David E. Riley

Criteria for the diagnosis of corticobasal degeneration.

Current criteria for the clinical diagnosis of pathologically confirmed corticobasal degeneration (CBD) no longer reflect the expanding understanding of this disease and its clinicopathologic correlations. An international consortium of behavioral neurology, neuropsychology, and movement disorders specialists developed new criteria based on consensus and a systematic literature review. Clinical diagnoses (early or late) were identified for 267 nonoverlapping pathologically confirmed CBD cases from published reports and brain banks. Combined with consensus, 4 CBD phenotypes emerged: corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). Clinical features of CBD cases were extracted from descriptions of 209 brain bank and published patients, providing a comprehensive description of CBD and correcting common misconceptions. Clinical CBD phenotypes and features were combined to create 2 sets of criteria: more specific clinical research criteria for probable CBD and broader criteria for possible CBD that are more inclusive but have a higher chance to detect other tau-based pathologies. Probable CBD criteria require insidious onset and gradual progression for at least 1 year, age at onset ≥50 years, no similar family history or known tau mutations, and a clinical phenotype of probable CBS or either FBS or naPPA with at least 1 CBS feature. The possible CBD category uses similar criteria but has no restrictions on age or family history, allows tau mutations, permits less rigorous phenotype fulfillment, and includes a PSPS phenotype. Future validation and refinement of the proposed criteria are needed.

Prospective randomized double-blind trial of bilateral thalamic deep brain stimulation in adults with Tourette syndrome

OBJECT The severity of Tourette syndrome (TS) typically peaks just before adolescence and diminishes afterward. In some patients, however, TS progresses into adulthood, and proves to be medically refractory. The authors conducted a prospective double-blind crossover trial of bilateral thalamic deep brain stimulation (DBS) in five adults with TS. METHODS Bilateral thalamic electrodes were implanted. An independent programmer established optimal stimulator settings in a single session. Subjective and objective results were assessed in a double-blind randomized manner for 4 weeks, with each week spent in one of four states of unilateral or bilateral stimulation. Results were similarly assessed 3 months after unblinded bilateral stimulator activation while repeated open programming sessions were permitted. RESULTS In the randomized phase of the trial, a statistically significant (p < 0.03, Friedman exact test) reduction in the modified Rush Video-Based Rating Scale score (primary outcome measure) was identified in the bilateral on state. Improvement was noted in motor and sonic tic counts as well as on the Yale Global Tic Severity Scale and TS Symptom List scores (secondary outcome measures). Benefit was persistent after 3 months of open stimulator programming. Quality of life indices were also improved. Three of five patients had marked improvement according to all primary and secondary outcome measures. CONCLUSIONS Bilateral thalamic DBS appears to reduce tic frequency and severity in some patients with TS who have exhausted other available means of treatment.

The spectrum of levodopa‐related fluctuations in Parkinson's disease

One of the most common and difficult management problems in Parkinson’s disease (PD) is the development of a fluctuant response following treatment with levodopa. For most patients, these fluctuations take the form of variations in the severity of motor manifestations of PD, which are assumed to reflect changes in the availability and efficacy of dopamine in the striatum.’X2 The proportion of patients with motor fluctuations (MF) increases with the duration of levodopa treatment, and the majority of PD patients develop MF within approximately 5 y e a r s a f t e r in i t ia t ion of levodopa MF are more common and occur sooner in patients who develop PD a t a younger age.6J The most commonly encountered form of fluctuating response is the predictable “wearing-off” of levodopa motor benefit, causing a transition from relative mobility (“on”) to increased parkinsonism (“off”), with a return to the “on” state after the next dose of levodopa. Many other forms of MF are recognized (table 11, and combinations of these features are frequent, especially in the later stages of PD . Although there has been considerable emphasis on these classic motor swings, a number of other types of fluctuations occur, many of a nonmotor nature, which may be equally, or more, incapacitating. We report selected patients who exhibited such relatively underappreciated fluctuations and attempt to organize these fluctuations into a rational classification.

Clinically deployable Kinesia technology for automated tremor assessment.

The objective was to design, build, and assess Kinesia™, a wireless system for automated assessment of Parkinsons disease (PD) tremor. The current standard in evaluating PD is the Unified Parkinsons Disease Rating Scale (UPDRS), a qualitative ranking system typically completed during an office visit. Kinesia integrates accelerometers and gyroscopes in a compact patient‐worn unit to capture kinematic movement disorder features. Objectively quantifying PD manifestations with increased time resolution should aid in evaluating efficacy of treatment protocols and improve patient management. In this study, PD subjects performed the tremor subset of the UPDRS motor section while wearing Kinesia. Quantitative kinematic features were processed and highly correlated to clinician scores for rest tremor (r2 = 0.89), postural tremor (r2 = 0.90), and kinetic tremor (r2 = 0.69). The quantitative features were used to develop a mathematical model that predicted tremor severity scores for new data with low errors. Finally, PD subjects indicated high clinical acceptance.

Frozen shoulder and other shoulder disturbances in Parkinson's disease.

The frequency of shoulder disturbances, particularly frozen shoulder, has not been assessed previously in Parkinsons disease. In a survey of 150 patients compared with 60 matched control subjects a significantly higher incidence of both a history of shoulder complaints (43% vs. 23%) and frozen shoulder (12.7% vs. 1.7%) was found in the Parkinsons disease population. Those developing a frozen shoulder had initial disease symptoms indicative of akinesia twice as frequently as tremor while the ratio was reversed in those without frozen shoulder. In at least 8% of the patients frozen shoulder was the first symptom of disease, occurring 0-2 years prior to the onset of more commonly recognised features. Parkinsons disease should be added to the list of causes of frozen shoulder, and clinicians must be aware that the latter is often the presenting symptom of Parkinsons disease.

Pathophysiology of slow vertical saccades in progressive supranuclear palsy

Objectives: To investigate the relative roles of burst neurons (which generate the saccadic command) and omnipause neurons (which gate the activity of burst neurons) in the pathogenesis of slow saccades in progressive supranuclear palsy (PSP). Background: Experimental inactivation of mesencephalic burst neurons impairs vertical but not horizontal saccades. Experimental inactivation of omnipause neurons causes slowing of both horizontal and vertical saccades. Combining saccadic with vergence movements in healthy subjects induces small, high-frequency, conjugate oscillations, which indicate that omnipause neurons are inhibited. Methods: The authors studied seven patients with PSP, six patients with other parkinsonian syndromes, and seven age-matched control subjects. They compared vertical saccades of similar sizes made with or without associated vergence movements. They compared the speed of vertical and horizontal saccades. Results: Five patients with PSP and the six patients with other parkinsonian made vertical saccades in combination with horizontal vergence; all showed conjugate horizontal oscillations (29 to 41 Hz) during 27% to 93% of saccade–vergence trials. Vertical saccades made in conjunction with vergence movements were not speeded up or increased in size compared with saccades made between equidistant targets for the PSP or parkinsonian groups. Vertical saccades were slowed more than horizontal saccades in the PSP group (p < 0.005) but not in the parkinsonian group. Conclusions: Dysfunction of omnipause neurons (“gate dysfunction”) is unlikely to be the primary cause of slow vertical saccades in progressive supranuclear palsy. Deficient generation of the motor command by midbrain burst neurons is the more likely cause.

Autonomic nervous system testing may not distinguish multiple system atrophy from Parkinson’s disease

Background: Formal laboratory testing of autonomic function is reported to distinguish between patients with Parkinson’s disease and those with multiple system atrophy (MSA), but such studies segregate patients according to clinical criteria that select those with autonomic dysfunction for the MSA category. Objective: To characterise the profiles of autonomic disturbances in patients in whom the diagnosis of Parkinson’s disease or MSA used criteria other than autonomic dysfunction. Methods: 47 patients with parkinsonism and autonomic symptoms who had undergone autonomic laboratory testing were identified and their case records reviewed for non-autonomic features. They were classified clinically into three diagnostic groups: Parkinson’s disease (19), MSA (14), and uncertain (14). The performance of the patients with Parkinson’s disease was compared with that of the MSA patients on five autonomic tests: RR variation on deep breathing, heart rate changes with the Valsalva manoeuvre, tilt table testing, the sudomotor axon reflex test, and thermoregulatory sweat testing. Results: None of the tests distinguished one group from the other with any statistical significance, alone or in combination. Parkinson’s disease and MSA patients showed similar patterns of autonomic dysfunction on formal testing of cardiac sympathetic and parasympathetic, vasomotor, and central and peripheral sudomotor functions. Conclusions: This study supports the clinical observation that Parkinson’s disease is often indistinguishable from MSA when it involves the autonomic nervous system. The clinical combination of parkinsonism and dysautonomia is as likely to be caused by Parkinson’s disease as by MSA. Current clinical criteria for Parkinson’s disease and MSA that direct patients with dysautonomia into the MSA group may be inappropriate.

Clinico-immunologic aspects of botulinum toxin type B treatment of cervical dystonia

In this multicenter study of 100 patients with cervical dystonia, we examined the immunogenicity of botulinum toxin type B (BTX-B) and correlated the clinical response with the presence of blocking antibodies (Abs) using a novel mouse protection assay. One-third of the patients who were negative for BTX-B Abs at baseline became positive for BTX-B Abs at last visit. Thus, the high antigenicity of BTX-B limits its long-term efficacy.

Cognitive processes in idiopathic dystonia treated with high-dose anticholinergic therapy : implications for treatment strategies

Studies utilizing single doses of scopolamine have suggested a role for the cholinergic system in memory. Results are consistent in identifying a selective effect on the early encoding stage of information processing. In terms of long-term administration of anticholinergics, patients with Parkinsons disease often display memory deficits. However, underlying pathology within the forebrain cholinergic system complicates the study of treatment effects in this disorder. We therefore assessed multiple memory routines in 20 cognitively intact patients with dystonia where no such pathology has been identified. Patients were tested before and after 2-4 months of 15-74 mg of trihexyphenidyl daily. Twelve tolerated this regime. Compared to control subjects, matched for age and I.Q., only tests with a single presentation of the material to be remembered were affected at follow-up. The speed of information processing was also significantly reduced. Age was strongly related to memory performance in the patient group alone and interacted with dose and duration of treatment. Results suggest that drug-induced slowing of mentation was responsible for impaired encoding, particularly in older patients. These findings affect treatment strategies, especially now that injections of botulinum toxin have proved to be highly effective for certain forms of focal dystonia.

The Disturbance of Gaze in Progressive Supranuclear Palsy: Implications for Pathogenesis

Progressive supranuclear palsy (PSP) is a disease of later life that is currently regarded as a form of neurodegenerative tauopathy. Disturbance of gaze is a cardinal clinical feature of PSP that often helps clinicians to establish the diagnosis. Since the neurobiology of gaze control is now well understood, it is possible to use eye movements as investigational tools to understand aspects of the pathogenesis of PSP. In this review, we summarize each disorder of gaze control that occurs in PSP, drawing on our studies of 50 patients, and on reports from other laboratories that have measured the disturbances of eye movements. When these gaze disorders are approached by considering each functional class of eye movements and its neurobiological basis, a distinct pattern of eye movement deficits emerges that provides insight into the pathogenesis of PSP. Although some aspects of all forms of eye movements are affected in PSP, the predominant defects concern vertical saccades (slow and hypometric, both up and down), impaired vergence, and inability to modulate the linear vestibulo-ocular reflex appropriately for viewing distance. These vertical and vergence eye movements habitually work in concert to enable visuomotor skills that are important during locomotion with the hands free. Taken with the prominent early feature of falls, these findings suggest that PSP tauopathy impairs a recently evolved neural system concerned with bipedal locomotion in an erect posture and frequent gaze shifts between the distant environment and proximate hands. This approach provides a conceptual framework that can be used to address the nosological challenge posed by overlapping clinical and neuropathological features of neurodegenerative tauopathies.