Biomedical subjects

R Pahwa

Publications and source records attributed to R Pahwa.

At least 19 recordsLinked to original sources

PubMed2006

Neuropathologic findings in essential tremor.

Pathologic findings, including cerebellar changes and brainstem Lewy bodies, distinguished 10 essential tremor (ET) cases from 12 controls. Numbers of torpedoes (p = 0.009) and Bergmann glia (p = 0.046) were increased in cases. Six cases (60%) had Lewy bodies vs 2 controls (16.7%) (odds ratio 7.5, 95% CI 1.04 to 54.1; p = 0.035). Four of these six had an atypical distribution of brainstem Lewy bodies. ET may be pathologically heterogeneous.

Aged, 80 and over↗

PubMed2006

Practice Parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.

OBJECTIVE: To make evidence-based treatment recommendations for the medical and surgical treatment of patients with Parkinson disease (PD) with levodopa-induced motor fluctuations and dyskinesia. To that end, five questions were addressed. 1. Which medications reduce off time? 2. What is the relative efficacy of medications in reducing off time? 3. Which medications reduce dyskinesia? 4. Does deep brain stimulation (DBS) of the subthalamic nucleus (STN), globus pallidus interna (GPi), or ventral intermediate (VIM) nucleus of the thalamus reduce off time, dyskinesia, and antiparkinsonian medication usage and improve motor function? 5. Which factors predict improvement after DBS? METHODS: A 10-member committee including movement disorder specialists and general neurologists evaluated the available evidence based on a structured literature review including MEDLINE, EMBASE, and Ovid databases from 1965 through June 2004. RESULTS, CONCLUSIONS, AND RECOMMENDATIONS: 1. Entacapone and rasagiline should be offered to reduce off time (Level A). Pergolide, pramipexole, ropinirole, and tolcapone should be considered to reduce off time (Level B). Apomorphine, cabergoline, and selegiline may be considered to reduce off time (Level C). 2. The available evidence does not establish superiority of one medicine over another in reducing off time (Level B). Sustained release carbidopa/levodopa and bromocriptine may be disregarded to reduce off time (Level C). 3. Amantadine may be considered to reduce dyskinesia (Level C). 4. Deep brain stimulation of the STN may be considered to improve motor function and reduce off time, dyskinesia, and medication usage (Level C). There is insufficient evidence to support or refute the efficacy of DBS of the GPi or VIM nucleus of the thalamus in reducing off time, dyskinesia, or medication usage, or to improve motor function. 5. Preoperative response to levodopa predicts better outcome after DBS of the STN (Level B).

Dyskinesias↗

PubMed2006

Topiramate in essential tremor: a double-blind, placebo-controlled trial.

BACKGROUND: Essential tremor is most prevalent and most disabling in older patients. Additional therapies are required for patients with an inadequate response or intolerable side effects. In small trials, topiramate appeared to be beneficial in essential tremor. METHODS: In this multicenter, double-blind, placebo-controlled, parallel-design trial, patients with moderate to severe essential tremor of the upper limbs were randomized to 24 weeks of treatment with placebo or topiramate (target dose, 400 mg/day) as monotherapy or as an adjunct to one antitremor medication. The primary efficacy variable was the final visit tremor score based on the Fahn-Tolosa-Marin Tremor Rating Scale (TRS). RESULTS: The intent-to-treat population was 208 patients (topiramate, 108; placebo, 100). The final visit score (last observation carried forward) was lower in the topiramate group than with placebo (p < 0.001). Mean percentage improvement in overall TRS scores was 29% with topiramate at a mean final dose of 292 mg/day and 16% with placebo (p < 0.001). Topiramate was associated with greater improvement in function and disability (p = 0.001). A between-group difference (p < 0.001) was observed at the first on-treatment visit at 4 weeks when the target topiramate dose was 100 mg/day (mean achieved dose, 62 +/- 9 mg/day). The most common treatment-limiting adverse events in topiramate-treated patients were paresthesia (5%), nausea (3%), concentration/attention difficulty (3%), and somnolence (3%). Adverse events were treatment limiting in 31.9% of topiramate patients and 9.5% of placebo patients. CONCLUSIONS: Topiramate was effective in the treatment of moderate to severe essential tremor. Tremor reduction was accompanied by functional improvements, such as in motor tasks, writing, and speaking.

Adult↗

PubMed2005

Quantitative assessments of the effect of bilateral subthalamic stimulation on multiple aspects of sensorimotor function for patients with Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective for the treatment of advanced Parkinson's disease. Most studies have evaluated the effectiveness of DBS of the STN using clinical motor scores or simple timed tests of motor function. There have been few studies that quantitatively assessed the outcome of STN DBS using multiple testing paradigms. In the current study, 11 patients who had bilateral STN DBS were quantitatively evaluated under four conditions using gait, postural control, and gait initiation. The four conditions included the medication on/stimulation on (M_on/S_on), medication on/stimulation off (M_on/S_off), medication off/stimulation on (M_off/S_on), and medication off/stimulation off (M_off/S_off) conditions. DBS of the STN significantly increased walking speed with and without levodopa, but had no influence on the cadence. The addition of levodopa had a minimal additional effect on walking speed. The effect of STN DBS on gait initiation approached the significant level. The mean values of lateral body sway during quiet standing increased moderately with medication and/or DBS, but the changes were not statistically significant. Future studies need to determine whether or not there is a potential negative effect of STN DBS on the postural control.

Adult↗

PubMed2005

Bilateral subthalamic stimulation improves gait initiation in patients with Parkinson's disease.

Impaired gait initiation is one of the typical sign of advanced Parkinson's disease (PD). This is the first study to examine quantitatively the effect of deep brain stimulation of the subthalamic nucleus on the performance of gait initiation for patients with advanced PD. A total of 11 patients after surgery of bilateral deep brain stimulation of the subthalamic nucleus (STN) were tested in both the deep brain stimulation (DBS) ON and OFF conditions and/or in both the medication ON (i.e., with the usual dosage of antiparkinsonian medications administered) and OFF (i.e., with the usual dosage of antiparkinsonian medications withheld) conditions. DBS had no effect on the onset of anticipatory postural adjustment (APA). The effect of DBS approached significant level for the onset of swing foot lifting, but reached significant level for the delay of swing foot lifting. DBS significantly increased the amplitude of the APA, amplitude of reactive shear forces on both feet, and amplitude of COP in both anterior-posterior and medial-lateral directions. It is concluded that DBS significantly improved the performance of patients with advanced PD in gait initiation.

Adult↗

PubMed2004

Development and initial validation of a screening tool for Parkinson disease surgical candidates.

As there is currently no standardized assessment tool for evaluating Parkinson disease (PD) patients for deep brain stimulation (DBS), the authors developed the Florida Surgical Questionnaire for Parkinson Disease (FLASQ-PD). Part I of the study was a retrospective analysis of 174 patients presenting for a surgical screening. Part II was a multicenter study to assess the correlation of FLASQ-PD scores. The results of this study suggest that the FLASQ-PD may be a useful triage tool for screening PD patients for DBS surgery.

Deep Brain Stimulation↗

PubMed2004

Apolipoprotein E controls the risk and age at onset of Parkinson disease.

BACKGROUND: Similarities between Alzheimer disease (AD) and Parkinson disease (PD) suggest a possible role for apolipoprotein E (APOE) in PD. Most previous studies seeking to establish such a link used case-control datasets and results have been inconsistent. OBJECTIVE: To investigate APOE's role in PD using family-based association analyses. METHODS: APOE functional polymorphisms were genotyped for 658 PD affected families, including 282 multiplex and 376 singleton families. The pedigree disequilibrium test (PDT) and the genotype-PDT were used to test the risk effect of APOE. The Monks-Kaplan test was used to evaluate the effect of APOE on age at onset of PD. RESULTS: APOE was significantly associated with risk of developing PD. Stratified analysis revealed that APOE was most strongly associated with families with a positive PD family history (global p = 0.003). Like AD, the APOE-4 allele increases disease risk while the APOE-3 allele decreases risk. We detected a positive association of APOE-3 (p = 0.019) and a negative association of APOE-4 (p = 0.015) with age at onset in PD. CONCLUSIONS: The APOE-4 allele increases risk and decreases age at onset of PD, an association that may not be dependent upon cognitive impairment.

Adult↗

PubMed2003

Genetic polymorphisms of the N-acetyltransferase genes and risk of Parkinson's disease.

Recently, the authors demonstrated linkage in idiopathic PD to a region on chromosome 8p that contains the N-acetyltransferase genes, NAT1 and NAT2. The authors examined NAT1 and NAT2 for association with PD using family-based association methods and single nucleotide polymorphisms (SNPs). The authors did not find evidence for association with increased risk for PD between any individual NAT1 or NAT2 SNP or acetylation haplotype (N = 397 families, 1,580 individuals).

Aged↗

PubMed2003

Neuropsychological and quality of life outcomes 12 months after unilateral thalamic stimulation for essential tremor.

OBJECTIVES: To evaluate the one year cognitive, mood state, and quality of life (QoL) outcomes of unilateral thalamic deep brain stimulation (DBS) for essential tremor (ET). METHODS: 40 patients diagnosed with ET completed comprehensive neuropsychological assessments about one month before and three and 12 months after DBS electrode implantation. Data were subjected to multivariate analyses, and significant results were further analysed using univariate techniques. RESULTS: Analyses revealed statistically significant improvements on a cognitive screening measure and in aspects of fine visuomotor and visuoperceptual functions, verbal memory, mood state, and QoL. No group-wise declines in cognition were observed, but more patients showed declines than improvements on language and visual memory tests. Semantic verbal fluency declined significantly in four (10%) of the patients. In these four patients, diminished lexical verbal fluency was present at baseline. CONCLUSION: Cognitive, mood, and QoL outcomes after one year of DBS for ET are favourable; there were no overall deleterious effects on cognition, and DBS was accompanied by a significant reduction in anxiety and improvements in quality of life. However, preoperative verbal fluency diminution may predispose to further fluency declines after DBS.

Aged↗

PubMed2002

Neuropsychological deficits in essential tremor: an expression of cerebello-thalamo-cortical pathophysiology?

Few studies have been published regarding the neuropsychological characteristics of patients with essential tremor (ET), but preliminary findings suggest that mild attentional and executive dysfunction accompany the disorder. A consecutive series of 101 patients with ET referred for thalamotomy and/or thalamic deep brain stimulation candidacy work-up also underwent neuropsychological evaluation. Average neuropsychological test scores were calculated, along with the proportions of subjects whose scores fell within or more than one SD above or below the mean (using demographically corrected normative data). Significantly lower than average (T-score of 50) scores were evident on measures of complex auditory attention, visual attention and response inhibition, recall of a word list, verbal fluency, and visual confrontation naming. A significantly greater proportion of patients (ranging from about 34 to 60%) than might be expected on the basis of a normal distribution obtained scores more than one SD below the normative mean on select measures of attention, verbal fluency, immediate word list recall, semantic encoding, and facial matching. Consistent with prior research, notable, albeit clinically subtle, deficits in attention and select executive functions are evident in patients with ET. Although not specific to ET or cerebellar dysfunction, the observed pattern of cognitive deficits is consistent with cerebello-thalamo-cortical circuit dysfunction.

Aged↗

PubMed2001

Interactions between deep brain stimulation and levodopa in Parkinson's disease.

OBJECTIVE: To quantify the effects of deep brain stimulation (DBS) of globus pallidus interna (GPi) and subthalamic nucleus (STN) on motor fluctuations and dyskinesia in PD and to determine how the response to levodopa was modified by DBS. BACKGROUND: Patients report that DBS reduces levodopa-induced motor fluctuations and dyskinesia throughout the day, but this has not been objectively measured. Further, the means by which DBS alters the response to levodopa to improve motor fluctuations is unknown. METHODS: Twelve subjects, six with bilateral GPi electrodes and six with bilateral STN electrodes, were studied 12 to 33 months after surgery. To quantify motor fluctuations and dyskinesia, subjects were monitored hourly throughout 2 waking days with their usual oral medications, 1 day with DBS on and 1 day with DBS off, with subjects and nurse raters blinded to DBS status. To examine the effects of DBS on levodopa pharmacodynamics, the effects of a 2-hour levodopa infusion were examined, 1 day with DBS on and 1 day with DBS off, again under double-blind conditions. Time course of variations in parkinsonism was evaluated by tapping speed, arising and walking speed, tremor scores, and dyskinesia scores. RESULTS: DBS raised the mean tapping speed and reduced the coefficient of variation during the waking day. This was achieved by increasing the lowest or trough tapping speed between doses of antiparkinson medications. Mean walking speed was modestly increased and mean tremor scores were reduced. DBS increased the drug-off tapping speed, but neither the peak response nor the duration of response to levodopa was affected by DBS. The study was not powered to detect differences between GPi and STN stimulation and the only difference that approached significance was that GPi reduced peak dyskinesia and STN tended to increase peak dyskinesia. CONCLUSION: DBS objectively reduces motor fluctuations. This is achieved by reduction of drug-off disability and not by alterations in levodopa pharmacodynamics. This finding suggests alleviation of interdose trough disability as an alternative strategy to prolonging the effects of each dose of levodopa as a means to reduce motor fluctuations.

Adult↗

PubMed2001

Complete genomic screen in Parkinson disease: evidence for multiple genes.

CONTEXT: The relative contribution of genes vs environment in idiopathic Parkinson disease (PD) is controversial. Although genetic studies have identified 2 genes in which mutations cause rare single-gene variants of PD and observational studies have suggested a genetic component, twin studies have suggested that little genetic contribution exists in the common forms of PD. OBJECTIVE: To identify genetic risk factors for idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Genetic linkage study conducted 1995-2000 in which a complete genomic screen (n = 344 markers) was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. A total of 870 family members were studied: 378 diagnosed as having PD, 379 unaffected by PD, and 113 with unclear status. MAIN OUTCOME MEASURES: Logarithm of odds (lod) scores generated from parametric and nonparametric genetic linkage analysis. RESULTS: Two-point parametric maximum parametric lod score (MLOD) and multipoint nonparametric lod score (LOD) linkage analysis detected significant evidence for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene (MLOD = 5.07; LOD = 5.47) in families with at least 1 individual with PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62), 8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and in families with late-onset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients. CONCLUSIONS: Our data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD.

Adult↗

PubMed2001

Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease.

CONTEXT: The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease. OBJECTIVE: To investigate whether the tau gene is involved in idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene. MAIN OUTCOME MEASURE: Family-based tests of association, calculated using asymptotic distributions. RESULTS: Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P =.03; SNP 9i, P =.04; and SNP 11, P =.04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P =.11, and SNP 9iii, P =.87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P =.009) and a negative association with another haplotype (P =.007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3, 9i, 9ii, and 11). CONCLUSIONS: This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.

Age of Onset↗

PubMed2001

Human immunodeficiency virus gag and pol-specific CD8 T cells in perinatal HIV infection.

BACKGROUND: Binding of fluorochrome-conjugated MHC class I tetramers is a powerful means to detect antigen-specific CD8 T lymphocytes. In human immunodeficiency virus (HIV) infection, cellular immune response is essential in curtailing HIV disease progression but gaps persist in our understanding of HIV-specific cells during the disease course. In this study, we evaluated tetramer binding HIV-specific CD8 T cells in HIV-infected children. METHODS: Fluorescently labeled tetramers for HIV gag and pol were utilized to quantify antigen-specific cells by flow cytometry using a whole blood labeling method in a cohort of 19 HLA-A2+ HIV-infected children (age range 1 month to 17 years). RESULTS: Fourteen children had detectable gag (median 0.4%) and pol (median 0.1%) binding CD8 T cells, three children had gag binding cells only, and two had neither. Numbers of gag and pol binding cells correlated with each other and each correlated independently with total CD8 T cells and total CD4 T cells. CONCLUSIONS: HIV gag and pol-specific CD8 T cells are maintained during the chronic phase of HIV infection in children and CD4 lymphocytes appear to be important for sustaining their levels.

Adolescent↗

PubMed2001

The HIV protease inhibitor Indinavir inhibits cell-cycle progression in vitro in lymphocytes of HIV-infected and uninfected individuals.

Indinavir (IDV) is a potent and selective human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) widely used in antiretroviral therapy for suppression of HIV, but its effects on the immune system are relatively unknown. Recently, it has been reported that PIs inhibit lymphocyte apoptosis. In the present study we have investigated the effects of ex vivo addition of IDV on lymphocyte activation and apoptosis in cells from HIV-infected children (n = 18) and from healthy uninfected individuals (controls, n = 5) as well as in Jurkat and PM1 T-cell lines. Pretreatment of control peripheral blood mononuclear cell (PBMC) cultures with IDV resulted in a dose-dependent inhibition of lymphoproliferative responses to different activation stimuli. Additionally, this treatment led to cell-cycle arrest in G0/G1 phase in anti-CD3 monoclonal antibody-stimulated PBMC cultures in controls and in 15 of 18 HIV-infected children. Spontaneous- or activation-induced apoptosis of PBMCs from HIV-infected or uninfected individuals or of Fas-induced apoptosis in Jurkat and PM1 T cell lines were not inhibited by IDV. Moreover, IDV did not inhibit activation of caspases-1, -3, -4, -5, -9, and -8 in lysates of Jurkat T cells undergoing Fas-induced apoptosis. The findings indicate that IDV interferes with cell-cycle progression in primary cells but does not directly affect apoptosis. It is concluded that IDV may prolong cell survival indirectly by inhibiting their entry into cell cycle. In individuals on PI therapy, PI-mediated effects could potentially modulate immunologic responses independently of antiviral activity against HIV.

Adolescent↗

PubMed2001

A randomized, controlled trial of remacemide for motor fluctuations in Parkinson's disease.

BACKGROUND: Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy. RESULTS: Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant. CONCLUSION: Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD.

Acetamides↗

PubMed2001

Comparison of thalamotomy to deep brain stimulation of the thalamus in essential tremor.

OBJECTIVE: To compare outcome in Essential Tremor (ET) patients who have undergone either thalamotomy or Deep Brain Stimulation (DBS) of the thalamus. BACKGROUND: Although both thalamotomy and thalamic DBS are effective surgical treatments of tremor, it is not known if one procedure is superior to the other. DESIGN/METHODS: Thirty-five ET patients underwent thalamotomy between 1994-1998. Data on 18 patients were excluded. The remaining 17 patients were matched for age, sex, side of surgery, and tremor severity to 17 ET patients who underwent thalamic DBS. There were nine men and eight women in each group. The mean age of the thalamotomy group was 74.4 years and that of the thalamic DBS group was 73.1 years. RESULTS: There were no significant differences between any efficacy outcome variables comparing thalamotomy to DBS of the thalamus at baseline or follow-up visits. The surgical complications were higher for the thalamotomy group as compared to the DBS group. However, a larger number of DBS patients underwent repeat surgeries due to problems with the device and the leads. CONCLUSION: Although the efficacy is similar for thalamotomy and DBS of the thalamus for ET, thalamotomy is associated with a higher complication rate. DBS of the thalamus should be the procedure of choice for the surgical treatment of ET in most cases.

Aged↗

PubMed2001

Transdermal dopaminergic D(2) receptor agonist therapy in Parkinson's disease with N-0923 TDS: a double-blind, placebo-controlled study.

N-0923 is a non-ergot, dopaminergic D(2) agonist designed to be transdermally available. It has anti-parkinsonian effects when infused intravenously. An adhesive matrix patch was developed to deliver N-0923 transdermally (N-0923 TDS). In this phase II trial, we evaluated the effectiveness of various doses of N-0923 TDS at replacing levodopa. Eighty-five Parkinson's disease (PD) patients were randomized to placebo or one of four doses of N-0923 TDS for 21 days. Change in daily levodopa dose was the primary efficacy measure. Significantly greater reductions in levodopa dose were achieved as compared to placebo for the two highest doses of N-0923 TDS. Patients treated with 33.5 mg and 67 mg N-0923 TDS decreased levodopa use by 26% and 28%, vs. 7% for placebo. N-0923 TDS was safe and well tolerated.

Administration, Cutaneous↗