported to lead movement during active oscillations at the wrist. In view of these monkey studies, the present results suggest that cells in Vim are deafferented and have a phase lag relative to tremor that is not found in normal active oscillations. The difference in phase of thalamic spike X EMG activity between Vim and Vop may contribute to tremor because lesions of pallidum or Vop are reported to relieve cerebellar tremor.

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.

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.

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.

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.

Thalamic single neuron activity in patients with dystonia: dystonia-related activity and somatic sensory reorganization.

Indirect evidence suggests that the thalamus contributes to abnormal movements occurring in patients with dystonia (dystonia patients). The present study tested the hypothesis that thalamic activity contributes to the dystonic movements that occur in such patients. During these movements, spectral analysis of electromyographic (EMG) signals in flexor and extensor muscles of the wrist and elbow exhibited peak EMG power in the lowest frequency band [0-0.78 Hz (mean: 0.39 Hz) dystonia frequency] for 60-85% of epochs studied during a pointing task. Normal controls showed low-frequency peaks for <16% of epochs during pointing. Among dystonia patients, simultaneous contraction of antagonistic muscles (cocontraction) at dystonia frequency during pointing was observed for muscles acting about the wrist (63% of epochs) and elbow (39%), but cocontraction was not observed among normal controls during pointing. Thalamic neuronal signals were recorded during thalamotomy for treatment of dystonia and were compared with those of control patients without motor abnormality who were undergoing thalamic procedures for treatment of chronic pain. Presumed nuclear boundaries of a human thalamic cerebellar relay nucleus (ventral intermediate, Vim) and a pallidal relay nucleus (ventral oral posterior, Vop) were estimated by aligning the anterior border of the principal sensory nucleus (ventral caudal, Vc) with the region where the majority of cells have cutaneous receptive fields (RFs). The ratio of power at dystonia frequency to average spectral power was >2 (P < 0.001) for cells in presumed Vop often for dystonia patients (81%) but never for control patients. The percentage of such cells in presumed Vim of dystonia patients (32%) was not significantly different from that of controls (31%). Many cells in presumed Vop exhibited dystonia frequency activity that was correlated with and phase-advanced on EMG activity during dystonia, suggesting that this activity was related to dystonia. Thalamic somatic sensory activity also differed between dystonia patients and controls. The percentage of cells responding to passive joint movement or to manipulation of subcutaneous structures (deep sensory cells) in presumed Vim was significantly greater in patients with dystonia than in control patients undergoing surgery for treatment of pain or tremor. Dystonia patients had a significantly higher proportion of deep sensory cells responding to movement of more than one joint (26%, 13/52) than did "control" patients (8%, 4/49). Deep sensory cells in patients with dystonia were located in thalamic maps that demonstrated increased representations of parts of the body affected by dystonia. Thus dystonia patients showed increased receptive fields and an increased thalamic representation of dystonic body parts. The motor activity of an individual sensory cell was related to the sensory activity of that cell by identification of the muscle apparently involved in the cell's receptive field. Specifically, we defined the effector muscle as the muscle that, by contraction, produced the joint movement associated with a thalamic neuronal sensory discharge, when the examiner passively moved the joint. Spike X EMG correlation functions during dystonia indicated that thalamic cellular activity less often was related to EMG in effector muscles (52%) than in other muscles (86%). Thus there is a mismatch between the effector muscle for a thalamic cell and the muscles with EMG correlated with activity of that cell during dystonia. This mismatch may result from the reorganization of sensory maps and may contribute to the simultaneous activation of multiple muscles observed in dystonia. Microstimulation in presumed Vim in dystonia patients produced simultaneous contraction of multiple forearm muscles, similar to the simultaneous muscle contractions observed in dystonia. (ABSTRACT TRUNCATED)

Stereotactic thalamotomy in the treatment of essential tremor of the upper extremity: reassessment including a blinded measure of outcome.

The effectiveness of high frequency stimulation of the thalamic nucleus ventralis intermedius (Vim-HFS) for treatment of tremor has been studied by blinded assessment. The effectiveness of thalamotomy for essential tremor of the upper extremity by use of a blinded measure of outcome is now reported. Thalamotomy was performed in 21 patients (three operated on bilaterally) with medically intractable, essential tremor. Assessments of function, handwriting/drawing, and tremor amplitude were done before and at 3 and 12 months after surgery. The handwriting/drawing score was rated by a neurologist blinded to patient identity, laterality, and operative status. By comparison with baseline, both the total functional score and the total score from blinded assessment of handwriting/drawing improved significantly at 3 and 12 months after surgery. The two scores were significantly correlated, suggesting that the blinded assessment is a good predictor of a total disability from tremor. Complications after unilateral thalamotomy included transient dysarthria, permanent perioral numbness, and permanent mild disequilibrium in one patient each. Permanent mild dysarthria occurred in two of three patients operated bilaterally. Thus a blinded assessment of outcome establishes that unilateral thalamotomy is an effective, safe procedure for the treatment of essential tremor.

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.

The role of the thalamus and basal ganglia in parkinsonian tremor.

The mechanism of parkinsonian tremor may involve a central oscillator, peripheral feedback to the central nervous system (CNS), or both. The thalamus or the globus pallidus is the most likely site for a central oscillator and would be predicted to generate thalamic tremor-related activity characterized, respectively, by calcium spike-associated bursts and by maximal tremor-related activity in the pallidal relay nucleus of thalamus. Thalamic spike trains demonstrate neither of these characteristics. However, cross-correlation, latency, and transfer function analysis indicate that sensory feedback is a critical element in the relationship between thalamic activity and parkinsonian tremor. Therefore, thalamic spike train activity is most consistent with parkinsonian tremor being mediated by peripheral inputs involved in either an unstable reflex loop or sensory modulation of a central oscillator.

Pallidal activity during dystonia: somatosensory reorganisation and changes with severity.

A woman with progressive, medically intractable right upper limb dystonia underwent a pallidotomy with only transient improvement. During the procedure her dystonia became more severe as she repeatedly made a fist to command in order to provoke dystonia transiently (movement provoked dystonia). Comparisons within cells in the internal segment of the globus pallidus (Gpi) disclosed that the firing rate was the same at rest, with making a fist, and during movement provoked dystonia. However, the firing rate compared between cells decreased significantly throughout the procedure as the patient made a fist repeatedly. During the second half of the procedure the firing rate of cells in the Gpi was similar to that in hemiballismus. The proportion of cells in the GPi which responded to sensory stimulation was significantly higher in dystonia (53%) than in hemiballismus (13%). These results suggest that pallidal activity can correlate inversely with the severity of dystonia, perhaps due to activity dependent changes in neuronal function resulting from repeated voluntary movement.

Pachymeningitis with multiple cranial neuropathies and unilateral optic neuropathy secondary to Pseudomonas aeruginosa: case report and review.

Hypertrophic cranial pachymeningitis is a rare disorder that frequently presents with multiple cranial neuropathies. This disorder, which is characterized by thickening and infiltration of the cranial dura, can result from a variety of inflammatory and infectious conditions. A patient with hypertrophic cranial pachymeningitis is described in whom meningeal biopsy and bacterial cultures of the biopsy specimen revealed Pseudomonas aeruginosa. The authors believe this to be the first documented case of pachymeningitis secondary to this organism.

Thalamic neuronal activity correlated with essential tremor.

Animal studies suggest that an olivocerebello-bulbospinal pathway mediates harmaline induced tremor, which resembles essential tremor in humans. However, recent evidence suggests that thalamocortical pathways participate in essential tremor. Thalamic single neuron activity has been analysed during thalamotomy for essential tremor. It has been shown by spectral cross correlation analysis that thalamic activity has a significant, linear relation to forearm EMG activity during tremor. The presence of this tremor related activity at the site where a lesion abolishes essential tremor suggests that the thalamus has an important role in the mechanism of essential tremor.