Parkinson Disease: Sethi KD

Mehta SH, Morgan JC, Sethi KD. · Movement Disorders Program, Department of Neurology, Medical College of Georgia, 1429 Harper Street, HF-1121, Augusta, GA 30912, USA. · Curr Neurol Neurosci Rep. · Pubmed #18590613 No free full text.

Abstract: Parkinson's disease is a progressive, widespread, neurodegenerative disease in which the involvement of the dopaminergic neurons of the substantia nigra results in significant dopamine depletion in the striatum. Newer imaging modalities reviewed here, using various radioligands, positron emission tomography, and single-photon emission computed tomography, have made it possible to assess the in vivo presynaptic and postsynaptic dopaminergic function. This is not only important from a diagnostic standpoint; these tests are being increasingly studied as surrogate markers to assess disease progression and responses to various interventions, including drugs. A brief comment on their role as a putative biomarker of the disease is also included. Because Parkinson's disease involves multiple neurotransmitter systems, neuroimaging of neurotransmitter systems other than dopamine is also discussed. Lastly, the evidence supporting the use of transcranial ultrasonography and substantia nigra hyperechogenicity in the diagnosis of Parkinson's disease is presented, along with some controversies that surround this technique.

Mehta SH, Morgan JC, Sethi KD. · Movement Disorders Program, Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA. · CNS Spectr. · Pubmed #18323761 links to  free full text

Abstract: Sleep dysfunction is common among patients with Parkinson's disease and occurs in approximately two thirds of patients. The problems range from nocturnal issues such as difficulty with sleep initiation, sleep fragmentation, disturbance of circadian rhythm, and rapid eye movement sleep behavior disorder, to daytime problems such as excessive daytime sleepiness. Frequent nighttime awakening and sleep disruption are the most common sleep problems in Parkinson's disease. Dopamine plays an important role in maintaining wakefulness. To improve sleep in Parkinson's disease, it is important to achieve the critical balance of adequate dopaminergic therapy and control of symptoms. Increased dopaminergic agents can cause dyskinesias and painful dystonia, and undertreatment can cause nighttime akinesia, rigidity, and worse quality of sleep. Other nondopaminergic drugs commonly used in Parkinson's disease can also affect sleep. In patients with advanced Parkinson's disease, deep brain stimulation of the subthalamic nucleus has a favorable impact on sleep quality and sleep architecture.

Morgan JC, Sethi KD. · Movement Disorders Program, Department of Neurology, Medical College of Georgia,1429 Harper Street, HF-1121 Augusta, GA 30912, USA. · Expert Rev Neurother. · Pubmed #17009915 No free full text.

Abstract: Dopaminergic therapies, including levodopa and dopamine agonists, are the mainstays of therapy in Parkinson's disease. With the exception of the injectable short-acting dopamine agonist apomorphine, there is no other widely available non-oral dopaminergic therapy. Rotigotine is a lipid-soluble, non-ergot, D3, D2, D1 dopamine receptor agonist that has demonstrated efficacy as an alternative therapeutic option in both early and advanced Parkinson's disease. More importantly, it is uniquely formulated as a transdermal patch delivery system allowing for continuous, once-daily administration and better patient compliance. Preclinical and clinical trials have shown rotigotine to be a well-tolerated and effective treatment for early-stage Parkinson's disease. Rotigotine has also shown promise as adjunctive therapy with levodopa for the treatment of advanced Parkinson's disease.

Morgan JC, Sethi KD. · Medical College of Georgia, Movement Disorders Program, Department of Neurology, 1429 Harper Street, HF-1121, Augusta, GA 30912, USA. · Expert Opin Emerg Drugs. · Pubmed #16939381 No free full text.

Abstract: Parkinson's disease (PD) afflicts millions of people worldwide. There are numerous drugs available for PD; however, levodopa remains the gold standard of pharmacotherapy to which all other therapies are compared. Levodopa is quite effective for many motor symptoms (bradykinesia, tremor, rigidity) of PD; however, non-levodopa-responsive motor symptoms (postural instability) and nonmotor symptoms are frequently the most troublesome in middle and later stages of disease. Although motor symptoms remain an important focus for emerging drugs, current research is largely geared to identify and develop disease-slowing therapies. Another important area of focus has become treatment of the nonmotor symptoms of PD (especially depression and dementia). This review discusses emerging drugs in the management of the motor and nonmotor symptoms of PD and drugs under study as disease-slowing/neuroprotective agents.

Ravina B, Eidelberg D, Ahlskog JE, Albin RL, Brooks DJ, Carbon M, Dhawan V, Feigin A, Fahn S, Guttman M, Gwinn-Hardy K, McFarland H, Innis R, Katz RG, Kieburtz K, Kish SJ, Lange N, Langston JW, Marek K, Morin L, Moy C, Murphy D, Oertel WH, Oliver G, Palesch Y, Powers W, Seibyl J, Sethi KD, Shults CW, Sheehy P, Stoessl AJ, Holloway R. · National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. · Neurology. · Pubmed #15668415 No free full text.

Abstract: Radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in Parkinson disease (PD). Here the authors review the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD: [18F]fluorodopa PET, (+)-[11C]dihydrotetrabenazine PET, [123I]beta-CIT SPECT, and [18F]fluorodeoxyglucose PET. Biomarkers used to study disease biology and facilitate drug discovery and early human trials rely on evidence that they are measuring relevant biologic processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.

Sethi KD. · Medical College of Georgia, Augusta, GA 30912, USA. · Curr Opin Neurol. · Pubmed #12869807 No free full text.

Abstract: PURPOSE OF REVIEW: Tremors can be encountered in a variety of disease states but the most common causes are Parkinson disease and essential tremor. This review was undertaken to highlight advances in the field during the last 12 months. RECENT FINDINGS: Kinetic tremor may be more prominent in essential tremor than postural tremor. Clinically Parkinson disease and essential tremor may be confused with each other but it may be possible to distinguish between these two nitrites using sophisticated electrophysiology. Monosymptomatic rest tremor has recently been shown to be associated with decreased fluorodopa uptake on the positron emission tomography scan suggesting its relationship to Parkinson disease. SUMMARY: Significant advances have been made in the understanding of the pathophysiology, genetics and therapy of tremor disorders during the last 12 months. This review will consider Parkinson disease, essential tremor and other tremors and highlight advances in the field.

Sethi KD. · Department of Neurology, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912, USA. · Curr Opin Neurol. · Pubmed #12151843 No free full text.

Abstract: Parkinson disease is a slowly progressive neurodegenerative disorder with a varied clinical picture and a variable rate of progression. Recently, there have been some studies conducted to assess the diagnostic accuracy and other clinical aspects of the disease. In the absence of a biomarker the clinical diagnosis is imprecise. This leads to a significant number of misdiagnoses, especially in early disease. Assessment of the clinical features suggests that an accuracy of 90% may be the highest that can be expected using current diagnostic criteria. In addition to bradykinesia, which is a core symptom, different types of tremors occur. Whereas the rest tremor is characteristic, action tremor, re-emergent tremor and orthostatic tremor may occur in Parkinson disease. Symptomatic treatments are quite effective in early disease but clinical course is complicated by the appearance of motor fluctuations and dyskinesias in more advanced disease. Non-motor complications, such as cognitive, psychiatric and autonomic problems, become bothersome and disabling in some patients.

Ondo WG, Sethi KD, Kricorian G. · Baylor College of Medicine, Department of Neurology, 6550 Fannin, Houston, TX 77030, USA. · Clin Neuropharmacol. · Pubmed #17909308 No free full text.

Abstract: BACKGROUND: Selegiline orally disintegrating tablet (ODT; Zelapar) is a selective monoamine oxidase B inhibitor developed as an adjunct to levodopa (LD) for Parkinson disease. Most patients on long-term LD therapy eventually experience deterioration at the end of the LD dosing interval, with predictable "wearing off" and "on-off" fluctuations. METHODS: We conducted a 12-week, double-blind, placebo-controlled, parallel-design trial of selegiline ODT. The primary efficacy point was reduction in the percentage of average daily "off" time. Secondary measures included reductions in daily off hours and total daily off time, Clinical Global Impressions-Improvement (CGI-I), and Patient Global Impression-Improvement (PGI-I). Patients on LD received selegiline ODT (1.25 mg/d for 6 weeks, then 2.5 mg/d for 6 weeks) or placebo. Safety and tolerability were measured. RESULTS: The intent-to-treat population included 98 patients receiving selegiline ODT and 50 patients receiving placebo. Combined efficacy results for weeks 10 and 12 revealed an 11.6% reduction in percentage of daily off time for selegiline ODT versus a 9.8% reduction for placebo (NS). PGI-I detected a statistically significant difference between treatment groups in favor of selegiline ODT (P = 0.02), whereas CGI-I detected a strong trend toward improvement (P = 0.06). Selegiline ODT was safe and well tolerated. CONCLUSIONS: This study showed no significant difference in improvement in percentage of off time with selegiline ODT versus placebo. Some clinical impressions (e.g., PGI-I, CGI-I) improved. This result contrasts with an identically designed study that showed a significant improvement in off time with selegiline ODT. A combined analysis of both studies suggested overall efficacy.

Morgan J, Sethi KD. · Department of Neurology, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912, USA. · Curr Neurol Neurosci Rep. · Pubmed #15987609 No free full text.

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Morgan J, Sethi KD. · Department of Neurology, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912, USA. · Curr Neurol Neurosci Rep. · Pubmed #15987608 No free full text.

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Morgan JC, Sethi KD. · No affiliation provided · Curr Neurol Neurosci Rep. · Pubmed #15217540 No free full text.

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Morgan JC, Sethi KD. · No affiliation provided · Curr Neurol Neurosci Rep. · Pubmed #15217539 No free full text.

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Waters CH, Sethi KD, Hauser RA, Molho E, Bertoni JM, Anonymous00092. · Department of Neurology, Columbia University, New York, New York 10032, USA. · Mov Disord. · Pubmed #15077240 No free full text.

Abstract: Zydis selegiline dissolves on contact with saliva and undergoes pregastric absorption. This minimizes first-pass metabolism and provides high plasma concentrations of selegiline. In this study, the efficacy and safety of Zydis selegiline was assessed in Parkinson's disease (PD) patients who were experiencing motor fluctuations with levodopa. Patients were randomly assigned to either drug or placebo in a 2:1 ratio in this double-blind, multicenter trial. Significant reductions in daily off time occurred at 4 to 6 weeks with the 1.25 mg dose (9.9%, P = 0.003) and 10 to 12 weeks with the 2.5 mg dose (13.2%, P < 0.001). The total number of off hours was reduced by 2.2 hours at Week 12 from baseline (compared with 0.6 hours in the placebo group). The average number of dyskinesia-free on hours for the Zydis selegiline patients increased by 1.8 hours at Week 12. There was no change in mean percentage of "Asleep" time throughout the study. No apparent differences were detected in the occurrence of drug-related adverse events between the Zydis selegiline group and placebo-treated groups. Adverse events were consistent with known effects of levodopa therapy. Zydis selegiline safely reduces daily off time when used as adjunctive therapy with levodopa in patients with PD.

Mehta SH, Prakash R, Prisant LM, Isales CM, Morgan JC, Williams H, Sethi KD. · Movement Disorders Program, Department of Neurology, Medical College of Georgia, 1429 Harper Street, Augusta, GA 30912, USA. · Nat Rev Neurol. · Pubmed #19498437 No free full text.

Abstract: BACKGROUND: A 59-year-old man with a 7-year history of Parkinson disease (PD) presented with episodes of sudden, severe headaches with neck pain, tachycardia, sweating and pallor. During these episodes, the patient showed marked elevations in blood pressure, regardless of posture. This was unusual, given that he had no prior history of hypertension. The array of symptoms raised suspicions of pheochromocytoma, but diagnosis was challenging, as the standard diagnostic biochemical tests were confounded by dopaminergic medications. Further work-up revealed left adrenal medullary hyperplasia. Several reports exist of pseudopheochromocytoma in patients on dopaminergic therapy, but this is the first documented case of pheochromocytoma syndrome due to adrenal medullary hyperplasia in a patient with PD. This case highlights the challenges of performing a diagnostic work-up in a PD patient with symptoms suggestive of pheochromocytoma, and illustrates the utility of (123)I-metaiodobenzylguanidine ((123)I-MIBG) single-photon emission CT in making a diagnosis.Investigations. Physical examination, laboratory tests, abdominal MRI scan, abdominal (123)I-MIBG scan, abdominal (18)F-fluorodeoxyglucose PET scan. DIAGNOSIS: Pheochromocytoma syndrome due to adrenal medullary hyperplasia.Management. Surgical excision of the left adrenal gland.

Ho B, Prakash R, Morgan JC, Sethi KD. · Tufts-New England Medical Center Department of Neurology, USA. · Nat Clin Pract Neurol. · Pubmed #17805247 No free full text.

Abstract: BACKGROUND: A 48-year-old man with a 9-year history of Parkinson's disease who had previously shown a good response to levodopa presented for evaluation of increasingly disabling motor fluctuations and marked camptocormia. INVESTIGATIONS: Video-recorded neurological examinations when in 'off' and 'on' states, brain MRI scan. DIAGNOSIS: Advanced Parkinson's disease complicated by levodopa-responsive camptocormia. MANAGEMENT: Adjustment of dopaminergic therapy (carbidopa-levodopa and entacapone) to minimize motor fluctuations and camptocormia.

Matsukawa N, Maki M, Yasuhara T, Hara K, Yu G, Xu L, Kim KM, Morgan JC, Sethi KD, Borlongan CV. · Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA. · Brain Res. · Pubmed #17573046 No free full text.

Abstract: Ropinirole, which is a non-ergot dopamine agonist derivative, exerts therapeutic benefits in Parkinson's disease (PD). Based on recent studies implicating dopamine receptors 2 and 3 (D2R and D3R) as possible targets of ropinirole, we over-expressed these dopamine receptor genes in the dopamine-denervated striatum of rodents to reveal whether their over-expression modulated ropinirole activity. Adult Sprague-Dawley rats initially received unilateral 6-hydroxydopamine lesion of the medial forebrain bundle. At 1 month after surgery, successfully lesioned animals (3 or less forelimb akinesia score, and 8 or more apomorphine-induced rotations/min over 1 h) were randomly assigned to intrastriatal injection (ipsilateral to the lesion) of blank lentiviral vector, D2R, D3R or both genes. At about 5 months post-lesion, ropinirole (0.2 mg/kg, i.p.) was administered daily for 9 consecutive days. The subtherapeutic dose of ropinirole improved the use of previously akinetic forelimb and produced robust circling behavior in lesioned animals with striatal over-expression of both D2R and D3R compared to lesioned animals that received blank vector. In contrast, the subtherapeutic dose of ropinirole generated only modest motor effects in lesioned animals with sole over-expression of D2R or D3R. Western immunoblot and autoradiographic assays showed enhanced D2R and D3R protein levels coupled with normalized D2R and D3R binding in the ventral striatum of lesioned animals with lentiviral over-expression of both D2R and D3R relative to vehicle-treated lesioned animals. Immunohistochemical analyses showed that D2R and D3R GFP fluorescent cells colocalized with enkephalin and substance P immunoreactive medium spiny neurons. These data support the use of the subtherapeutic dose of ropinirole in a chronic model of PD.

Morgan JC, Sethi KD. · Movement Disorders Program, National Parkinson Foundation Center of Excellence, Department of Neurology, Medical College of Georgia, Augusta, GA, USA. · Clin Neuropharmacol. · Pubmed #17272971 No free full text.

Abstract: Impaired gastrointestinal motility and constipation are common problems in Parkinson disease (PD). Many patients with PD continue to experience constipation, despite multiple interventions (dietary modification, bulk-forming agents, stool softeners, and laxatives). Tegaserod is a 5-hydroxytryptamine type 4 agonist that stimulates gastrointestinal motility and is approved for the treatment of chronic idiopathic constipation. We report our experience with tegaserod in 5 patients with PD-associated constipation. Tegaserod was well tolerated and improved both bowel movement frequency and stool consistency in most of our patients. Further trials with tegaserod are warranted in PD-associated constipation.

Morgan JC, Sethi KD. · Movement Disorders Program, Department of Neurology, Medical College of Georgia, 1429 Harper Street, HF-1121, Augusta, GA 30912, USA. · Neurology. · Pubmed #16832086 No free full text.

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Hunt AL, Sethi KD. · Department of Neurology, Beth Israel Medical Center, New York, New York 10003, USA. · Mov Disord. · Pubmed #16685683 No free full text.

Abstract: The pull test (PT) is used as a measure of postural instability in Parkinson's disease (PD) and other movement disorders. In 1987, it was incorporated into the Unified Parkinson's Disease Rating Scale (UPDRS), a scale used to measure the severity and treatment response in PD both in research studies and in clinical practice. However, the origins of the observation of postural instability in movement disorders and the attempt to quantify it are much older. Here, we trace the history of postural instability first described as a feature of PD by Romberg in 1853. Attempts to evaluate postural instability began with the first measurement by Charcot in the 1880s by pulling the clothes of patients and progressed to the push on the sternum by Hoehn and Yahr in the 1960s. Eventually, this evolved into the formal PT proposed by Fahn in the 1980s. Despite the widespread use of the PT as part of the UPDRS, variability exists in its execution. Recommendations have been made for training of examiners in clinical trials to improve its accuracy in assessing postural instability. We agree with improving PT technique for clinical trials and advocate for its routine use in clinical practice when diagnosing and treating movement disorders. Further, we propose the name "Fahn pull test" for the maneuver based on his significant contribution to its development.

Sharma P, Morgan JC, Sethi KD. · Movement Disorders Program, Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA. · Neurology. · Pubmed #16534128 No free full text.

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Iyer SS, Morgan JC, Sethi KD. · Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA. · Neurology. · Pubmed #16275853 No free full text.

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Iyer SS, Morgan JC, Glover AL, Sethi KD. · Movement Disorders Program, Department of Neurology, Medical College of Georgia, Augusta, Georgia 30912, USA. · Mov Disord. · Pubmed #16001408 No free full text.

Abstract: The presenting manifestations of Parkinson's disease (PD) are variable, but a majority of patients note tremor as the initial symptom. Others complain of slowing of movements, loss of dexterity, fatigue, or changes in handwriting as initial symptoms. We describe a patient who developed an unusual clicking sound emanating from his throat as the initial manifestation of PD.

Aranke SV, Sethi KD. · Movement Disorder Clinic, Medical College of Georgia, Augusta 30912-3200, USA. · Neurology. · Pubmed #14581695 No free full text.

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Morgan JC, Sethi KD. · Department of Neurology, University of Virginia, Charlottesville 22908, USA. · Neurology. · Pubmed #12821767 No free full text.

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Morgan JC, Sethi KD. · No affiliation provided · Arch Neurol. · Pubmed #16533980 No free full text.

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