Persistent dyskinesias in patients with fetal tissue transplantation for Parkinson disease.

Cell transplants are being developed for patients with Parkinson disease (PD) who have insufficient benefit with standard medical treatment. We describe the clinical features of five patients who developed persistent dyskinesias after fetal dopaminergic tissue transplantation. All had levodopa-induced dyskinesias preoperatively. We implanted fetal mesencephalic dopaminergic tissue into the putamina bilaterally in 34 patients with advanced PD. They were not immunosuppressed. Five of 34 patients (15%) developed troublesome choreic or dystonic dyskinesias that persisted despite lowering or discontinuing medications. Attempts to treat the involuntary movements with amantadine, clozapine, anticholinergics, dopamine depletors and other medicines had limited success. Metyrosine eliminated dyskinesias but led to the parkinsonian "off" state. Increasing the dose of levodopa worsened the dyskinesias. Three patients required placement of pallidal stimulators, bilaterally in two and unilaterally in one patient who had only contralateral dyskinesias. The two with the bilateral stimulators had improvement in dyskinesias. The patient with the unilateral pallidal stimulator had a substantial reduction of the dyskinesias, but attempts to treat residual "off" symptoms with levodopa were limited by worsening dyskinesias. Although the number of patients developing these persistent dyskinesias was small, these five patients had dramatic improvement after transplant. As a group, they had milder Parkinson signs at baseline and improved to the point of having minimal parkinsonism, with reduction or elimination of levodopa therapy prior to developing persistent dyskinesias. These involuntary movements establish the principle that fetal dopaminergic tissue transplants can mimic the effects of levodopa, not only in reducing bradykinesia, but also in provoking dyskinesias.

Motor fluctuations due to interaction between dietary protein and levodopa in Parkinson's disease.

BACKGROUND: The modulation of levodopa transport across the blood brain barrier by large neutral amino acids is well documented. Protein limitation and protein redistribution diets may improve motor fluctuations in patients with Parkinson's disease but the pharmacokinetics and pharmacodynamics of levodopa and amino acids are highly variable. METHODS: Clinical records of 1037 Parkinson's disease patients were analyzed to determine the proportion of patients with motor fluctuations related to protein interaction with levodopa. Motor fluctuations due to protein interaction with levodopa were defined as dietary protein being associated with (i) longer time to levodopa effectiveness, (ii) reduced benefit or duration of benefit, (iii) dose failures or (iv) earlier wearing off from a previously effective dose. Dose failures, sudden, painful or behavioral wearing-off periods, gait freezing, nausea, hallucinations, orthostasis, and dyskinesias were taken as markers of motor fluctuations, disease severity, and levodopa side effects potentially influenced by protein. RESULTS: 5.9 % of Parkinson's disease patients on levodopa, and 12.4 % with motor fluctuations on levodopa correlated their fluctuations with the relative timing of levodopa and protein intake. These patients were younger at disease onset, had worse motor fluctuations and had a higher incidence of family members with Parkinson's disease. Early wearing off or decreased dose efficacy were most commonly associated with protein interaction. 60 % of patients who modified their diets had weight loss. CONCLUSIONS: This study suggests that clinically significant protein interaction with levodopa may occur mostly in a subset of Parkinson's disease patients with earlier disease onset and those with familial disease.

Improvement of Primary Writing Tremor in Parkinson's Disease with Carbidopa/Levodopa.

BACKGROUND: Primary writing tremor is a task-specific phenomenon that has been described as variants of essential tremor or dystonia. PHENOMENOLOGY SHOWN: We describe the case of a 63-year-old female who initially had primary writing tremor, later developed Parkinson's disease, and once initiated on carbidopa/levodopa had improvement in her parkinsonism and her writing tremor. EDUCATIONAL VALUE: As neither essential tremor nor typical brachial dystonia respond to carbidopa/levodopa, our case documents that at least some cases of primary writing tremor are not variants of either dystonia or essential tremor.

Stereotypies in autism: a video demonstration of their clinical variability.

In autism, stereotypies are frequent and disabling, and whether they correspond to a hyperkinetic movement disorder, a homeostatic response aiming at sensory modulation, or a regulator of arousal remains to be established. So far, it has been challenging to distinguish among these different possibilities, not only because of lack of objective and quantitative means to assess stereotypies, but in our opinion also because of the underappreciated diversity of their clinical presentations. Herein, we illustrate the broad spectrum of stereotypies and demonstrate the usefulness of video-assisted clinical observations of children with autism. The clips presented were extracted from play sessions of 129 children with autism disorder. We conclude that compared to widely used questionnaires and interviews, systematic video observations provide a unique means to classify and score precisely the clinical features of stereotypies. We believe this approach will prove useful to both clinicians and researchers as it offers the level of detail from retrievable images necessary to begin to assess effects of age and treatments on stereotypies, and to embark on the type of investigations required to unravel the physiological basis of motor behaviors in autism.

Myoclonus and tremor response to thalamic deep brain stimulation parameters in a patient with inherited myoclonus-dystonia syndrome.

We present a 74-year-old woman with inherited myoclonus-dystonia, with predominant myoclonus and a novel mutation in the epsilon-sarcoglycan gene. The patient reports a life-long history of rapid, jerking movements, most severe in the upper extremities as well as a postural and action tremor. Bilateral deep brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus was performed, and the patient demonstrated moderate clinical improvement in myoclonus. We studied the effects on myoclonus and tremor of varying DBS frequency and amplitude. The frequency tuning curve for myoclonus was similar to that of tremor, suggesting similar mechanisms by which DBS alleviates both disorders.

Motor stereotypies in children with autism and other developmental disorders.

The purpose of the study was to count and characterize the range of stereotypies--repetitive rhythmical, apparently purposeless movements--in developmentally impaired children with and without autism, and to determine whether some types are more prevalent and diagnostically useful in children with autism. We described each motor stereotypy recorded during 15 minutes of archived videos of standardized play sessions in 277 children (209 males, 68 females; mean age 4y 6mo [SD 1y 5mo], range 2y 11mo-8y 1mo), 129 with autistic disorder (DSM-III-R), and 148 cognitively-matched non-autistic developmentally disordered (NADD) comparison children divided into developmental language disorder and non-autism, low IQ (NALIQ) sub-groups. The parts of the body involved and characteristics of all stereotypies were scored blind to diagnosis. More children with autism had stereotypies than the NADD comparison children. Autism and, to a lesser degree, nonverbal IQ (NVIQ) <80, especially in females contributed independently to the occurrence, number, and variety of stereotypies, with non-autistic children without cognitive impairment having the least number of stereotypies and children with autism and low NVIQ the most. Autism contributed independently to gait and hand/finger stereotypies and NVIQ <80 to head/trunk stereotypies. Atypical gazing at fingers and objects was rare but virtually limited to autism. Stereotypies are environmentally modulated movement disorders, some highly suggestive, but not pathognomonic, of autism. Their underlying brain basis and genetic correlates need investigation.

Tetrabenazine therapy of pediatric hyperkinetic movement disorders.

Tetrabenazine (TBZ), a presynaptic dopamine depletor and postsynaptic dopamine receptor blocker, is widely used for the treatment of hyperkinetic movement disorders in adults. However, reports of its use in children are limited. We review the efficacy and tolerability of TBZ therapy in 31 children with hyperkinetic movement disorders refractory to other medications. TBZ was effective in reducing the severity of movement disorders resistant to treatment with other medicines. When compared to adult patients, pediatric patients required higher doses. Side effects were similar to the adult population; however, children had a lower incidence of drug-induced Parkinsonism.

Reaction time and movement time after embryonic cell implantation in Parkinson disease.

BACKGROUND: Embryonic nigral cell implants are a novel treatment for Parkinson disease (PD). Reaction time (RT) and movement time (MT) analysis, validated quantitative measures of premovement neural processing and motor execution, can be used as objective physiological markers of motor performance in PD. OBJECTIVES: To gauge the change in motor performance in patients with PD who received implants, and to determine whether the physiological findings correlate with clinical outcome measures after transplantation. DESIGN: Double-blind, placebo-controlled trial. Patients Forty patients with levodopa-responsive, Hoehn and Yahr stage III or greater PD. INTERVENTIONS: Random assignment to embryonic tissue implants or placebo (sham) operation. MAIN OUTCOME MEASURES: Combined RT + MT scores measured preoperatively and at 4 and 12 months postoperatively in the "off" state. RESULTS: The difference in mean RT + MT scores between the sham and implant groups was statistically significant (P =.005) and was greatest in those 60 years or older (P =.003). Changes correlated with Unified Parkinson's Disease Rating Scale off scores at 4 (r = 0.87, P =.001) and 12 (r = 0.75, P =.01) months in those younger than 60 years. There was a significant deterioration in the sham surgery group at 12 months (P =.03) that was thought to be due to worsening in subjects 60 years and older (P<.001). CONCLUSIONS: The physiological measures detected significant changes in patients undergoing embryonic nigral cell implants and correlated directly with clinical outcome measures. Comprehensive analyses of RT paradigms can document subtle changes in motor performance over time, making them useful outcome measures in therapeutic trials of PD. These findings support further research into nigral cell implantation for PD.

Extensor digitorum brevis test and resistance to botulinum toxin type A.

We studied 22 patients with dystonia to determine the normal range of values for the extensor digitorum brevis (EDB) test, and to determine its sensitivity and specificity in detecting resistance to botulinum toxin type A (BTX-A). Three compound muscle action potentials (CMAPs) elicited by peroneal nerve stimulation were averaged before and 2 weeks after injection of 20 units of BTX-A into the EDB. Amplitude and area ratios were calculated by dividing the averaged postinjection CMAP by the averaged preinjection CMAP values. The difference in means of this ratio between clinically sensitive and resistant subjects was statistically significant (P < 0.002). A normal range of <0.45 for each ratio was determined by adding two standard deviations to the ratio mean of 14 clinically sensitive subjects. Four of five resistant patients had values outside the normal range. The EDB test is a simple quantitative method of detecting resistance to BTX-A, with a sensitivity of 80% and specificity of 94%.

Status of fetal tissue transplantation for the treatment of advanced Parkinson disease.

In the first double-blind, placebo-controlled randomized study of fetal tissue transplantation for the treatment of patients with advanced Parkinson disease (PD), investigators found that implanted dopaminergic tissue can produce measurable improvement in young PD in the absence of medication (that is, the "off" state). The results of the study, however, also highlighted several serious limitations of transplantation. In the group of older patients in the study (in the typical age range of individuals afflicted with PD) no improvement was derived from the implant despite positron emission tomography-documented scan evidence that the graft survived and produced dopamine. Patients in the study were selected because they experienced motor fluctuations, and the transplant did not improve dyskinesias or the time required to remain "on" medication for any subgroup of patients, including young patients. Five of 33 implant-treated patients developed involuntary movements (dyskinesias or dystonia) that could not be eliminated by reducing antiparkinsonian medications. These included four patients with the best responses to transplantation. Finally, some sham-operated patients experienced a dramatic placebo effect lasting at least 1 year, which justified the controversial sham surgery. The authors believe that these problems must be solved before fetal tissue transplantation can be considered a therapeutic option for PD.