Ron Tintner

Double-blind, placebo-controlled, unforced titration parallel trial of quetiapine for dopaminergic-induced hallucinations in Parkinson's disease

We completed a single site, double‐blind, placebo‐controlled, parallel design study of quetiapine for hallucinations in PD. Thirty‐one subjects with PD and prominent visual hallucinations and Mini‐Mental State Examination score >21 were randomly assigned in a 2:1 drug to placebo ratio, up to 200 mg daily of quetiapine or matching placebo given in two doses. They were seen at 3 weeks (100 mg/day) and 12 weeks (200 mg/day, with optional dose reduction). Evaluation included the Unified Parkinsons Disease Rating Scale (UPDRS), the Baylor PD Hallucination Questionnaire, and a battery of neuropsychological tests. The demographics between subjects randomized to drug (n = 21) vs. placebo (n = 10) were similar. The final dose of active drug was 200 (n = 11), 150 (n = 2), 100 (n = 3), and 75 (n = 1) mg per day. All placebo subjects were on the equivalent of 200 mg per day. The UPDRS Activities of Daily Living and Motor scores did not significantly change compared to placebo. Compared to placebo, there were no significant changes in our hallucination questionnaire, the Brief Psychiatric Rating Scale (BPRS), or question 12 (hallucination item) of the BPRS. There were no significant changes on any of the neuropsychological measures. Adverse events on drug included sedation (n = 9), but no drug‐related adverse events precipitated discontinuation and none were rated as serious. Quetiapine, up to 200 mg daily, was well tolerated and did not worsen UPDRS scores; however, there was no significant improvement in psychosis rating scales compared to placebo. Larger doses of drug and greater sample sizes might be considered in future studies.

Intrafamilial phenotypic variability of the DYT1 dystonia: From asymptomatic TOR1A gene carrier status to dystonic storm

When primary torsion dystonia is caused by a GAG deletion in the TOR1A gene (DYT1 dystonia), it typically presents with an early‐onset dystonia involving distal limbs, subsequently spreading to a generalized dystonia. We describe a large family with an unusually broad variability in the clinical features of their dystonia both with regard to severity and age of onset. The proband of this family succumbed in his second decade to malignant generalized dystonia, whereas other family members carrying the same mutation are either asymptomatic or display dystonia that may be focal, segmental, multifocal, or generalized in distribution. One family member had onset of her dystonia at age 64 years, probably the oldest reported in genetically confirmed DYT1 dystonia. We conclude that marked phenotypic heterogeneity characterizes some families with DYT1 dystonia, suggesting a role for genetic, environmental, or other modifiers. These findings have implications for genetic testing and counseling.

Benefits and Risks of Pharmacological Treatments for Essential Tremor

Essential tremor can cause significant functional disability in some patients. The arms are the most common body part affected and cause the most functional disability. The treatment of essential tremor includes medications, surgical options and other forms of therapy. Presently there is no cure for essential tremor nor are there any medications that can slow the progression of tremor.Treatment for essential tremor is recommended if the tremor causes functional disability. If the tremor is disabling only during periods of stress and anxiety, propranolol and benzodiazepines can be used during those periods when the tremor causes functional disability. The currently available medications can improve tremor in approximately 50% of the patients. If the tremor is disabling, treatment should be initiated with either primidone or propranolol. If either primidone or propranolol do not provide adequate control of the tremor, then the medications can be used in combination. If patients experience adverse effects with propranolol, occasionally other β-adrenoceptor antagonists (such as atenolol or metoprolol) can be used. If primidone and propranolol do not provide adequate control of tremor, occasionally the use of benzodiazepines (such as clonazepam) can provide benefit. Other medications that may be helpful include gabapentin or topiramate. If a patient has disabling head or voice tremor, botulinum toxin injections into the muscles may provide relief from the tremor. Botulinum toxin in the hand muscles for hand tremor can result in bothersome hand weakness and is not widely used. There are other medications that have been tried in essential tremor and have questionable efficacy. These drugs include carbonic anhydrase inhibitors (e.g. methazolamide), phenobarbital, calcium channel antagonists (e.g. nimodipine), isoniazid, clonidine, clozapine and mirtazapine.If the patient still has disabling tremor after medication trials, surgical options are usually considered. Surgical options include thalamotomy and deep brain stimulation of the thalamus. These surgical options provide adequate tremor control in approximately 90% of the patients. Surgical morbidity and mortality for these procedures is low. Deep brain stimulation and thalamotomy have been shown to have comparable efficacy but fewer complications have been reported with deep brain stimulation. In patients undergoing bilateral procedures deep brain stimulation of the thalamus is the procedure of choice to avoid adverse effects seen with bilateral ablative procedures. The use of medication and/or surgery can provide adequate tremor control in the majority of the patients.

Striatal deformities of the hand and foot in Parkinson's disease

Striatal deformities of the hand and foot are abnormal postures that are common in patients with advanced Parkinsons disease (PD); they can present in the early stages of PD and in other parkinsonian disorders. Over a century ago, Charcot and Purves-Stewart recognised these deformities, which cause substantial functional disability and discomfort. The term striatal is used because pathology in the neostriatum (putamen and caudate) has been suggested to cause the deformities, but the pathogenesis is unknown. Misdiagnosis of the deformities is common-particularly when they occur early and in the absence of cardinal parkinsonian signs, such as tremor, bradykinesia, and rigidity-because the hand deformities are similar to those in rheumatoid arthritis, equinovarus foot deformity typically suggests an orthopaedic problem, and toe extension may be thought to be the Babinski sign of upper-motor-neuron syndromes. Here we review the background and clinical features of these deformities to highlight these commonly unrecognised and poorly understood parkinsonian signs.

Tetrabenazine treatment for Huntington's disease-associated chorea.

Tetrabenazine (TBZ), a monoamine depleter and dopamine receptor blocker, is used to treat a variety of hyperkinetic movement disorders. The objective was to study the efficacy and tolerability of TBZ for chorea associated with Huntingtons disease (HD). Nineteen patients (12 female), mean age 56.3 ± 12.4 years (range 37–76 years) diagnosed with HD were prospectively evaluated at initial and follow-up visits using a modified Abnormal Involuntary Movement Scale (AIMS). Patients were videotaped, and the randomized videotapes were rated with the motor subset of the AIMS by two investigators who were blinded to treatment assignment. Eighteen patients completed and were rated after 5.9 ± 3.3 months (range 2–11) at a final mean TBZ dose of 62.5 ± 37.4 mg/day (range 25–150). The blinded videotaped motor scores showed that 15 were better on TBZ, 2 were better before TBZ, and 1 was unchanged (p < 0.001, Wilcoxon signed rank test). The mean score improved from 16.2 ± 4.8 to 12.8 ± 4.4. Adverse events included akathisia, insomnia, constipation, depression, drooling, and subjective weakness. All 18 of these patients have continued to take TBZ since completion of the study. TBZ was well tolerated and resulted in a significant improvement in modified AIMS scores in HD patients. These results support the use of TBZ for chorea in patients with HD.

Autonomic function after botulinum toxin type A or B: A double-blind, randomized trial

To compare autonomic effects of botulinum toxin (BTX), we randomized patients with cervical dystonia to receive either BTX-A or BTX-B in a double-blind manner. Efficacy and physiologic questionnaire measures of autonomic function were assessed at baseline and 2 weeks after injection. Patients treated with BTX-B had less saliva production (p < 0.01) and greater severity of constipation (p = 0.037) than those treated with BTX-A, but did not differ in other tests of autonomic functions.

Reliability of a new scale for essential tremor

The objective of this study was to determine the reliability of a new scale for the clinical assessment of essential tremor. The Essential Tremor Rating Assessment Scale contains 9 performance items that rate action tremor in the head, face, voice, limbs, and trunk from 0 to 4 in half‐point intervals. Head and limb tremor ratings are defined by specific amplitude ranges in centimeters.

Report from a U.S. conference on essential tremor.

Seventy researchers met in Washington, DC, on 20–21 October 2005 to identify and discuss the most pressing research issues in essential tremor (ET). The conference attendees concluded that the following six objectives are of immediate and overriding importance: (1) a collaborative network of research centers; (2) an international committee for developing a standard protocol for the diagnosis and quantification of ET; (3) the identification of one or more genes for ET; (4) a centralized repository of DNA and, ideally, immortalized cell lines from well‐characterized ET families and healthy controls; (5) a reliable and efficient repository of optimally prepared and categorized brain samples for hypothesis‐driven neuropathological examinations in well‐characterized ET patients; and (6) animal models of ET for screening promising drugs. The conference attendees hope that this statement from the United States will engender international collaboration in finding a cure for ET.

Dopamine agonists in Parkinson’s disease

Levodopa (LD), the immediate precursor of dopamine, is the most effective agent in the treatment of Parkinsons disease (PD). While quite successful in treating the primary motor deficits of PD, most patients eventually develop LD-related motor fluctuation, dyskinesias and other adverse effects associated with chronic LD therapy. There is also concern that LD is neurotoxic, although this has not been demonstrated in any in vivo studies. Dopamine agonists (DAs) have been shown to be about as effective as LD in symptomatic treatment of mild-to-moderate PD. In addition, there is a lower tendency to develop motor fluctuations and dyskinesias with DA treatment than after initiation of therapy with LD. Furthermore, there is preclinical and clinical data to suggest a slowing of neurodegeneration with DAs. The adverse effects of DAs are similar to those experienced with LD, except that the ergot agents are associated with a small risk of tissue fibrosis not noted with the non-ergot DAs.

Botulinum toxin for the treatment of cervical dystonia.

Cervical dystonia (CD) manifests clinically through involuntary spasms of neck muscles, producing abnormal head and neck movements and postures, which is often associated with pain. CD is the most common form of focal dystonia presenting to movement disorders clinics. Chemodenervation with botulinum toxin (BTX) has become the first-line treatment for CD, producing satisfactory relief of symptoms in > 80% of cases. Unresolved issues that may impact on the overall results include the method of selection for injection sites (clinical vs. electromyography), dosing, dilution and the role and relative efficacy of the different BTX serotypes. A guiding therapeutic principle of BTX injections is to achieve optimal results with the lowest possible dosage and frequency of administration. This strategy is critical in order to keep the risk of immunoresistance at a minimum. Development of antibodies that block the effects of BTX, usually associated with frequent injections of high doses, is the main reason for secondary unresponsiveness to this treatment. Although the mechanism of denervation at the neuromuscular junction by BTX is relatively well understood, the role of changes in muscle spindles and myopathic pain mechanisms, as well as secondary changes at the level of the basal ganglia, thalamus and cortex and their role in response to BTX, all need further exploration.