Changes in the thalamus in atypical parkinsonism detected using shape analysis and diffusion tensor imaging.

BACKGROUND AND PURPOSE: The thalamus is interconnected with the nigrostriatal system and cerebral cortex and has a major role in cognitive function and sensorimotor integration. The purpose of this study was to determine how regional involvement of the thalamus differs among Parkinson disease, progressive supranuclear palsy, and corticobasal syndrome. MATERIALS AND METHODS: Nine patients with Parkinson disease, 5 with progressive supranuclear palsy, and 6 with corticobasal syndrome underwent 3T MR imaging along with 12 matched, asymptomatic volunteers by using a protocol that included volumetric T1 and diffusion tensor imaging. Acquired data were automatically processed to delineate the margins of the motor and nonmotor thalamic nuclear groups, and measurements of ADC were calculated from the DTI data within these regions. Thalamic volume, shape, and ADC were compared across groups. RESULTS: Thalamic volume was smaller in the progressive supranuclear palsy and corticobasal syndrome groups compared with the Parkinson disease and control groups. Shape analysis revealed that this was mainly due to the diminished size of the lateral thalamus. Overall, ADC measurements were higher in the progressive supranuclear palsy group compared with both the Parkinson disease and control groups, and anatomic subgroup analysis demonstrated that these changes were greater within the motor regions of the thalamus in progressive supranuclear palsy and corticobasal degeneration. CONCLUSIONS: Reduced size and increased ADC disproportionately involve the lateral thalamus in progressive supranuclear palsy and corticobasal syndrome, consistent with selective neurodegeneration and atrophy in this region. Because these findings were not observed in Parkinson disease, they may be more specific markers of tau-related neurodegeneration.

Fall frequency and risk assessment in early Parkinson's disease.

BACKGROUND: We sought to define the frequency of falls in early PD and assess potential risk factors for falls in this population. METHODS: We analyzed the data from two randomized, placebo controlled trials (NET-PD FS1 and FS-TOO) of 413 individuals with early PD over 18 months of follow-up in FS1 and 12 months in FS-TOO. Falls were defined as any report of falls on the UPDRS or the adverse event log. We assessed the frequency of falls overall and by age. The relationship between prespecified fall risk markers and the probability of falling was assessed using logistic and multiple logistic regression. A hurdle Poisson model was used to jointly model the probability of remaining fall-free and the number of falls. RESULTS: During the follow-up period, 23% of participants fell, and 11% were habitual fallers. In a multiple logistic regression model, age, baseline UPDRS Falling score, and baseline PDQ-39 scores were associated with subsequent fall risk (p < 0.001). Similarly, in a hurdle Poisson regression model, age, baseline UPDRS falling item, and baseline PDQ-39 were all significantly related to the probability of falling, but only UPDRS falling >0 was associated with the number of falls. CONCLUSION: Falls are frequent and are associated with impaired quality of life, even in early PD. Current standard rating scales do not sufficiently explain future fall risk in the absence of a prior fall history. New assessment methods for falls and postural instability are required to better evaluate this important problem in clinical trials and clinical practice.

Trends in American Board of Psychiatry and Neurology specialties and neurologic subspecialties.

OBJECTIVE: To review the current status and recent trends in the American Board of Psychiatry and Neurology (ABPN) specialties and neurologic subspecialties and discuss the implications of those trends for subspecialty viability. METHODS: Data on numbers of residency and fellowship programs and graduates and ABPN certification candidates and diplomates were drawn from several sources, including ABPN records, Web sites of the Accreditation Council for Graduate Medical Education and the American Medical Association, and the annual medical education issues of the Journal of the American Medical Association. RESULTS: About four-fifths of neurology graduates pursue fellowship training. While most recent neurology and child neurology graduates attempt to become certified by the ABPN, many clinical neurophysiologists elect not to do so. There appears to have been little interest in establishing fellowships in neurodevelopmental disabilities. The pass rate for fellowship graduates is equivalent to that for the "grandfathers" in clinical neurophysiology. Lower percentages of clinical neurophysiologists than specialists participate in maintenance of certification, and maintenance of certification pass rates are high. CONCLUSION: The initial enthusiastic interest in training and certification in some of the ABPN neurologic subspecialties appears to have slowed, and the long-term viability of those subspecialties will depend upon the answers to a number of complicated social, economic, and political questions in the new health care era.

Safety and tolerability of putaminal AADC gene therapy for Parkinson disease.

BACKGROUND: In Parkinson disease (PD), the benefit of levodopa therapy becomes less marked over time, perhaps because degeneration of nigrostrial neurons causes progressive loss of aromatic l-amino acid decarboxylase (AADC), the enzyme that converts levodopa into dopamine. In a primate model of PD, intrastriatal infusion of an adeno-associated viral type 2 vector containing the human AADC gene (AAV-hAADC) results in robust response to low-dose levodopa without the side effects associated with higher doses. These data prompted a clinical trial. METHODS: Patients with moderately advanced PD received bilateral intraputaminal infusion of AAV-hAADC vector. Low-dose and high-dose cohorts (5 patients in each) were studied using standardized clinical rating scales at baseline and 6 months. PET scans using the AADC tracer [(18)F]fluoro-L-m-tyrosine (FMT) were performed as a measure of gene expression. RESULTS: The gene therapy was well tolerated, but 1 symptomatic and 2 asymptomatic intracranial hemorrhages followed the operative procedure. Total and motor rating scales improved in both cohorts. Motor diaries also showed increased on-time and reduced off-time without increased "on" time dyskinesia. At 6 months, FMT PET showed a 30% increase of putaminal uptake in the low-dose cohort and a 75% increase in the high-dose cohort. CONCLUSION: This study provides class IV evidence that bilateral intrastriatal infusion of adeno-associated viral type 2 vector containing the human AADC gene improves mean scores on the Unified Parkinson's Disease Rating Scale by approximately 30% in the on and off states, but the surgical procedure may be associated with an increased risk of intracranial hemorrhage and self-limited headache.

Recommendations for the clinical use of somatosensory-evoked potentials.

The International Federation of Clinical Neurophysiology (IFCN) is in the process of updating its Recommendations for clinical practice published in 1999. These new recommendations dedicated to somatosensory-evoked potentials (SEPs) update the methodological aspects and general clinical applications of standard SEPs, and introduce new sections dedicated to the anatomical-functional organization of the somatosensory system and to special clinical applications, such as intraoperative monitoring, recordings in the intensive care unit, pain-related evoked potentials, and trigeminal and pudendal SEPs. Standard SEPs have gained an established role in the health system, and the special clinical applications we describe here are drawing increasing interest. However, to prove clinically useful each of them requires a dedicated knowledge, both technical and pathophysiological. In this article we give technical advice, report normative values, and discuss clinical applications.

Results from a phase I safety trial of hAADC gene therapy for Parkinson disease.

BACKGROUND: In a primate model of Parkinson disease (PD), intrastriatal infusion of an adeno-associated viral (AAV) vector containing the human aromatic l-amino acid decarboxylase (hAADC) gene results in robust gene expression. After gene transfer, low doses of systemically administered l-dopa are converted to dopamine in the transduced striatal neurons, resulting in behavioral improvement without the side effects typically associated with higher doses of l-dopa. These studies led to the initiation of a phase I safety trial. Here we report the findings for the first cohort of five patients. METHODS: Patients with moderate to advanced PD received bilateral infusion of a low dose of the AAV-hAADC vector into the putamen. PET scans using the AADC tracer, 6-[18F]fluoro-l-m-tyrosine (FMT), were performed at baseline and at 1 and 6 months after infusion as an in vivo measure of gene expression. RESULTS: PET results showed an average 30% increase in FMT uptake (K(i)(c)) in the putamen after gene transfer. Preliminary analysis of clinical data indicates a modest improvement, but absence of a control and the nonblinded analyses make interpretation difficult. CONCLUSIONS: Thus far, this gene therapy approach has been well tolerated and shows PET evidence of sustained gene expression. These initial findings demonstrate the safety of the therapy; higher doses of adeno-associated viral vector containing the human aromatic l-amino acid decarboxylase gene in the next cohort of patients may further increase dopamine production in the putamen and provide more profound clinical benefit.

The Brown-Séquard and S. Weir Mitchell letters.

The two prominent nineteenth-century neurophysiologists/neurologists C.E. Brown-Séquard and S.W. Mitchell maintained an active correspondence during their careers. These letters, never before studied as a unit, provide insight into the men's close collegial association in several domains. They shared camaraderie as pioneer physiologists who tried to bring experimental discoveries from the laboratory to the clinical setting. They critiqued each other's research and facilitated its publication in journals over which they had influence. Through letters of recommendation, they also helped foster each other's local careers. In a period of transition in neuroscience from a traditional anatomic focus to the emerging predominance of neurophysiology and neuropharmacology, their correspondence documents the views of two late nineteenth-century leaders in science and international academic medicine.

Parkinson's disease.

A number of changes have occurred in the management of Parkinson's disease in recent years, with the development of new therapeutic strategies based upon advances in pharmacotherapy and interventional procedures. The treatment of patients with Parkinson's disease is considered here with these advances in mind. Potential neuroprotective agents that might slow disease-progression are also considered, but at the present time these agents are more of academic interest than clinical relevance and their role remains to be established. Ablative surgery and stimulation procedures are also helpful in the management of Parkinson's disease, and the utility and limitations of these approaches are briefly summarized.

Studies of the human stretch reflex.

We recorded the late electromyographic (EMG) responses to predictable and unpredictable stretches of the wrist flexor and extensor muscles during ballistic movement or isometric contractions. We simultaneously recorded the accompanying cerebral responses. Our findings suggest that the late EMG responses are influenced by suprasegmental (cerebral) phasic mechanisms that seem to have a dual functional role, being involved in the control of limb stiffness and in a servomechanism to return the displaced limb to its intended position.

Effect of pallidotomy on postural control and motor function in Parkinson disease.

OBJECTIVE: To investigate the effects of pallidotomy on postural reactions and other motor parkinsonian deficits. DESIGN: Comparison of performance by patients before and after pallidotomy on tests of balance and function. SETTING: A Parkinson disease Center of Excellence and Center for Human Performance Testing at a university hospital and research center. PARTICIPANTS: Twenty-nine patients with Parkinson disease undergoing pallidotomy. MAIN OUTCOME MEASURES: Performance results on the United Parkinson's Disease Rating Scale (UPDRS), activities of daily living and motor subscales (parts II and III). and posturography (sensory organization test), which were collected before and 3 and 6 months after surgery with patients in the practically defined off state (medication withheld for at least 12 hours). RESULTS: Data were analyzed with a paired Wilcoxon and Spearman correlation. There was a significant improvement in mean +/- SD UPDRS motor subscale score after pallidotomy (before surgery, 52.43+/-13.46; after surgery, 43.93+/-15.15; z= 3.63; P=.003). There were no significant changes in the UPDRS activities of daily living subscale or average stability scores when the group was examined as a whole. However, examination of individual data revealed that 9 (56%) of 16 patients who could stand independently before surgery showed improvement in either the number of falls or the average stability score. No patient who was unable to stand independently before surgery was able to stand independently after it. CONCLUSION: Pallidotomy helped improve overall motor function in patients with parkinsonism and, for some patients, also improved postural stability.

Changes of forearm EMG and cerebral evoked potentials following sudden muscle stretch in patients with Huntington's disease.

Various investigators have reported that the late-reflex electromyographic (EMG) activity following muscle stretch is decreased in Huntington's disease. To explore the basis of this decreased activity, we recorded the late EMG responses together with associated cerebral responses following muscle stretch in patients with Huntington's disease. Five patients and seven controls voluntarily participated in two sets of experiments in which they grasped a handle attached to a torque motor and maintained the wrist isometrically against a constant flexor force of 2.3 newtons (N). The force was changed unpredictably (first set of experiments) or predictably (second set) to 10.4 N, causing a stretch of wrist extensors or flexors. Rectified surface EMG from the extensor and flexor carpi radialis muscles was integrated for the M2 and M3 components of the late responses. Cerebral responses were recorded from F3, F4, C3, C4, and Cz and averaged separately depending upon condition. The late muscle responses to unpredictable muscle stretch were decreased or absent in patients with Huntington's disease. The cerebral responses recorded at Cz differed markedly between patients and controls, beginning approximately 15 ms prior to the onset of the late M2 muscle response. Although the initial positivity was similar in amplitude, all other cerebral components were markedly reduced in the patient group. Both controls and patients showed a markedly attenuated cerebral response when the muscle stretch was predictable. The electrocerebral response to muscle stretch is thus altered prior to the onset of M2 in patients with Huntington's disease, suggesting that the long-latency reflex involves transcerebral pathways that are affected in this disease.

Order effects in response times of parkinsonian patients and normal controls.

Response latencies were measured in 6 parkinsonian patients and 6 normal subjects in a choice reaction task requiring the discrimination of two different tones with different probabilities of occurrence (frequent and rare). Response latency was measured from stimulus onset to onset of electromyographic activity in the responding muscle. Rare-tone responses were separated on the basis of the number of frequent tones intervening between the rare tone of interest and the immediately preceding rare tone (defined as rare-tone position). Frequent-tone responses were separated by the number of consecutive frequent tones occurring either before or after a rare tone (defined as frequent-tone position). Rare- and frequent-tone position had a significant impact on response latency. Both patients and controls had the shortest response latencies to rare tones when four frequent tones (the median interval for these experiments) intervened. Similarly, the response latency to frequent tones increased at approximately this same median interval after a rare event for both patients and controls. These findings suggest that normal controls utilize probability information about both global probabilities and their immediate past experience in order to modify upcoming responses. Our findings also indicate that patients with Parkinson's disease do not differ from normal subjects in this regard, and thus that even subtle attributes of preprogramming are not affected in Parkinson's disease, despite suggestions by others to the contrary.

Simple and choice reaction time in Parkinson's disease.

Reaction-times were evaluated in 6 parkinsonian patients and 6 normal control subjects using a simple reaction task and 3 choice reaction tasks of differing complexity. Reaction-times were measured as the time from stimulus onset to the onset of electromyographic activity in the responding muscle. Reaction-time was significantly delayed in patients compared to controls in all tasks, but to a greater extent in the more difficult tasks. The relative magnitude of the change, however, was only 4% in the simple reaction task and 8% in the more difficult choice tasks. These results suggest that the deficit in Parkinson's disease is unlikely to represent a defect in preprogramming as suggested by some investigators. Instead, our results indicate a disturbance in the cerebral processing of the auditory stimuli after their occurrence and prior to the initiation of motor activity.

Clinical neurophysiologic studies: which test is useful and when?

Neurophysiological studies test the integrity of nerve roots and nerves at different points from the spinal cord to the periphery. EMG is the most sensitive neurophysiological test for evaluating patients with radiculopathy, providing information on diagnosis, location, and prognosis. F-wave and H-reflex studies may be abnormal, but the information that they provide is nonspecific and usually redundant because the needle examination is abnormal anyway. Somatosensory evoked potentials are less sensitive and specific than EMG for diagnosing a radiculopathy, but uncommonly may be the only abnormality. Magnetic stimulation, paraspinal mapping, and cervical root stimulation are investigational techniques of uncertain utility.

AAEM minimonograph 32: the electrodiagnostic examination in patients with radiculopathies. American Association of Electrodiagnostic Medicine.

The anatomy and pathophysiology of radiculopathies are reviewed, and the electrodiagnostic approaches used in evaluating patients with suspected root lesions are discussed. Such electrophysiologic procedures include motor and sensory nerve conduction studies, late-response studies, somatosensory and motor evoked potentials, nerve root stimulation, and needle electromyography. The value and limitations of these different procedures are considered. At the present time, needle electromyography is the single most useful approach. The findings in patients with radiculopathies at different levels are summarized.

Dystonia and chorea in acquired systemic disorders.

Dystonia and chorea are uncommon accompaniments, but sometimes the presenting features of certain acquired systemic disorders that presumably alter basal ganglia function. Hypoxia-ischaemia may injure the basal ganglia through hypoperfusion of subcortical vascular watershed regions and by altering striatal neurotransmitter systems. Toxins interfere with striatal mitochondrial function, resulting in cellular hypoxia. Infections may affect the basal ganglia by causing vasculitic ischaemia, through the development of antibodies to basal ganglia epitopes, by direct invasion of the basal ganglia by the organism, or through cytotoxins causing neuronal injury. Autoimmune disorders alter striatal function by causing a vasculopathy, by direct reaction of antibodies with basal ganglia epitopes, or by stimulating the generation of a cytotoxic or inflammatory reaction. Endocrine and electrolyte abnormalities influence neurotransmitter balance or affect ion channel function and signalling in the basal ganglia. In general, the production of chorea involves dysfunction of the indirect pathway from the caudate and putamen to the internal globus pallidus, whereas dystonia is generated by dysfunction of the direct pathway. The time of the onset of the movement disorder relative to the primary disease process, and course vary with the age of the patient and the underlying pathology. Treatment of dystonia or chorea associated with a systemic medical disorder must initially consider the systemic disorder.

Cerebral accompaniments to simple and choice reaction tasks in Parkinson's disease.

In order to clarify the nature and basis of the delayed reaction time that occurs in Parkinson's disease, we measured reaction times and cerebral responses in six parkinsonian patients and six normal age-matched control subjects. Each participated in one simple reaction task and three choice reaction tasks of different complexity. The reaction times were delayed in the parkinsonian patients in all conditions but especially in the more difficult choice tasks. In addition, the cerebral responses showed delayed latencies of the N1, N2, and P3 components of the event-related cerebral potential. These findings are similar to the changes that we observed previously in patients with both Parkinson's disease and dementia, and suggest that bradyphrenia may account, in part, for the slowing of response time in Parkinson's disease.

Management of status epilepticus.

The pharmacologic management of major motor status epilepticus is summarized. When general anesthesia is required, the electroencephalogram (EEG) is used for monitoring the adequacy of treatment. The EEG findings may also be important in recognizing status epilepticus and monitoring its response to treatment when this is clinically difficult, as when it occurs in comatose or pharmacologically paralyzed patients or in the context of severe brain damage. Finally, the EEG helps to clarify the nature of motor activities of uncertain basis in patients in the intensive care unit and has indicated that non-convulsive seizures or status are more common than clinically suspected in such patients.