Clinical presentation and pharmacological therapy in corticobasal degeneration.

BACKGROUND: To date, to our knowledge, there is no systematic presentation of treatment outcome in large series of patients clinically diagnosed as having corticobasal degeneration. OBJECTIVE: To evaluate the clinical presentation and treatment outcome of patients clinically diagnosed as having corticobasal degeneration. SUBJECTS: We gathered case patients seen in 8 major movement disorder clinics during the last 5 years who were diagnosed as having corticobasal ganglionic degeneration. METHODS: Using a chart review method, we recorded the clinical presentation, medications used, response to medications, and adverse effects. RESULTS: A total of 147 case patients were reviewed, 7 were autopsy proven. Parkinsonian features were present in all, other movement disorders in 89%, and higher cortical dysfunction in 93%. The most common parkinsonian sign was rigidity (92%), followed by bradykinesia (80%), gait disorder (80%), and tremor (55%). Other movement disorders were dystonia in 71% and myoclonus in 55%. Higher cortical dysfunction included dyspraxia (82%), alien limb (42%), cortical sensory loss (33%), and dementia (25%). Ninety-two percent of the case patients received dopaminergic drugs, which resulted in a beneficial effect for 24%. Parkinsonian signs were the elements improving the most and levodopa was the most effective drug. Benzodiazepines, primarily clonazepam, were administered to 47 case patients, which resulted in improvement of myoclonus in 23% and dystonia in 9%. The most frequent disabling adverse effects of drug trials in these case patients were somnolence (n = 24), gastrointestinal complaints (n = 23), confusion (n = 16), dizziness (n =12), hallucinations (n = 5), and dry mouth (n = 5). CONCLUSIONS: Pharmacological intervention was largely ineffective in the management of corticobasal degeneration, and new treatments are needed for ameliorating the symptoms of this syndrome.

Acute delirium after withdrawal of amantadine in Parkinson's disease.

We present three patients who, after long-term therapy with amantadine (4 to 18 years), experienced an acute delirium with confusion, disorientation, agitation, and paranoia on withdrawal. These patients had Parkinson's disease for 5 to 29 years; mean age was 73 years. All had a history of varying degrees of dementia and transient hallucinations in the past. Adjustment of other medications was ineffective in improving their condition and no other cause was found. Only with reinstitution of amantadine did the patients return to baseline status (usually within days).

Clozapine: a 2-year open trial in Parkinson's disease patients with psychosis.

We treated 17 patients with Parkinson's disease (PD) complicated by psychosis with the atypical antipsychotic drug, clozapine, for 6 to 24 months (mean, 15 months) in a prospective, open-label trial. At 3-month intervals we evaluated patients, using a simplified brief Psychiatric Rating Scale (PRS), the motor examination portion of the Unified Parkinson's Disease Rating Scale, and the Mini-Mental State Examination (MMSE). Mean PRS score was significantly improved when compared with baseline over 1 year (p < 0.01) and nonsignificantly improved for the second year. We maintained the levodopa dose at levels that were 17 to 68% higher than baseline, and the mean motor examination score improved by 11 to 22% in the first 15 months. Clozapine dosage utilized in the trial ranged from 6.25 mg every other day to 150 mg/d. Adverse effects, including sedation and confusion, were common. These results demonstrate that clozapine therapy can be effective in treating psychosis in PD patients over 1 to 2 years. The decline in efficacy in the second year was most likely related to an increase in daily levodopa dose, progression of dementia (illustrated by a decline in MMSE score), and an inability of PD patients to tolerate higher doses of clozapine.

The use of pramipexole, a novel dopamine (DA) agonist, in advanced Parkinson's disease.

We evaluated the efficacy, safety and tolerability of a new dopamine D-2 receptor agonist, pramipexole [(S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzathiazol-dihydro chloride], as adjunctive therapy in patients with advanced Parkinson's disease (PD). Twenty-four PD patients with motor fluctuations were treated in an 11 week prospective, single-blind parallel-group, placebo-controlled trial. The pramipexole treated group experienced a significant improvement in "off" time functioning as measured by the activities of daily living portion of the United Parkinson's Disease Rating Scale. In addition, the active treatment group was able to reduce total levodopa dose by 30% (p < 0.05). Pramipexole was well tolerated and the side effects reported were typical of other dopamine agonists. We conclude that pramipexole has antiparkinsonian effects which make it potentially useful in the treatment of motor fluctuations in PD.

An open-label study of botulinum toxin A for treatment of tardive dystonia.

Tardive dystonia is a form of tardive dyskinesia for which there is little satisfactory treatment. We reviewed our experience at four movement disorder centers in the treatment of tardive dystonia with botulinum toxin A (BTX-A). Thirty-four patients with relatively localized tardive dystonia unresponsive to oral medications were treated with injections of BTX-A into dystonia muscles. Cervical dystonia was the most frequent manifestation of tardive dystonia in this group of patients. There was marked or moderate improvement in 29 of 34 patients. Eighteen of 24 patients with cervical dystonia showed either marked or moderate improvement. In this retrospective review, BTX-A provided useful symptomatic treatment for localized dystonia in patients with tardive dystonia unresponsive to other treatment. A controlled, prospective trial of BTX-A in tardive dystonia is warranted.

Long-term comparative experience with tolcapone and entacapone in advanced Parkinson's disease.

The objective of this study was to compare the long-term tolerability and efficacy of tolcapone and entacapone in patients with fluctuating Parkinson's disease (PD). Tolcapone and entacapone are two currently available catechol- O -methyltransferase inhibitors that have demonstrated efficacy in the treatment of advanced PD. There are little published data on long-term experience and no direct comparisons. We compared the results of two separate, simultaneous, long-term open label extensions, one for tolcapone and the other for entacapone. The inclusion/exclusion criteria were similar. Data were collected prospectively at 6, 12, 24, and 36 months. Efficacy measures included the Unified Parkinson's Disease Rating Scale (UPDRS) total score, subscores, items 32 (duration of dyskinesia) and 39 (duration of "off" time), and levodopa dose. The two groups were compared using a Mann-Whitney U test for change from baseline and analysis of variance. Tolerability was defined as the ability of patients to maintain therapy and was compared using a Kaplan-Meier analysis. Eleven patients enrolled in the entacapone study and 14 in the tolcapone study. The tolcapone group had more severe disease with significantly higher UPDRS motor score, duration of "off," and levodopa dose requirement. Tolcapone was more effective in lowering UPDRS motor and complication subscores, duration of "off" time, and levodopa doses. UPDRS motor scores and change in levodopa dose in the tolcapone group remained below baseline level for 36 months; however, they were above baseline in the entacapone group from 6 months on. Tolerability was the same for both treatments. Tolcapone appears to have greater and longer efficacy with regard to motor symptoms, "off" time, and change in levodopa requirements than entacapone. These findings indicate that tolcapone continues to have a place in the treatment of advanced PD. However, the risks associated with this drug, particularly hepatic injury, and the requirement for rigorous blood monitoring, need to be considered when choosing an appropriate treatment for patients with advanced PD.

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.

Parkinson's disease: drug-induced psychiatric states.

Drug-induced psychiatric states occur frequently in PD. In the prelevodopa era, depression and other psychiatric disorders were described in PD, but in untreated patients psychosis was rare. Since the development of levodopa and other pharmacological treatments for PD, however, psychotic symptoms have become much more common (10-50%). In some individuals these problems can be more disabling than the motor features of PD and, as a result, pose a serious threat to the patient's ability to maintain independence. The drug-induced psychoses consist of several distinct psychiatric syndromes that can be divided broadly into those occurring on a background of a clear sensorium and those which are accompanied by confusion and clouding of consciousness. Benign organic hallucinosis is the most common of these syndromes (30%). It usually occurs on a background of a clear sensorium and may not be a particularly troublesome problem if the patient is able to retain insight into the nature of these symptoms. More disabling syndromes usually include delusional thinking that is frequently paranoid, confusion and even frank delirium. Although all these psychotic syndromes can occur in isolation, there is a tendency for mild symptoms to progress to more disabling ones if adequate and timely treatment is not instituted. Abnormal dreaming and sleep disruption often precede these difficulties by weeks to months and may provide an important early clue to their onset. The mechanisms responsible for drug-induced psychotic symptoms in PD are unknown, but dopaminergic (especially mesolimbic) and serotoninergic systems are likely to be involved. The treatment of the drug-induced psychoses in PD should be undertaken in a stepwise manner. A detailed discussion of this approach, including the use of anti-PD medication adjustment, clozapine, and other medications (neuroleptic and nonneuroleptic) and ECT is provided (see Fig. 1). Although drug-induced psychoses are the most important of the drug-induced psychiatric states, mania, anxiety, and hypersexuality may also occur. Depression is also common in PD, but it is unlikely to occur as a side effect of antiparkinsonian medications.

Cognitive performance of GBA mutation carriers with early-onset PD: the CORE-PD study.

OBJECTIVE: To assess the cognitive phenotype of glucocerebrosidase (GBA) mutation carriers with early-onset Parkinson disease (PD). METHODS: We administered a neuropsychological battery and the University of Pennsylvania Smell Identification Test (UPSIT) to participants in the CORE-PD study who were tested for mutations in PARKIN, LRRK2, and GBA. Participants included 33 GBA mutation carriers and 60 noncarriers of any genetic mutation. Primary analyses were performed on 26 GBA heterozygous mutation carriers without additional mutations and 39 age- and PD duration-matched noncarriers. Five cognitive domains, psychomotor speed, attention, memory, visuospatial function, and executive function, were created from transformed z scores of individual neuropsychological tests. Clinical diagnoses (normal, mild cognitive impairment [MCI], dementia) were assigned blind to genotype based on neuropsychological performance and functional impairment as assessed by the Clinical Dementia Rating (CDR) score. The association between GBA mutation status and neuropsychological performance, CDR, and clinical diagnoses was assessed. RESULTS: Demographics, UPSIT, and Unified Parkinson's Disease Rating Scale-III performance did not differ between GBA carriers and noncarriers. GBA mutation carriers performed more poorly than noncarriers on the Mini-Mental State Examination (p = 0.035), and on the memory (p = 0.017) and visuospatial (p = 0.028) domains. The most prominent differences were observed in nonverbal memory performance (p < 0.001). Carriers were more likely to receive scores of 0.5 or higher on the CDR (p < 0.001), and a clinical diagnosis of either MCI or dementia (p = 0.004). CONCLUSION: GBA mutation status may be an independent risk factor for cognitive impairment in patients with PD.

A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2.

OBJECTIVES: To perform a comprehensive population genetic study of PARK2. PARK2 mutations are associated with juvenile parkinsonism, Alzheimer disease, cancer, leprosy, and diabetes mellitus, yet ironically, there has been no comprehensive study of PARK2 in control subjects; and to resolve controversial association of PARK2 heterozygous mutations with Parkinson disease (PD) in a well-powered study. METHODS: We studied 1,686 control subjects (mean age 66.1 ± 13.1 years) and 2,091 patients with PD (mean onset age 58.3 ± 12.1 years). We tested for PARK2 deletions/multiplications/copy number variations (CNV) using semiquantitative PCR and multiplex ligation-dependent probe amplification, and validated the mutations by real-time quantitative PCR. Subjects were tested for point mutations previously. Association with PD was tested as PARK2 main effect, and in combination with known PD risk factors: SNCA, MAPT, APOE, smoking, and coffee intake. RESULTS: A total of 0.95% of control subjects and 0.86% of patients carried a heterozygous CNV mutation. CNV mutations found in 16 control subjects were all in exons 1-4, sparing exons that encode functionally critical protein domains. Thirteen patients had 2 CNV mutations, 5 had 1 CNV and 1 point mutation, and 18 had 1 CNV mutation. Mutations found in patients spanned exons 2-9. In whites, having 1 CNV was not associated with increased risk (odds ratio 1.05, p = 0.89) or earlier onset of PD (64.7 ± 8.6 heterozygous vs 58.5 ± 11.8 normal). CONCLUSIONS: This comprehensive population genetic study in control subjects fills the void for a PARK2 reference dataset. There is no compelling evidence for association of heterozygous PARK2 mutations, by themselves or in combination with known risk factors, with PD.

Adult-onset tics associated with peripheral injury.

We report the cases of two patients with adult-onset, simple, nonvarying tic disorder that commenced after a peripheral (non-CNS) injury. The first patient is a 38-year-old man who suffered a right facial injury when his car fell off its jack while he was working underneath. Bilateral facial twitching began hours after the trauma and was characterized as a sniffinglike gesture. The movements waxed and waned, were suppressible, and were associated with a premonitory sensation. The tics remitted after 9 months but still recur occasionally under stressful situations. The second patient is a 34-year-old man with a 3-year history of abrupt, rapid head-turning movements that began 12 months after a motor vehicle accident in which he injured his neck. The tics continue to wax and wane, are suppressible, and are associated with an urge. Neither patient suffered a head injury or had a family history of Tourette syndrome. Based on the clinical and historical features of these patients, the temporal relationship between the trauma and onset of tics, and the occurrence of tics only in the traumatized region, a causal relationship is possible. These may represent the first reported cases of tic disorder in association with peripheral injury. The mechanism by which the tic disorder resulted from the peripheral injury is unclear, but these patients might have been susceptible individuals and the trauma acted as a trigger.

Emergency department presentations of patients with Parkinson's disease.

Parkinson's disease (PD) is a chronic progressive neurological disorder characterized by tremor, muscle rigidity, slowness of movement (bradykinesia), and gait instability. In early disease, PD is well managed in an office setting, however, as the disease progresses, a variety of syndromes may result in emergency department visits. The scenarios most likely to require an emergent evaluation are severe motor "off" periods with immobility, involuntary movements (dyskinesia), psychosis, acute confusion, panic disorder, and pain. Other less frequent presentations are also discussed. This article uses illustrative cases to provide a framework to discuss emergency department diagnosis and management issues in caring for these patients.

Parkinson's disease: the treatment of drug-induced hallucinations and psychosis.

Drug-induced psychosis is one of the most disabling complications of advancing Parkinson's disease. It has also been one of the most difficult to treat. Clozapine was the first medication shown to be safe and effective in this setting, and it remains the standard by which newer atypical antipsychotics are measured. However, due to the small but significant risk of agranulocytosis and the need for frequent blood testing, alternatives have been sought. Risperidone, olanzapine, and quetiapine are new atypical antipsychotics that have each been proposed as an alternative to clozapine, but the literature concerning their use in Parkinson's disease is conflicted and confusing. Although quetiapine appears to be the best current choice, none of these medications have equaled clozapine's ability to safely treat drug-induced psychosis without the risk of worsening parkinsonism.

Basal ganglia infarction as a possible cause of cervical dystonia.

Cervical dystonia (CD) is usually an idiopathic disorder that results in abnormal movements and painful postures of the neck. Although symptomatic CD caused by focal CNS lesions has been described in the literature, it is an exceedingly rare phenomenon. We report two women who had an abrupt onset of CD at the ages of 39 and 68 years. Each patient had rotation of the head to the right and was found to have a lacunar infarction in the left putamen on magnetic resonance imaging scan. The abrupt onset of symptoms and appropriate location and laterality of the cerebral lesions suggest an etiologic link between the infarctions and the patients' CD. These cases are the first reports of CD possibly caused by basal ganglia infarction.

Worsening of motor features of parkinsonism with olanzapine.

Clozapine is the current treatment of choice for drug-induced psychosis (DIP) occurring in Parkinson's disease. However, alternative medications have been sought because of the small but significant risk of agranulocytosis and the need for frequent blood testing. The new "atypical" antipsychotic olanzapine (OLZ) has recently been proposed as a safe and effective option for treating psychosis in this setting. To investigate this, we retrospectively evaluated all 12 of our patients treated with OLZ for DIP. Symptoms of psychosis were improved in nine of 12 patients, but nine of 12 patients also experienced worsening of motor functioning while on OLZ. The worsening was considered dramatic in six of these patients. Overall, there was no significant increase in levodopa doses on OLZ. Only one patient remained on OLZ at the time of the analysis. Nine patients were switched to alternative treatment for DIP. We conclude that although OLZ may improve symptoms of psychosis in parkinsonian patients, it can also worsen motor functioning. In some patients, the degree of motor worsening may be intolerable.

Clinical comparison of tardive and idiopathic cervical dystonia.

It has been suggested that tardive cervical dystonia may be clinically indistinguishable from the idiopathic form and that the diagnosis rests solely on documenting an exposure to dopamine antagonist medications. To investigate this, we performed a retrospective evaluation of patient records on 102 patients with idiopathic and 20 patients with tardive cervical dystonia seen in our Movement Disorder Clinic over the past 8 years. Several clinical and demographic variables were compared and a number of differences were observed. The presence of extracervical involvement, retrocollis, and spasmodic head movements were individually found to be predictive of tardive cervical dystonia. Torticollis, laterocollis, and trick maneuvers were predictive of idiopathic cervical dystonia. Head tremor (42.2%) and family history of dystonia (9.8%) were present only in the idiopathic group. Cervical muscle hypertrophy was significantly more common in the idiopathic group (100% versus 75%). No difference was found between the two groups in their response to treatment with botulinum toxin A. These results indicate that clinical differences between idiopathic and tardive cervical dystonia exist. These differences may help to distinguish them in the clinical setting, improve diagnostic accuracy, and support the existence of a causal relationship between exposure to dopamine antagonist medications and chronic dystonia.

Psychogenic movement disorders: frequency, clinical profile, and characteristics.

Of 842 consecutive patients with movement disorders seen over a 71 month period, 28 (3.3%) were diagnosed as having a documented or clinically established psychogenic movement disorder. Tremor was most common (50%) followed by dystonia, myoclonus, and parkinsonism. Clinical descriptions of various types are reviewed. Clinical characteristics common in these patients included distractability (86%), abrupt onset (54%), and selective disabilities (39%). Distractability seems to be most important in tremor and least important in dystonia. Other diagnostic clues included entrainment of tremor to the frequency of repetitive movements of another limb, fatigue of tremor, stimulus sensitivity, and previous history of psychogenic illness. On examination, 71% had other psychogenic features. Over 60% had a clear history of a precipitating event and secondary gain and 50% had a psychiatric diagnosis (usually depression). Twenty five per cent of patients presented with combined psychogenic movement disorder and organic movement disorder; 35% resolved and this subgroup had a shorter duration of disease than those who are unresolved. Psychogenic movement disorder represents an uncommon diagnosis among patients with movement disorders. The ability to make a diagnosis rests on the presence of a multitude of clinical clues and therapeutic action should be taken as early as possible.

Combined clozapine and electroconvulsive therapy for the treatment of drug-induced psychosis in Parkinson's disease.

Drug-induced psychosis is a serious late complication of Parkinson's disease (PD) that requires aggressive treatment. Recent studies have found clozapine a highly effective and ECT a possibly useful intervention. Two cases are presented that illustrate a possible treatment role for ECT. The cases demonstrate that ECT has significant but short-lived antipsychotic effects when used alone. However, patients who do not respond to clozapine monotherapy can be given adjunctive treatment with ECT. The combination therapy resulted in abrupt alleviation of psychotic symptoms in one of the cases, and maintenance with low-dose clozapine allowed for long-term efficacy. On the basis of these findings, a therapeutic approach to patients with drug-induced psychosis in PD is suggested.

A pilot evaluation of the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in untreated Parkinson's disease patients. Tolcapone De Novo Study Group.

Tolcapone is a potent, reversible catechol-O-methyltransferase (COMT) inhibitor with both peripheral and central activity. It has been demonstrated to improve motor function and allow levodopa dose reductions in Parkinson's disease (PD) patients who are experiencing either a stable response or motor fluctuations while on levodopa/dopa decarboxylase inhibitor therapy. Because striatal dopamine is metabolized by COMT and monoamine oxidase (MAO), central COMT inhibition alone or in combination with MAO inhibition might provide symptomatic benefit for patients not receiving levodopa. We conducted a pilot study to evaluate the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in early untreated PD patients. Patients were randomized to receive 200 mg tolcapone three times a day or placebo for the 8 weeks of the study. Open-label oral selegiline (5 mg in the morning and midday) was administered to all patients during the second 4 weeks of the study. There was no difference between treatment groups according to the investigator's assessment of tolerability at week 4. Ninety-five percent of tolcapone-treated patients and 98% of placebo-treated patients experienced excellent or good tolerability during the first 4 weeks (95% confidence interval [CI]: -10.3, 5.7; p = 0.57). A decrease in tolerability occurred in the tolcapone group during the second 4 weeks of the study following the addition of selegiline. The most commonly reported side effects were diarrhea (31% tolcapone, 7% placebo), nausea (21% tolcapone, 2% placebo), urine discoloration (12% tolcapone, 0% placebo), dizziness (12% tolcapone, 5% placebo), headaches (12% tolcapone, 10% placebo), and abdominal pain (10% tolcapone, 5% placebo). We did not identify symptomatic benefit associated with tolcapone alone or in combination with oral selegiline in this group of otherwise untreated PD patients.

Cervical dystonia severity scale reliability study.

Cervical dystonia (CD) is characterized by sustained contractions of the neck musculature, resulting in abnormal head postures. The Cervical Dystonia Severity Scale (CDSS) was developed to provide a reliable measure of treatment response in patients with CD. The CDSS uses a protractor and wall chart to rate the severity of the head's deviation from neutral in each of three planes of motion (rotation, laterocollis, anterocollis/retrocollis), which is then scored in 5 degree intervals (1 degree to 5 degrees deviation = 1; 86 degree to 90 degrees deviation = 18). To test the reliability of the CDSS, four centers, each with two independent examiners, evaluated 42 patients with CD. At each site, each of the two examiners used the CDSS to evaluate the head position of each patient twice, on the same day, for a total of four evaluations. The kappa value for intra-examiner agreement was 0.94 (95% confidence limit of 0.900-0.972), indicating excellent intra-examiner reliability. The kappa value for interexaminer reliability was 0.79 for the first evaluation and 0.86 for the second evaluation (95% confidence limits of 0.668-0.920 and 0.790-0.920) indicating excellent interexaminer reliability. Thus, the CDSS was highly reliable in both intra-examiner and interexaminer scoring comparisons.