Deep brain stimulation in early Parkinson's disease: enrollment experience from a pilot trial.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus is an accepted therapy for advanced Parkinson's disease (PD). In animal models, pharmacologic ablation and stimulation of the subthalamic nucleus have resulted in clinical improvement and, in some cases, improved survival of dopaminergic neurons. DBS has not been studied in the early stages of PD, but early application should be explored to evaluate safety, efficacy, and the potential to alter disease progression. METHODS: We are conducting a prospective, randomized, single-blind clinical trial of optimal drug therapy (ODT) compared to medication plus DBS (ODT + DBS) in subjects with Hoehn & Yahr Stage II idiopathic PD who are without motor fluctuations or dementia. We report here subject screening, enrollment, baseline characteristics, and adverse events. RESULTS: 30 subjects (average age 60 ± 6.9 years, average duration of medicine 2.1 ± 1.3 years, average UPDRS-III scores 14.9 on medication and 27.0 off medication) are enrolled in the ongoing study. Twelve of 15 subjects randomized to DBS experienced perioperative adverse events, the majority of which were related to the procedure or device and resolved without sequelae. Frequently reported adverse events included wound healing problems, headache, edema, and confusion. CONCLUSION: This report demonstrates that subjects with early stage PD can be successfully recruited, consented and retained in a long-term clinical trial of DBS. Our ongoing pilot investigation will provide important preliminary safety and tolerability data concerning the application of DBS in early stage PD.

Predictors of effective bilateral subthalamic nucleus stimulation for PD.

To identify factors predictive of effective bilateral subthalamic nucleus (STN) stimulation for PD with severe motor complications, pre- and postoperative Unified PD Rating Scale (UPDRS) scores were analyzed in a series of 54 patients who received bilateral STN stimulation. Younger age and levodopa responsiveness predict a favorable response to bilateral STN stimulation. For individual PD symptoms, those that improve with a suprathreshold dose levodopa challenge are likely to improve with stimulation.

Classification of tremor and update on treatment.

Tremor is a symptom of many disorders, including Parkinson's disease, essential tremor, orthostatic tremor, cerebellar disease, peripheral neuropathy and alcohol withdrawal. Tremors may be classified as postural, rest or action tremors. Symptomatic treatment is tailored to the tremor type. Combination therapy with carbidopa and levodopa remains the first-line approach for parkinsonian tremor. Essential tremor may be amenable to propranolol or primidone. Propranolol may be useful in treating alcohol withdrawal tremor, and isoniazid may control the cerebellar tremor associated with multiple sclerosis. Clonazepam may relieve orthostatic tremor. Other agents are also available for the treatment of tremor. When medical therapy fails to control the tremor, surgical options such as thalamotomy, pallidotomy and thalamic stimulation should be considered in severe cases. Thalamic stimulation, the most recent of these surgical approaches, offers the advantage over ablative procedures of alleviating tremor without the creation of a permanent lesion.

How much neurology should a medical student learn? a position statement of the AAN Undergraduate Education Subcommittee.

Neurologic disease, already common in the United States, will become even more common in the future. But presently, neurology education at the undergraduate level and in primary care residencies is declining and does not adequately train physicians to manage neurologic illness. The authors maintain that this serious problem can be partially addressed by improving the neurology education of all primary care physicians and by allowing students access to neurology specialists. The education of medical students in the basic and clinical neurosciences must be integrated into a seamless curriculum over the four years of medical education. This education experience must be taught through a team approach and must be led by both a clinician and a basic scientist. All medical students must acquire the knowledge, skills, and attitudes necessary to perform an initial evaluation of the patient with a neurologic complaint. Finally, students must understand the role and recognize the importance of the neurologist and know when consultation is needed. This continuum of neurology education must be financially supported by the institution, and course leaders who show excellence in education must be rewarded with compensation and promotion.

Multiple system atrophy: clinical presentation and diagnosis.

Multiple system atrophy (MSA) describes a relatively uncommon, debilitating disorder that is frequently misdiagnosed as Parkinson's disease. Patients with MSA show various combinations of parkinsonism, cerebellar ataxia, pyramidal signs and progressive autonomic failure, especially cardiovascular and urologic autonomic dysfunction. Few treatment options exist. Although some patients initially respond well to dopaminergic treatment for their parkinsonian symptoms, striatal degeneration occurs, and levodopa often becomes ineffective. Thus, physicians may provide only symptomatic treatment and support for patients with MSA. In this paper, we present a case study of a 68-year-old woman who came to the Vanderbilt Movement Disorders Clinic with severe autonomic dysfunction and parkinsonism, previously diagnosed as Parkinson's disease. Following autonomic function tests as well as clinical evaluation, she was diagnosed with MSA and began treatment for orthostatic hypotension and micturition dysfunction.

A definition of "on": patient diaries compared to the UPDRS.

This study investigates the relationship of the Unified Parkinson's Disease Rating Scale (UPDRS) to the patient's perception that they are "on". Following the first dose of medication, patients reported that they were "on" when their UPDRS-III reached a mean of 8+/-2, representing a decrease of 67+/-8% from their early morning rating. Patients reported that they were "off" when their UPDRS-III score increased to 20+/-5, representing an increase of 50+/-12% from their initial "on" score. A 67% improvement in the baseline UPDRS-III score may be useful in defining "on".

Tongue protrusion dystonia: treatment with botulinum toxin.

We report the treatment experience in a series of patients with involuntary tongue protrusion resulting from oromandibular dystonia (OMD) or Meige's syndrome. A retrospective analysis of clinical findings and results of treatment was conducted on patients treated at Vanderbilt University Medical Center between 1989 and 1995. After unsuccessful treatment with conventional oral medications, nine patients having involuntary tongue protrusion resulting from OMD or Meige's syndrome were treated with botulinum toxin type A (BTX-A) injected into the genioglossus muscle at four sites via a submandibular approach. A marked reduction in tongue protrusion was achieved in six patients (67%). Of 35 consecutive injections, 83% were successful at reducing tongue protrusion. Mild dysphagia complicated 14% of the injections. The average dose injected was 34 (+/- 3) units producing a 15 (+/- 2) week average duration of effect. Injection of the genioglossus with BTX-A may prove to be a valid treatment option for involuntary tongue protrusion related to OMD or Meige's syndrome. A double-blind, placebo-controlled trial is needed to better define efficacy and adverse events.

Occipital pole area and language dominance.

A previous report demonstrated a relationship between asymmetries of occipital lobe length measured on magnetic resonance images (MRIs) and the hemisphere verified as dominant for language. This study sought to discern whether asymmetry in occipital pole area is more predictive of the hemisphere dominant for language. Language dominance was identified by the Wada test in 55 patients evaluated for surgical treatment of epilepsy. In a blinded fashion, an examiner measured bilateral occipital pole area on MRIs for each patient. Asymmetry of the occipital pole area on the MRI made at 10 mm above the tentorium was significantly related to language dominance. This two-dimensional analysis was better than previously described linear measurements in discriminating patients with left-hemisphere dominance for language.

Adult-onset focal dystonias: presentation and treatment options.

Adult-onset focal dystonias (AFD) are common disorders that are often misdiagnosed and incorrectly treated. Their presentation is readily recognized, and botulinum toxin has become the agent of choice for treating these disorders. Most of the focal dystonias include cervical dystonia, blepharospasm, oromandibular dystonia, spasmodic dysphonia, and limb dystonia, specifically writer's cramp. Their onset is either idiopathic, familial, or post-traumatic, and the pathophysiology of the focal dystonias is not currently known. Local injections of botulinum toxin into the affected area result in chemical denervation of the muscle, resulting in a weakness of the muscles that are involved in the sustained contractions. This weakness alleviates the painful contraction of the dystonia. In this paper we present a case study of the most common type of focal dystonia, cervical dystonia. The etiology in this case was post-traumatic, and significant improvement resulted after treatment with botulinum toxin type A.

Midsagittal corpus callosum area, intelligence, and language dominance in epilepsy.

Alterations in midsagittal corpus callosum (CC) area and morphology have been suggested in several disease processes of the nervous system. In addition, some studies found a relation of CC area to handedness, language dominance, and gender. The relation of CC area to measures of intelligence and memory and the effect of epilepsy on CC area have received less attention. In this study CC area was measured on midsagittal magnetic resonance images in 48 patients undergoing presurgical evaluation of epilepsy and in 20 control subjects. All patients had the Wada test and formal neuropsychological testing. The mean CC area of the epilepsy group was significantly smaller than that of control subjects (p < 0.00001). CC area showed a positive correlation with presurgical performance IQ (p = 0.008) and full-scale IQ (p = 0.048), but not with memory scores or language dominance. There was no relation of CC area to location of epileptic focus, seizure types, age at onset, epilepsy duration, or etiology. The presence of an atrophic lesion was associated with a smaller CC area. The correlation of total CC area with performance and full-scale IQs may reflect axonal loss in patients with a low IQ resulting from the etiology of epilepsy or the epilepsy itself.

Drug therapy for Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by tremor, rigidity, bradykinesia, and loss of postural reflexes. Although the agents available for symptomatic treatment now allow most parkinsonian patients to live a normal life-span, these patients become progressively unable to participate in social functions, perform activities of daily living, and work. Therapy for PD may be associated with many complications that contribute to these disabilities. For this reason, education is helpful for the patient newly diagnosed with PD. Over the past 6 years, three new medications (selegiline, pergolide, and controlled-release levodopa) have been approved for use in Parkinson's disease. Other agents now available for the treatment of psychiatric illness may also be helpful in selected cases of PD. With this in mind, we review the commonly prescribed drugs and outline a rational plan for treatment of parkinsonism.

Clonazepam-sensitive intermittent dystonic tremor.

We report three cases and a literature review describing a syndrome of intermittent idiopathic focal or segmental dystonic tremor dramatically responsive to clonazepam. All patients were young men who had intermittent symptoms. After magnetic resonance imaging of the brain and laboratory analysis of blood, each patient was treated with clonazepam and clinically observed for 1 year. In all three cases clonazepam produced full abatement of the tremor. None of the patients displayed progression of symptoms, and all have remained tremor free with stable doses of clonazepam. Clonazepam-sensitive intermittent dystonic tremor may represent a benign syndrome occurring in young men.

Dystonia and unique muscle features. A 23-year follow-up and correction of diagnosis in two brothers.

OBJECTIVE: To provide follow-up information and a corrected diagnosis on two brothers who were primarily described in the ARCHIVES in 1971 as having had a genetic dystonia with unusual muscle biopsy features. MEASURES: Clinical observation of response to treatment and muscle histologic findings. RESULTS: These brothers are an unusual example of dopa-responsive dystonia that was present since birth. The muscle histopathologic features were caused by an abnormal cerebral influence on the developing motor unit and were not a primary abnormality. A repeated muscle biopsy performed 1 year after treatment continued to show the same pattern of fiber-type abnormalities. CONCLUSIONS: Dopa-responsive dystonia can be present from birth or early infancy. The response to levodopa is excellent even after a delay in treatment of more than 20 years. Intrauterine dystonia can cause a predominance of small type 2 fibers. A trial of levodopa/carbidopa is indicated in all patients with a childhood-onset dystonia or gait disturbance.

MRI asymmetries and language dominance.

OBJECTIVE: To examine the relationship between language dominance, as measured by Wada testing, and hemispheric asymmetries on MR brain images. BACKGROUND: A previous report that did not include verification of language dominance compared the length of the planum temporale with hemispheric asymmetries seen on CT and inferred that occipital lobe asymmetry is related to language dominance. METHODS: Language dominance was identified by the Wada test in 57 patients evaluated for surgical treatment of epilepsy. Fifty-five had an MRI scan that allowed accurate measurement. In a blinded fashion, two examiners independently measured bilateral frontal, parietal, and occipital lobe lengths on MR scan for each patient. Measurements of asymmetries were compared with language dominance established by the Wada test. RESULTS: Reliability of measurement between the examiners was 97%. Asymmetry of the occipital lobe length on MR scan 10 mm above the tentorium was the only measurement significantly related to language dominance (p < 0.01). Occipital lobe length was longer on the left in 19 (40%) and on the right in 10 (21%) patients with left dominance. The right lobe was longer in six of seven (86%) patients with bilateral dominance. One patient with right hemisphere dominance had a longer left lobe. None of the measurements significantly related to handedness. CONCLUSION: Asymmetries of occipital lobe length relate to language dominance, but such dominance cannot be reliably identified by MR in an individual patient.

Sneddon and antiphospholipid antibody syndromes causing bilateral thalamic infarction.

A child suffered bilateral thalamic infarction secondary to Sneddon and antiphospholipid antibody syndromes. Her initial findings of hypersomnolence, mood disturbance, and amnesia are characteristic of bilateral thalamic infarction. Clinical and laboratory evaluation confirmed the diagnosis of both Sneddon and antiphospholipid antibody syndromes as the cause of her unusual stroke. The treatment of this patient, based on experience with adult patients, was long-term, high-intensity warfarin anticoagulation.

Role of transforming growth factor-beta and epidermal growth factor in the wound-healing process: an in vivo biomechanical evaluation.

The purpose of this study was to assess and evaluate the role of transforming growth factor-beta(1), epidermal growth factor, and their respective carriers (collagen and liposomes) in the early phases of the wound-healing process in linear incision wounds; we used an in vivo biomechanical testing system. One hundred twenty specific pathogen-free male Sprague-Dawley rats were divided into five experimental groups (n = 24), including one group receiving no treatment at all. Each animal received one abdominal midline incision. At 3 and 5 days after wounding, 12 animals per group were randomly selected for in vivo biomechanical evaluation. Specimens were also randomly obtained from nondisrupted tissues for histologic analysis. Statistical analysis comparing groups revealed that transforming growth factor-beta(1) significantly increased wound strength at day 5, and liposomes decreased wound strength at day 3. There were no other significant differences among groups for each of the time intervals studied. Our results suggest that in vivo biomechanical evaluation of tissue response to injury and treatments will add new dimension to future studies of skin and wound healing.