Outcomes of pregnancy associated with antiepileptic drugs.

OBJECTIVE: To determine whether exposure to antiepileptic drugs during pregnancy is associated with poor fetal outcomes (anomalies and death) and to assess the relative risks with phenobarbital, phenytoin sodium, and carbamazepine. DESIGN: The design was a prospective case-control cohort study of pregnant women with epilepsy and their offspring. Outcomes were compared with those of a control group of 355 healthy women and their offspring. SETTING: The obstetrics service at Los Angeles County/University of Southern California Medical Center, Los Angeles, a large, inner-city, teaching hospital. PATIENTS: Two hundred eleven subjects who were pregnant during the years 1987 through 1990, 174 of whom were delivered of infants, were available for analysis. A control group of 355 healthy women and their offspring from the same hospital were randomly selected from a computerized database. INTERVENTION: None. MAIN OUTCOME MEASURE: Anomalies and fetal death were the primary outcome measures. RESULTS: Offspring of women with epilepsy who were exposed to antiepileptic drugs had a higher rate of fetal death and anomalies than did the control population (P = .001). Abnormal outcomes were associated with the three major antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital). In terms of abnormal outcome (death and anomalies), phenobarbital was associated with the highest relative risk, phenytoin with intermediate relative risk, and carbamazepine with the lowest relative risk (P = .019). Numbers were insufficient for assessment of risk associated with valproic acid. CONCLUSION: All three major antiepileptic drugs (phenobarbital, phenytoin, and carbamazepine) are associated with an increased risk of fetal death and anomalies. We found phenobarbital to be most associated with poor pregnancy outcome.

Managing the late complications of Parkinson's disease.

Most patients with Parkinson's disease (PD) receiving chronic levodopa therapy eventually manifest one or more motor response complications, including "wearing-off" phenomena and "on-off" phenomena. Additionally, as the disease progresses, motor, neurologic, and neuropsychiatric complications increase and may include freezing spells, falls, dementia, depression, and psychosis. The management of patients with advanced PD presents a special clinical challenge because patients may experience an enhanced sensitivity to small changes in plasma levodopa levels and because they may suffer adverse reactions to antiparkinsonian drugs. Management of advanced PD is directed toward decreasing the dose of the offending drug while raising the dose of an alternative drug, with the goal of maintaining symptom control. In this article, the spectrum of late complications experienced by patients with advanced PD and their management are discussed.

Tolcapone in stable Parkinson's disease: efficacy and safety of long-term treatment. Tolcapone Stable Study Group.

In this double-blind, placebo-controlled trial, we investigated the effect of the catechol-O-methyltransferase inhibitor tolcapone 100 or 200 mg three times daily on activities of daily living and motor function in 298 patients with parkinsonism receiving levodopa but without motor fluctuations. At 6 months, both dosages of tolcapone produced significant reductions in the Unified Parkinson's Disease Rating Scale scores for activities of daily living (Subscale II) and motor function (Subscale III) and in the total score for Subscales I to III. These improvements were maintained up to the 12-month assessment. At 6 months, both tolcapone groups had changes in levodopa dosage that were significantly different from placebo: the tolcapone groups had decreases in mean total daily dose of levodopa, whereas the placebo group had a mean increase. Tolcapone was well tolerated. The principal adverse events were levodopa-related, but these were generally mild or moderate. Diarrhea was the most frequent nondopaminergic adverse event. Tolcapone appears to be beneficial in the treatment of patients with parkinsonism who have not yet developed motor fluctuations.

Tolcapone in stable Parkinson's disease: efficacy and safety of long-term treatment. The Tolcapone Stable Study Group.

In this double-blind, placebo-controlled trial, we investigated the effect of the catechol-O-methyltransferase inhibitor tolcapone 100 or 200 mg three times daily on activities of daily living and motor function in 298 patients with parkinsonism receiving levodopa but without motor fluctuations. At 6 months, both dosages of tolcapone produced significant reductions in the Unified Parkinson's Disease Rating Scale scores for activities of daily living (Subscale II) and motor function (Subscale III) and in the total score for Subscales I to III. These improvements were maintained up to the 12-month assessment. At 6 months, both tolcapone groups had changes in levodopa dosage that were significantly different from placebo: the tolcapone groups had decreases in mean total daily dose of levodopa, whereas the placebo group had a mean increase. Tolcapone was well tolerated. The principal adverse events were levodopa-related, but these were generally mild or moderate. Diarrhea was the most frequent nondopaminergic adverse event. Tolcapone appears to be beneficial in the treatment of patients with parkinsonism who have not yet developed motor fluctuations.

A multicenter trial of ropinirole as adjunct treatment for Parkinson's disease. Ropinirole Study Group.

OBJECTIVE: To evaluate the nonergot dopamine agonist ropinirole as an adjunct to L-dopa in a randomized, double-blind trial in PD patients with motor fluctuations. BACKGROUND: L-dopa in the treatment of PD is associated with motor fluctuations, dyskinesia, and other adverse effects. The use of dopamine agonists in the treatment of PD delays recourse to L-dopa and thus delays the possibility of adverse effect onset. METHODS: Ropinirole (n = 95) or placebo (n = 54) was added to L-dopa, and L-dopa was then reduced in a planned manner during the 6-month trial. RESULTS: A significantly greater number of ropinirole patients were able to achieve a 20% or greater reduction in both L-dopa dose and in percent time spent "off" compared with placebo (35.0% versus 13.0%; p = 0.003). The mean daily L-dopa dose was reduced significantly with ropinirole treatment (242 mg versus 51 mg; p < 0.001) as was the percent awake time spent "off" (11.7% versus 5.1%; p = 0.039). There was no difference in the percent of patients who withdrew because of adverse effects (15.8% on ropinirole versus 16.7% on placebo). CONCLUSIONS: Ropinirole permits a reduction in L-dopa dose with enhanced clinical benefit for PD patients with motor fluctuations.

Phenotypic expression of X-linked dystonia-parkinsonism (lubag) in two women.

Lubag (X-linked dystonia-parkinsonism) has been considered a sex-linked recessive trait and has been mapped to the pericentromeric region of the X chromosome. We studied a 54-year-old man with lubag and two of his female first cousins. Genetic typing was carried out using X chromosome markers. Fluorodopa PET was performed on the man and one of the women. The man had moderately severe parkinsonism and dystonia. A 61-year-old female first cousin had mild left-sided dystonia and her 54-year-old sister had mild generalized chorea. Genetic typing data revealed that all three inherited an X chromosome with marker alleles strongly associated with lubag. Cytologic analysis did not reveal evidence of X chromosomal deletion. Fluorodopa PET in both the man and one affected cousin revealed reduced striatal uptake rate constants consistent with nigrostriatal involvement. These observations suggest that lubag may be a codominant disorder and that it is possible for women to be affected.

Multicenter, placebo-controlled trial of cabergoline taken once daily in the treatment of Parkinson's disease.

Cabergoline is a dopaminergic agonist relatively specific for the D2 receptor and much longer-acting than other dopamine agonists. We conducted a randomized, placebo-controlled, double-blind study of cabergoline in 188 levodopa/carbidopa-treated patients with suboptimally controlled Parkinson's disease (PD). The cabergoline patients had significantly better Activities of Daily Living (p = 0.032) and Motor Examination (p = 0.031) scores at the conclusion of the trial compared with the placebo group. The daily levodopa dose for the cabergoline patients decreased 18% compared with a 3% reduction for the placebo group (p < 0.001). The amount of time in the "on" state increased more in the cabergoline group (p = 0.022). The side-effect was similar to that seen with other dopamine agonists, and cabergoline was generally well tolerated. We conclude that cabergoline is an effective adjunct to levodopa for the treatment of PD.

Genome-wide scan for Parkinson's disease: the GenePD Study.

A genome-wide scan for idiopathic PD in a sample of 113 PD-affected sibling pairs is reported. Suggestive evidence for linkage was found for chromosomes 1 (214 cM, lod = 1.20), 9 (136 cM, lod = 1.30), 10 (88 cM, lod = 1.07), and 16 (114 cM, lod = 0.93). The chromosome 9 region overlaps the genes for dopamine beta-hydroxylase and torsion dystonia. Although no strong evidence for linkage was found for any locus, these results may be of value in comparison with similar studies by others.

Epidemiologic study of 203 sibling pairs with Parkinson's disease: the GenePD study.

OBJECTIVE: To examine patterns of familial aggregation and factors influencing onset age in a sample of siblings with PD. METHODS: Sibling pairs (n = 203) with PD were collected as part of the GenePD study. Standardized family history, medical history, and risk factor data were collected and analyzed. RESULTS: The mean age at onset was 61.4 years and did not differ according to sex, exposure to coffee, alcohol, or pesticides. Head trauma was associated with younger onset (p = 0.03) and multivitamin use with later onset (p = 0.007). Age at onset correlation between sibling pairs was significant (r = 0.56, p = 0.001) and was larger than the correlation in year of onset (r = 0.29). The mean difference in onset age between siblings was 8.7 years (range, 0 to 30 years). Female sex was associated with increased frequency of relatives with PD. The frequency of affected parents (7.0%) and siblings (5.1%) was increased when compared with frequency in spouses (2.0%). CONCLUSIONS: The greater similarity for age at onset than for year of onset in sibling pairs with PD, together with increased risk for biological relatives over spouses of cases, supports a genetic component for PD. Risk to siblings in this series is increased over that seen in random series of PD cases; however, patients in this sample have similar ages at onset and sex distribution as seen for PD generally. These analyses suggest that factors influencing penetrance are critical to the understanding of this disease.

Utilization of unilateral and bilateral stereotactically placed adrenomedullary-striatal autografts in parkinsonian humans: rationale, techniques, and observations.

A limited clinical pilot study involving an amalgam of specialized disciplines including neurology, neuropharmacology, neuropsychology, neurosurgery, neuroanesthesia, neuroradiology, surgical pathology, neuropathology, and urological surgery was organized to clarify issues related to patient selection, optimization of grafting materials, design of a safe, effective, standardized, and reproducible surgical technique, and possible modification of clinical patterns. After initial assessment of 82 Parkinsonian patients for periods of 6 to 20 months, 10 (age, 39-68 years) were selected for unilateral or bilateral adrenomedullary autografts to the caudate nucleus with ependymal and cerebrospinal fluid contact, employing image-directed stereotactic methods. Selection was made only after clear definition of clinical pattern and optimization of medication responses. Adrenal glands were harvested by a retroperitoneal approach (mean estimated blood loss less than 75 ml). Care was taken to maximize the graft content of medullary tissue. Stereotactic methods afforded standardized, reproducible, precise targeting and transit trajectory with unilateral or bilateral placement of materials within the striatum (tissue volume, 80 mm3) with access to the ventricular fluid of the frontal horn. Considerable variability in satisfactory donor medullary tissue was encountered. One patient did not undergo grafting because of unsatisfactory medullary tissue. No significant surgical complications were noted and all patients were ready for discharge 7 days after surgery. One patient who manifested no apparent clinical change died 6 weeks after bilateral grafting of unrelated causes during a lithotripsy procedure. Postmortem examination disclosed precise graft placement with a paucity of structurally preserved medullary cells. Postoperative observations, including parameters of clinical observation, medication schedules and records, patient and family commentaries, and imaging studies (computed tomograms and single photon emission computed tomograms), have been made for periods from 16 to 20 months. Sustained improvement in preexisting clinical patterns and reduction in drug requirements were observed in 4 of 8 patients. No increased benefit could be ascribed to bilateral graft placement. These observations would indicate a safe, and reproducible surgical method. In addition, the clinical observations indicate favorable alterations in the established pattern of the disorder, which would justify further cautious exploration of alternate donor sources or refinements of biological graft site manipulations.

Ventroposterior medial pallidotomy in patients with advanced Parkinson's disease.

In a preliminary study, the effects of ventroposterior medial pallidotomy were evaluated in five patients with advanced Parkinson's disease in whom medical therapy had failed. The mean age was 67.0 +/- 5.6 years, and the mean Hoehn and Yahr stage when "off" was 3.9 +/- 1.3. Three patients received unilateral pallidotomies; two of these received another pallidotomy after 8 weeks. Two other patients received staged bilateral pallidotomies. No significant differences in overall function could be seen before and after the first surgical procedure. All three patients with peak-dose dyskinesias or dystonia had marked contralateral reduction in these symptoms. Ventroposterior medial pallidotomy can ameliorate peak-dose dyskinesias in patients with advanced Parkinson's disease. Overall function improvement is not remarkable.

Comparative tolerability of the newer generation antiparkinsonian agents.

In recent years, the treatment of Parkinson's disease has undergone an immense amount of research, resulting in the development of multiple new medications. This has largely been fuelled by dissatisfaction over the development of motor complications secondary to long term levodopa therapy. Different treatment approaches are applied depending on the stage of Parkinson's disease. In early and mild Parkinson's disease, selegiline offers a limited symptomatic effect. Its neuroprotective effect, although at present theoretical, has questionable clinical relevance. Increased mortality associated with selegiline has been reported, although a meta-analysis of 5 different trials did not support this finding. The newer, non-ergoline dopamine agonists, pramipexole and ropinirole, have undergone extensive studies to evaluate their efficacy as monotherapy in early Parkinson's disease. These newer agonists are ideal initial symptomatic medications, primarily because they delay the onset of levodopa-induced motor fluctuations. Efficacy of the newer dopamine agonists in advanced disease seems to be comparable to that of the older agents, bromocriptine and pergolide. Adverse effects can be reduced by starting the medication at a very low dose and then slowly titrating upward. Catechol-O-methyl transferase (COMT) inhibitors are indicated for the treatment of motor fluctuations in advanced disease, particularly the 'wearing-off' phenomenon. Tolcapone, a peripheral and central COMT inhibitor, appears to be quite effective, producing a 47% reduction in 'off' time. Unfortunately, 3 deaths have been observed, which are presumably secondary to tolcapone therapy. The drug has been withdrawn in many countries, and liver enzyme testing is mandatory in the US. Entacapone, a purely peripheral COMT inhibitor with a lower potency than tolcapone, has also proved to be effective and has not been associated with liver damage, obviating the need for testing.

Side effects of selegiline (Eldepryl).

Selegiline (Eldepryl), recently approved as an adjunct to levodopa-carbidopa (Sinemet), was administered to eight patients with Parkinson's disease in an open-label study. Many side effects were seen pertinent in particular to the elderly patient. Urinary retention was precipitated in two gentlemen. We advise that this medication be used with caution in the parkinsonian patient.

Long-term follow-up of adrenal medullary transplantation for Parkinson's disease.

Long-term follow-up of eight patients who underwent stereotactic grafting of adrenal medullary tissue into unilateral or bilateral caudate nuclei is presented. We demonstrate that this procedure can be performed with minimal risk. Our results show little benefit when the group as a whole is analyzed. A subgroup of four patients was identified who responded to the procedure, as evidenced by a reduction in motor scores, reduction in medication requirements, and greater "on" time. Three of these patients continue to accrue benefit after 2 years. No characterization of a responder profile was evident. We conclude that a modest benefit is derived from this procedure that may persist for as long as 2 years. Future clinical studies to evaluate grafting procedures are encouraged.

Treatment of non-unions of fractures of the tibial diaphysis by posterolateral cortical cancellous bone-grafting.

A series of forty-four consecutive tibial diaphyseal fractures with non-unions were treated over a thirteen-year period (1965 to 1978). The majority of these injuries were complicated by severe soft-tissue damage, segmental bone loss, or infection, and multiple previous operative attempts had been made to obtain union. Cortical cancellous bone grafts were inserted posterolaterally and union was obtained in all but one fracture. Two bone-grafting procedures each were needed in three patients. Good to excellent functional results were obtained in forty-three of the forty-four involved extremities.

Fluoxetine and selegiline--lack of significant interaction.

The use of the combination of fluoxetine, an anti-depressant serotonin uptake inhibitor, and selegiline, a monoamine oxidase -B inhibitor, was reviewed in a large population of patients with Parkinson's disease. All records were reviewed from a Parkinson's disease clinic to determine how many patients were treated simultaneously with selegiline and fluoxetine. Patient characteristics, duration and dose of treatment, side effects and reasons for discontinuation were noted. Twenty-three patients received both medications at the same time. No additional side effects were noted with the combination therapy that had not already been reported with each medication alone. No serious side effects were found. In this clinic population, fluoxetine and selegiline were used in combination without major side effects, but further observation is warranted.

Advances in managing Parkinson's disease.

The medical choices are now more numerous: Dopamine agonists may have value not only for addressing the motor fluctuations of levodopa therapy but also for deferring the use of levodopa. Surgical choices are bolstered by the addition of investigational options such as neuronal transplantation, in addition to options currently approved, such as pallidotomy.

Autosomal dominant Lewy body parkinsonism in a four-generation family.

We report a family with autosomal dominant parkinsonism. The propositus developed parkinsonism at a relatively young age (45 years) and came to autopsy after a 6-year illness. She had typical features of Parkinson's disease except for an absence of rest tremor, although this was present in other family members. A diagnosis of Lewy body parkinsonism was confirmed by neuropathological examination. Additional pathological features included the presence of cortical Lewy bodies and anti-ubiquitin-positive neurites in the cornu Ammonis 2 and 3 (CA2-3) region of the hippocampus. This kindred is similar both clinically and pathologically to a few previously reported pedigrees, further strengthening recent evidence of a genetic etiology of some forms of Parkinson's disease.