Should continuous dopaminergic stimulation be a standard of care in advanced Parkinson's disease?

The standard of care is a term that refers to the level of care, skill, and treatment that a healthcare provider should offer to a patient based on the current scientific evidence and the level of medical knowledge available in the field. For Parkinson's disease (PD), the standard care is mostly considered to be oral treatment with dopaminergic drugs, particularly levodopa which remains the 'gold standard'. However, effective management with levodopa during the later stages of the disease becomes increasingly challenging due to the ongoing neurodegenerative process, the consequences of its pulsatile dopaminergic stimulation, and the gastrointestinal barriers to effective drug absorption. As a result, the concept of applying continuous dopaminergic stimulation has emerged with infusion therapies (continuous subcutaneous apomorphine, levodopa-carbidopa intestinal gel, and levodopa-entacapone-carbidopa intestinal gel infusion). These therapies seek to provide continuous stimulation of striatal dopamine receptors that is efficient not only in alleviating clinical symptoms, but also in delaying, reducing, and possibly preventing the onset of levodopa-related motor (fluctuations, dyskinesia) and non-motor complications; and they are also associated with clinically relevant side effects. Clinical studies and real-life experience support the notion that infusion therapies should be accepted as part of the standard of care for patients with advanced PD who have refractory, severe, and disabling motor complications that affect their quality of life. However, they should be considered based on the needs of individualized patients and the access to these advanced therapies needs to be made more accessible to the general PD population.

Management of dystonia in Europe: a survey of the European network for the study of the dystonia syndromes.

BACKGROUND AND PURPOSE: Dystonia is difficult to recognize due to its large phenomenological complexity. Thus, the use of experts in dystonia is essential for better recognition and management of dystonia syndromes (DS). Our aim was to document managing strategies, facilities and expertise available in various European countries in order to identify which measures should be implemented to improve the management of DS. METHODS: A survey was conducted, funded by the Cooperation in Science and Technology, via the management committee of the European network for the study of DS, which is formed from representatives of the 24 countries involved. RESULTS: Lack of specific training in dystonia by general neurologists, general practitioners as well as other allied health professionals was universal in all countries surveyed. Genetic testing for rare dystonia mutations is not readily available in a significant number of countries and neurophysiological studies are difficult to perform due to a lack of experts in this field of movement disorders. Tetrabenazine is only readily available for treatment of dystonia in half of the surveyed countries. Deep brain stimulation is available in three-quarters of the countries, but other surgical procedures are only available in one-quarter of countries. CONCLUSIONS: Internationally, collaboration in training, advanced diagnosis, treatment and research of DS and, locally, in each country the creation of multidisciplinary teams for the management of dystonia patients could provide the basis for improving all aspects of dystonia management across Europe.

Multivariate classification of patients with Alzheimer's and dementia with Lewy bodies using high-dimensional cortical thickness measurements: an MRI surface-based morphometric study.

CONTEXT: Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the most common neurodegenerative dementia types. It is important to differentiate between them because of the differences in prognosis and treatment approaches. OBJECTIVE: Investigate if sparse partial least squares (SPLS) classification of cortical thickness measurements could differentiate between AD and DLB. METHODS: Two independent cohorts without MR-protocol alignment in Norway and Slovenia with 97 AD and DLB subjects were enrolled. Cortical thickness measurements acquired with Freesurfer were used in subsequent SPLS classification runs. The cohorts were analyzed separately and afterwards combined. The models were trained with leave-one-out cross validation and test datasets where used when available. To study the impact of MR-protocol alignment, the classifiers were additionally tested on sets drawn exclusively from the independent cohorts. RESULTS: The obtained sensitivity/specificity/AUC values were 94.4/88.89/0.978 and 88.2/94.1/0.969 in the Norwegian and Slovenian cohorts, respectively. Both cohorts showed AD-associated pattern of thinning in mid-anterior temporal, occipital and subgenual cingulate cortex, whereas the pattern supportive for DLB included thinning in dorsal cingulate, posterior temporal and lateral orbitofrontal regions. When combining the cohorts, sensitivity/specificity/AUC were 82.1/85.7/0.948 for the training and 77.8/75/0.731 for the testing datasets with the same pattern-of-difference. The models tested on datasets drawn exclusively from the independent cohorts did not produce adequate accuracy. CONCLUSION: SPLS classification of cortical thickness is a good method for differentiating between AD and DLB, relatively stable even for mixed data, but not when tested on completely independent data drawn from different cohorts (without MR-protocol alignment).

Executive dysfunction in late-onset depression.

OBJECTIVE: Depression in the elderly is frequently accompanied by cognitive impairment. Executive dysfunction, including disturbances in planning, sequencing, organizing and abstracting has been reported in late-onset depression. They were found to be associated with relapse and recurrence of geriatric major depression and with residual depressive symptoms. SUBJECTS AND METHODS: A group of patients with late-onset depression, compared with age matched healthy volunteers, were assessed for deficits in executive functioning. We used the computer version of Stroop Color-Word test enabling more detailed reaction time analysis. Severity of depression was evaluated with Hamilton depression rating scale and Geriatric depression scale. RESULTS: The preliminary results of a study show that patients with late-onset depression have increased absolute reaction times in Stroop colour-word test. Significant differences in the magnitude of individual interference effects pointing towards a characteristic change in attentional processes in depressed patients. CONCLUSION: The preliminary results of a study comparing a group of elderly depressed patients with a control group of older healthy volunteers confirm changes in executive functions.

Postural stability of Parkinson's disease patients is improved by decreasing rigidity.

Postural instability has a big impact on the quality of life of patients with Parkinson's disease (PD) as it often leads to an insecure stance and fall. We investigated if postural stability in these patients improves by decreasing rigidity with a dopaminergic agonist. In our study, we tested eight PD patients with no concomitant diseases. Their age was 61 +/- 2 years (mean +/- SE) and their Hoehn-Yahr score was 3 +/- 0.1. The patients were evaluated according to the Unified Parkinson's Disease Rating Scale for motor function (mUPDRS) and with stabilometric measurements of forward-backward and side-to-side body oscillations during free stance with eyes open. Both evaluations were performed in an "off "state and in an apomorphine-induced "on" state. As expected, the mUPDRS score was significantly decreased in the "on" state with posture being improved in six patients, gait in eight patients and postural stability in seven of eight patients. In addition, apomorphine caused a significant reduction of the relative amplitude of lower frequencies and an increase of the relative amplitude of higher frequencies of forward-backward body oscillations. The results of stabilometry and mUPDRS evaluations are in agreement with the effect of apomorphine on rigidity, indicating that postural stability of PD patients is improved by decreasing rigidity.

Attention and cognition in bradykinetic-rigid syndromes: an event-related potential study.

Bradykinetic-rigid syndromes are often accompanied by cognitive impairment. Because prominent motor involvement in these disorders may interfere with neuropsychological testing, we used event-related potentials (ERPs) for the assessment of cognition and attention in 41 patients with various bradykinetic-rigid syndromes of less than 5 years duration: idiopathic Parkinson's disease corticobasal degeneration, Steele-Richardson-Olszewski syndrome (SRO), and multiple system atrophy. Patients were compared with matched normals. ERP abnormalities in the auditory "oddball" paradigm were found only in corticobasal degeneration and SRO. ERP abnormalities in selective attention tasks were present in all patient groups, changes in SRO being the most prevalent. Abnormalities in corticobasal degeneration were present under "less-attention-demanding" conditions and suggested involvement of posterior parts of the brain. Multiple system atrophy and idiopathic Parkinson's disease patient groups had minimal ERP abnormalities. However, reaction times in MSA were longer in all paradigms. The results of the study support the view that bradykinetic-rigid syndromes involve some attentional deficits, but also have distinct reaction time and ERP characteristics, which may be helpful in differential diagnosis.

Botulinum toxin in the treatment of writer's cramp.

Forty-four patients with disabling writer's cramp (WC) and one with a musician's cramp were treated with botulinum toxin (BT) injections for a mean period of 12 (range, 3-48) months. The forearm muscles causing the dystonic position were identified by inspection while writing; BT was then administered under electromyographic (EMG) guidance. The degree of improvement in writing and amelioration of pain were rated with self-assessment scales. Patients reported significant improvement in writing after 56% treatment sessions (TS) and in pain after 62% TS. Mild weakness occurred after 32% TS. Twenty-nine patients discontinued treatment, generally after the initial BT injection. In 16 patients who remained on treatment with a mean follow-up of 21 (range, 3-48) months, the improvement in writing and pain was present after 76 and 79% of the TS, respectively. We conclude that BT injections offered a worthwhile and sustained functional improvement to 36% of our patients with WC.

Ropinirole in the treatment of levodopa-induced motor fluctuations in patients with Parkinson's disease.

Forty-six patients with Parkinson's disease experiencing motor fluctuations and not optimally controlled on levodopa received as adjunct therapy a new nonergoline dopamine agonist, ropinirole, in a 3-month randomized placebo-controlled trial. Ropinirole significantly reduced the duration of off periods as assessed by self-scoring diary cards. There were more nonserious dopaminergic adverse events in the ropinirole group. More patients withdrew because of adverse events or insufficient therapeutic effect in the placebo group. Ropinirole has beneficial adjuvant effects in parkinsonian patients with moderate motor disability and motor fluctuations.

Magnetic resonance spectroscopic study of parkinsonism related to boxing.

Proton magnetic resonance spectroscopy, localised to the lentiform nucleus, was carried out in three ex-professional boxers who developed a parkinsonian syndrome, six patients with idiopathic Parkinson's disease, and six age matched controls. The three ex-boxers all showed a pronounced reduction in the absolute concentration of N-acetylaspartate compared with the patients with idiopathic Parkinson's disease and the control group. This reduction is likely to reflect neuronal loss occurring in the putamen and globus pallidus and supports the hypothesis that the extrapyramidal syndrome that may occur in ex-boxers is a distinct entity from idiopathic Parkinson's disease.

Botulinum toxin in the treatment of neurological disorders.

Botulinum toxin therapy is safe and effective in the treatment of different movement disorders, especially focal dystonias. We reviewed botulinum toxin treatment of 97 patients: 36 had blepharospasm, 41 had torticollis, and 20 had diverse movement disorders. Patients with blepharospasm and torticollis improved markedly after botulinum toxin injections. The most common side effect in BS patients was ptosis (44.4%); in TC patients, it was dysphagia (29.3%). The mean duration of the improvement in both groups was 3.4 months. Very promising results were obtained also in the heterogeneous group including patients with other focal dystonias and cerebral palsy. On the basis of these results, we concluded that BTA injections must now be considered the mainstay of therapy for focal dystonias and other involuntary movement disorders.

Preclamol and parkinsonian fluctuations.

Preclamol, the (-)enantiomer of 3-PPP (= 3(3-hydroxyphenyl)-N-n-propyl piperidine), has a selective dopamine autoreceptor- and postsynaptic mixed agonist-antagonist profile. Its action on patients with disabling on-off parkinsonian fluctuations has been studied and compared with those of placebo and subcutaneous apomorphine. Preclamol had a mild but unequivocal antiakinetic effect, less than that caused by subcutaneous apomorphine, but it provoked less dyskinesia. Further studies to explore the therapeutic potential of preclamol seem justified.

Cardiovascular reflexes in Parkinson's disease: effect of domperidone and apomorphine.

Cardiovascular reflexes were evaluated in 18 patients with idiopathic Parkinson's disease who had a Hoehn & Yahr score of III-IV. The effect of apomorphine and domperidone on blood pressure, heart rate, R-R interval variation, and the Valsalva ratio were studied. Autonomic dysfunction was not found in the patients and there were no differences between subgroups of patients on different treatments. Apomorphine altered cardiovascular reflexes to a greater degree in patients who received the drug for the first time than in chronically treated patients. The changes were antagonized by domperidone, a peripheral dopamine receptor antagonist. Apomorphine treated patients who were receiving long-term domperidone had similar abnormalities of cardiovascular reflexes to those who had been able to withdraw it.

Diurnal differences in response to oral levodopa.

Diurnal differences in duration and quality of motor response to levodopa are frequently described by patients. The quality and duration of motor responses were objectively assessed to morning and afternoon oral levodopa doses in five patients with Parkinsonian motor fluctuations who complained of diurnal variation in response to their normal levodopa medication. Results suggest that under controlled conditions which eliminated the effects of diet and overlapping levodopa effects the response to levodopa remained unchanged throughout the day, and that the duration of response could be predicted by plasma levodopa levels.