The estimated cost of managing focal spasticity: a physician practice patterns survey.

The purpose of this study was to estimate the overall cost of managing focal spasticity after stroke (CVA) and traumatic brain injury (TBI) and the cost impact of individual treatments. Sixty physicians described management strategies over six treatment visits for four focal spasticity case studies (one upper and one lower extremity case for CVA and TBI). Mean and median per-case costs were determined across physicians; median per-case costs of physicians who did or did not report use of specific treatments were compared. Mean per-case costs of managing spasticity are as follows: CVA upper, $5,131; CVA lower, $5,384; TBI upper, $14,615; and TBI lower, $13,966. Median per-case costs for strategies including botulinum toxin type A (BTX-A) were less than those without BTX-A in CVA upper; median costs for strategies including oral baclofen were more than those without baclofen in CVA lower. Fewer total treatments were reported with BTX-A than without; more total treatments were reported with baclofen than without. No individual treatment had a significant impact on median treatment costs in TBI. Physician-reported spasticity management costs are substantial. Despite higher drug costs for BTX-A compared with oral therapies like baclofen, strategies for managing spasticity in CVA that include BTX-A may cost less than those without BTX-A.

A home diary to assess functional status in patients with Parkinson's disease with motor fluctuations and dyskinesia.

In clinical trials for patients with Parkinson's disease (PD) with motor fluctuations, efficacy is generally ascribed to an intervention if motor function is significantly improved or if "off" time is significantly reduced. However, we have argued that patients might not be improved if off time is reduced only to the extent that unwanted dyskinesia is increased. Therefore, a home diary should include an assessment of dyskinesia to provide an accurate reflection of clinical status over a period of time. We undertook two studies to develop a home diary to assess functional status in patients with PD with motor fluctuations and dyskinesia. In both studies, patients concurrently completed a test and a reference diary. In Study I, we evaluated the impact of different severities of dyskinesia on patient-defined functional status. There were 1,149 evaluable half-hour time periods from 24 patients; 94.3% of off time was considered "bad" time and 90.2% of "on" time without dyskinesia, 72.6% of on time with mild dyskinesia, 43.0% of on time with moderate dyskinesia, and 15.2% of on time with severe dyskinesia was considered "good" time. In Study II, we evaluated a new home diary designed to separate dyskinesia that had a negative impact on patient-defined functional status from dyskinesia that did not. There were 816 evaluable time periods from 17 patients; 84.9% of off time and 89.9% of on time with troublesome dyskinesia was considered bad time while 85.5% of on time without dyskinesia and 93.8% of on time with nontroublesome dyskinesia was considered good time. With this diary (Diary II), the effect of an intervention can be expressed as the change in off time and the change in on time with troublesome dyskinesia (bad time). The sum can be used as an outcome variable and compared to baseline or across groups. In evaluating the efficacy of an intervention, assessment of change in off time and change in on time with troublesome dyskinesia provides a more accurate reflection of clinical response than change in off time alone.

Ropinirole for the treatment of early Parkinson disease: a 12-month experience. Ropinirole Study Group.

OBJECTIVE: To evaluate ropinirole hydrochloride as dopaminergic monotherapy in patients with early Parkinson disease. DESIGN: A 6-month extension of a double-blind, placebo-controlled study. SETTING: Ambulatory care at 22 different sites in the United States. PATIENTS: Patients who successfully completed the initial 6-month study could enter the 6-month extension study (ropinirole, n = 70; placebo, n = 77). INTERVENTION: Use of ropinirole or placebo therapy. MAIN OUTCOME MEASURES: The efficacy variables were the number of patients who successfully completed the 12-month study and did not require supplemental levodopa, the number of patients requiring supplemental levodopa, and the proportion of patients having an insufficient therapeutic response. RESULTS: Significantly fewer ropinirole-treated patients met criteria for insufficient therapeutic response (23 [19.8%] of 116) or required the initiation of levodopa therapy (22 [19%] of 116) compared with placebo-treated patients (60 [48%] of 125 patients for insufficient therapeutic response; 57 [45.6%] of 125 patients for additional levodopa). Significantly more ropinirole-treated patients (51 [44.0%] of 116) successfully completed the 12-month study and did not require supplemental levodopa compared with placebo-treated patients (28 [22.4%] of 125). The incidence of adverse experiences and patient withdrawals was low. CONCLUSION: Ropinirole was effective and well tolerated as monotherapy for 12 months in patients with early Parkinson disease.

Clozapine use in Parkinson's disease: a retrospective analysis of a large multicentered clinical experience.

We conducted a multicentered, retrospective review of clozapine's (CZP) effects on a range of psychiatric, sleep, cognitive, motor, and sensory disorders in Parkinson's disease (PD). Therapeutic outcomes and adverse events were compared with varying prescribing practices at participating sites. The medical records of 172 consecutive PD patients treated with CZP at four movement disorder clinics were reviewed. Low-dose CZP improved psychiatric symptoms of psychosis, anxiety, depression, hypersexuality, sleep disturbance, and akathisia. Tremor, torticollis, limb dystonia, and pain showed modest rates of improvement. Twenty-three percent of patients withdrew as a result of adverse events or treatment failure. Inpatient CZP initiation did not improve therapeutic efficacy, or reduce adverse events or the withdrawal rate. Low-dose CZP in the outpatient setting is generally an effective and well-tolerated treatment for many of the psychiatric, sleep, motor, and sensory disturbances common to late-stage PD.

Extending levodopa action: COMT inhibition.

Degradation of levodopa in the periphery is known to be associated with motor fluctuations and dyskinesia in Parkinson's disease (PD) patients. The enzyme catechol-O-methyltransferase (COMT) is responsible for much of this degradation. Therefore, inhibiting COMT activity is one method of extending the action of levodopa. The new nitrocatechol-type COMT inhibitors entacapone, nitecapone, and tolcapone inhibit COMT in the periphery; tolcapone also inhibits COMT activity centrally. COMT inhibitors increase patients' duration of response to levodopa and reduce response fluctuations. Administration may prolong levodopa-induced dyskinesia, but peak-dose dyskinesia does not appear to increase. To reduce dyskinesia, the total daily dose of levodopa can be reduced.

BotB (botulinum toxin type B): evaluation of safety and tolerability in botulinum toxin type A-resistant cervical dystonia patients (preliminary study).

Botulinum toxin (BTX) injection is considered the treatment of choice for patients with cervical dystonia (torticollis). We conducted a pilot, open-label, dose-escalation study with BTX type B in 12 patients who no longer responded clinically to injections with BTX type A. At the doses tested, BTX type B was safe and well tolerated without evidence of dose-limiting toxicity in this patient population. Mild-to-moderate adverse events generally resolved quickly and included asthenia, pain, nausea, dysphagia, hypertonia, and tremor. No serious adverse events or antibodies to type-B treatment were reported. Low-dosing-session (100-899 units) and high-dosing-session (900-1,500 units) groups were defined based on units administered per dosing session. Toronto Western Spasmodic Torticollis Rating Scale-Severity Scale (TWSTRS-Severity), Patient Analogue Pain Scale, and Physician and Patient Global Assessment Scales were measured during this study. The TWSTRS-Severity mean maximum percent improvement from baseline demonstrated a 9.9% versus 28.8% difference between the low-dose and high-dose groups, respectively. EFfectiveness was noted for the high-dose group on the Patient Analogue Pain Scale but not on the Global Assessment Scales.

Ropinirole for the treatment of early Parkinson's disease. The Ropinirole Study Group.

A prospective, randomized, placebo-controlled, double-blind, parallel-group, 6-month study assessed the efficacy and safety of ropinirole, a nonergoline D2-dopamine agonist, in patients with early Parkinson's disease (n = 241; Hoehn & Yahr stages I to III) with limited or no prior dopaminergic therapy. Patients (mean age, 62.8 years), stratified by concomitant use of selegiline, were randomized to ropinirole (n = 116) or placebo (n = 125). The starting dose of ropinirole was 0.25 mg tid with titration to at least 1.5 mg tid (maximum dose, 8 mg tid). Primary efficacy endpoint was the percentage improvement in Unified Parkinson's Disease Rating Scale (UPDRS) motor score. Ropinirole-treated patients had a significantly greater percentage improvement in UPDRS motor score than patients who received placebo (+24% vs -3%; p < 0.001). Ropinirole was well tolerated and patient withdrawals were infrequent. Most adverse experiences were related to peripheral dopaminergic activity. Ropinirole monotherapy is an effective and well-tolerated therapeutic option for treatment of early Parkinson's disease.

A controlled trial of fluoxetine in nondepressed patients with Huntington's disease.

To examine the antidepressant specificity of fluoxetine in Huntington's disease (HD), we carried out a randomized, double-blind, placebo-controlled trial of this medication in nondepressed HD patients. Thirty patients with early HD who were depressed (Hamilton Depression Inventory < 16) were randomized to placebo (N = 13) or fluoxetine 20 mg/day (N = 17) and were followed up for 4 months. Outcome measures included changes in total functional capacity (TFC) and in standardized neurological, cognitive, and behavioral ratings. After adjustment for the higher education level found in the placebo group at baseline, no differences between the treatment groups were found in TFC, neurological, or cognitive ratings. Fluoxetine-treated patients did show a slight reduction in agitation and in the need for routine. Although fluoxetine may be a useful antidepressant in depressed HD patients, it failed to exert substantial clinical benefits in nondepressed HD patients.

A clinical overview of treatment decisions in the management of spasticity.

Spasticity from an upper motor neuron syndrome may cause a variety of symptoms that interfere with function. Decisions regarding spasticity treatment are influenced by the chronicity, severity, and distribution of the spasticity; the locus of injury; the presence and severity of co-morbidities; the availability of support; and the goals of treatment. Not all spasticity can or even should be treated; tone reduction is indicated only if spasticity interferes with some level of function, positioning, care, or comfort. Treatment goals should be well outlined before treatment begins. Botulinum toxin may be used to treat focal spasticity as part of an overall treatment plan.

Injection techniques for botulinum toxin using electromyography and electrical stimulation.

Increasing data supports the use of botulinum toxin injection as a therapeutic intervention in the management of spasticity. The avid binding of botulinum toxin (BTX) to presynaptic neuron terminals and the diffusion characteristics of the medication allow relative ease of administration. For many clinical applications, efficacy may be improved, and adverse effects reduced, by more precise targeting of the muscles to be injected. Electromyographic guidance (EMG) is commonly used to confirm appropriate localization of the injection needle in specific muscles immediately before injection. Electrical stimulation (ES) may be more useful in patients who are unresponsive or sedated. Equipment options and technical aspects of EMG and ES are discussed, including some adjunctive imaging methods for injecting difficult-to-localize muscles.

Spasticity after stroke. Epidemiology and optimal treatment.

Spasticity following stroke reflects a spectrum of clinical problems including increased muscle tone, abnormal limb posture, excessive contraction of antagonist muscles and hyperactive cutaneous and tendon reflexes. The prevalence of stroke-related disability in stroke survivors is high, and spasticity may be a significant component of this. Management strategies include a multidisciplinary team approach utilising a variety of rehabilitation techniques. Although some interventions are well tolerated and fairly standardised, older adults may be particularly sensitive to drug treatment-related adverse effects. This article reviews some of the commonly employed interventions, such as oral medications, and some of the newer techniques, such as intrathecal baclofen infusion and botulinum toxin injections. The optimal management of spasticity following stroke in older adults requires careful goal setting and skilful combination of treatment modalities in order to produce the best outcome.

Botulinum toxin type A in the treatment of upper extremity spasticity: a randomized, double-blind, placebo-controlled trial.

Spasticity is a disorder of excess muscle tone associated with CNS disease. We hypothesized that botulinum toxin, a neuromuscular blocking agent, would reduce tone in spastic muscles after stroke. This randomized, double-blind, placebo-controlled, multicenter clinical trial evaluated the safety and efficacy of botulinum toxin type A (BTXA) in the treatment of chronic upper limb spasticity after stroke. Thirty-nine patients received IM injections of a total dose of either 75, 150, or 300 units of BTXA or placebo into the biceps, flexor carpi radialis, and flexor carpi ulnaris muscles. At baseline, patients demonstrated a mean wrist flexor tone of 2.9 and elbow flexor tone of 2.6 on the Ashworth Scale (0 to 4). Treatment with the 300-unit BTXA dose resulted in a statistically and clinically significant mean decrease in wrist flexor tone of 1.2 (p = 0.028), 1.1 (p = 0.044), and 1.2 (p = 0.026) points and elbow flexor tone of 1.2 (p = 0.024), 1.2 (p = 0.028), and 1.1 (p = 0.199) at weeks 2, 4, and 6 postinjection. In the placebo group, tone reduction at the wrist was 0.3, 0.2, and 0.0 and at the elbow was 0.3, 0.3, and 0.6 at weeks 2, 4, and 6 postinjection. BTXA groups reported significant improvement on the physician and patient Global Assessment of Response to Treatment at weeks 4 and 6 postinjection. There were no serious adverse effects. In this 3-month study, BTXA safely reduced upper extremity muscle tone in patients with chronic spasticity after stroke.

Heterogeneous dopamine receptor changes in early and late Huntington's disease.

Quantitative receptor autoradiography was used to study dopamine (DA) receptors in dorsal striatum and its projection regions in brains from individuals dying with Huntington's disease (HD) and controls. Heterogeneous loss of both D1 and D2 receptors was present in the striatum of early and late stage HD brains. The degree of receptor loss was greater for the D1 receptor than for the D2 receptor in early stage HD. The pattern of receptor loss did not correspond to heterogeneities identified with acetylcholinesterase staining. Progressive loss of D1 receptors in the internal globus pallidus and substantia nigra pars reticulata and D2 receptors in the external globus pallidus corresponded to advancing pathologic grade.

N-methyl-D-aspartate antagonists in the treatment of Parkinson's disease.

Current long-term treatment of Parkinson's disease is inadequate, and improved symptomatic and neuroprotective therapies are needed. Recent interest has focused on the use of antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in Parkinson's disease. Abnormally increased activity of the subthalamic nucleus is postulated to play a central pathophysiological role in the signs of Parkinson's disease, and NMDA antagonists may provide a means of decreasing this activity selectively. Like dopaminergic agonists, NMDA antagonists can reverse the akinesia and rigidity associated with monoamine depletion or neuroleptic-induced catalepsy. Very low doses of NMDA antagonists markedly potentiate the therapeutic effects of dopaminergic agonists. There is evidence that the beneficial effects of anticholinergic drugs and amantadine may be mediated, in part, by NMDA receptor blockade. Moreover, NMDA antagonists provide profound protection of dopaminergic neurons of the substantia nigra in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and methamphetamine models of Parkinson's disease. The clinical use of NMDA antagonists may prove useful in Parkinson's disease to treat symptoms and retard disease progression.