Depression in Parkinson's disease is not accompanied by more corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus.

BACKGROUND: Depression is frequently encountered in Parkinson's disease (PD). In addition, more than half of the PD patients have a disturbed dexamethasone suppression test, which is associated with increased activity of corticotropin-releasing hormone (CRH) neurons. We recently found an increase in CRH neuron number, CRH-messenger RNA, and vasopressin colocalization in CRH neurons in the paraventricular nucleus (PVN) of depressed patients, which may be involved in the pathogenesis of depression. METHODS: The number of neurons expressing CRH was determined in the PVN of 6 depressed PD patients with a high score (> or = 13) on the Hamilton Depression Rating Scale, 6 nondepressed PD patients, and 6 controls. RESULTS: The three groups did not differ in the number of neurons expressing CRH. CONCLUSIONS: We hypothesize that activation of CRH neurons in the PVN, as we recently observed in idiopathic depression, does not play an essential role in depression in PD.

Intranasal apomorphine in parkinsonian on-off fluctuations.

The efficacy of intranasal apomorphine was assessed in seven patients with Parkinson's disease and severe levodopa (L-dopa)-related "off-period" disabilities. All patients responded favorably to treatment with intranasal apomorphine. The speed and the quality of motor response and the pharmacokinetic profile showed results similar to those seen after subcutaneous injection of apomorphine administered by insulin pen syringe. The simplicity in the technique of intranasal apomorphine administration was found to be superior by all patients.

Olanzapine in the treatment of dopaminomimetic psychosis in patients with Parkinson's disease.

We studied the effect of olanzapine (1 to 15 mg/d) in 15 nondemented parkinsonian patients with drug-induced psychosis. Psychotic symptoms decreased significantly during treatment, and there was no worsening of extrapyramidal symptoms. These results suggest that olanzapine is a well-tolerated and effective treatment for drug-induced psychosis in nondemented patients with Parkinson's disease.

Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop.

Recent neuropathologic autopsy studies found that 15 to 25% of elderly demented patients have Lewy bodies (LB) in their brainstem and cortex, and in hospital series this may constitute the most common pathologic subgroup after pure Alzheimer's disease (AD). The Consortium on Dementia with Lewy bodies met to establish consensus guidelines for the clinical diagnosis of dementia with Lewy bodies (DLB) and to establish a common framework for the assessment and characterization of pathologic lesions at autopsy. The importance of accurate antemortem diagnosis of DLB includes a characteristic and often rapidly progressive clinical syndrome, a need for particular caution with neuroleptic medication, and the possibility that DLB patients may be particularly responsive to cholinesterase inhibitors. We identified progressive disabling mental impairment progressing to dementia as the central feature of DLB. Attentional impairments and disproportionate problem solving and visuospatial difficulties are often early and prominent. Fluctuation in cognitive function, persistent well-formed visual hallucinations, and spontaneous motor features of parkinsonism are core features with diagnostic significance in discriminating DLB from AD and other dementias. Appropriate clinical methods for eliciting these key symptoms are described. Brainstem or cortical LB are the only features considered essential for a pathologic diagnosis of DLB, although Lewy-related neurites, Alzheimer pathology, and spongiform change may also be seen. We identified optimal staining methods for each of these and devised a protocol for the evaluation of cortical LB frequency based on a brain sampling procedure consistent with CERAD. This allows cases to be classified into brainstem predominant, limbic (transitional), and neocortical subtypes, using a simple scoring system based on the relative distribution of semiquantitative LB counts. Alzheimer pathology is also frequently present in DLB, usually as diffuse or neuritic plaques, neocortical neurofibrillary tangles being much less common. The precise nosological relationship between DLB and AD remains uncertain, as does that between DLB and patients with Parkinson's disease who subsequently develop neuropsychiatric features. Finally, we recommend procedures for the selective sampling and storage of frozen tissue for a variety of neurochemical assays, which together with developments in molecular genetics, should assist future refinements of diagnosis and classification.

Gene expression of the nicotinic acetylcholine receptor alpha 4 subunit in the frontal cortex in Parkinson's disease patients.

Cognitive impairment in Parkinson's disease is accompanied by a marked decrease of cerebrocortical nicotinic receptors. To study the putative site of impaired receptor synthesis, frontal cortices of Parkinson patients with cognitive dysfunction have been screened for the expression of the nicotinic receptor alpha 4 subunit gene. Quantitative assessment of alpha 4 mRNA-expressing neurons did not show significant differences between patients and controls. Therefore, decreased nicotinic receptor sites cannot be attributed to alterations at the transcriptional level of the alpha 4 gene. Alternative causes have to be searched for at the translational and/or postranslational level.

Nigral and extranigral pathology in Parkinson's disease.

This article reviews data on the internal organization, neuronal types, and interconnections of limbic and motor components of the human brain, and the specific lesions which a few of them undergo during the course of Parkinson's disease (neuronal loss associated with the development of Lewy bodies and Lewy neurites). The severe involvement of nigral neuromelanin-laden projection cells has received particular attention during the past decades. This lesion interferes with normal function of the striatum and probably contributes to many of the motor dysfunctions characteristically occurring in Parkinson's disease. The similarly severe involvement of several areas and nuclei outside of the substantia nigra has often escaped notice. However, the pathology of Parkinson's disease cannot be completely described unless changes in these extranigral areas are taken into account. Interpretation of the characteristic lesional pattern is facilitated by combining schemata of both the limbic and motor systems. This approach reveals a key role by the amygdala and related structures in extranigral pathology. Severe lesions occur in the central amygdaloid nucleus, in nuclei projecting to the cerebral cortex in a non-specific manner, and in nuclei regulating endocrine and autonomic functions. It is suggested that extranigral lesions contribute to the development of behavioral changes and autonomic dysfunction.

New aspects of pathology in Parkinson's disease with concomitant incipient Alzheimer's disease.

Alzheimer's disease and Parkinson's disease are the most common age-related degenerative disorders of the human brain. Both diseases involve multiple neuronal systems and are the consequences of cytoskeletal abnormalities which gradually develop in only a small number of neuronal types. In Alzheimer's disease, susceptible neurons produce neurofibrillary tangles and neuropil threads, while in Parkinson's disease, they develop Lewy bodies and Lewy neurites. The specific lesional pattern of both illnesses accrues slowly over time. Presently available data support the view that fully developed Parkinson's disease with concurring incipient Alzheimer's disease is likely to cause impaired cognition.

Neurofibrillary tangles and neuropil threads as a cause of dementia in Parkinson's disease.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common age-related degenerative disorders of the human brain. Both diseases involve multiple neuronal systems and are the consequences of cytoskeletal abnormalities. In AD susceptible neurons produce neurofibrillary changes, while in Parkinson's disease, they develop Lewy bodies. In AD six developmental stages can be distinguished on account of the predictable manner in which the neurofibrillary changes spread across the cerebral cortex. During the course of PD numerous limbic determined parts of the brain undergo specific lesions regulating endocrine and autonomic functions. In general, the extranigral destructions are in themselves not sufficient to produce overt intellectual deterioration. Fully developed Parkinson's disease with concurring incipient Alzheimer's disease is likely to cause impaired cognition.

Pharmacokinetics of apomorphine in Parkinson's disease: plasma and cerebrospinal fluid levels in relation to motor responses.

In this study, we measured the relationship between plasma and cerebrospinal fluid (CSF) apomorphine levels and their clinical effects in two patients with Parkinson's disease (PD). After subcutaneous injection of apomorphine, serial samples of plasma and lumbal CSF were taken and serial scoring of motor responses was done using the Webster Rating Scale. The ratio of the highest level of apomorphine in CSF and plasma was 0.036 for patient A and 0.025 for patient B. The time lag between the highest level of apomorphine in plasma and CSF was 20 min for patient A and 10 min for patient B. Plasma levels of apomorphine correlated weakly with clinical motor responses. However, we could establish a highly strong correlation between apomorphine CSF levels and clinical motor responses: 0.93 and 0.89 for patients A and B, respectively. We conclude that a two-compartment pharmacokinetic model explains the clinical effects of apomorphine better than does a one-compartment model. In a two-compartment model, clinical effect can clearly be correlated to apomorphine levels in the central compartment.

Long-term treatment with high-dosage bromocriptine in advanced Parkinson's disease.

Long-term follow-up indicated that levodopa as a replacement therapy merely improves the parkinsonian symptoms, and does so for only a limited number of years. The reason for this tachyphylaxis or declining efficacy in levodopa therapy and the increasing number and intensity of various distressing difficulties in the management of Parkinson's disease, such as dyskinesias and on-off phenomena, is the main subject of many recent studies. It is still widely accepted that levodopa provides the best therapeutic tool for Parkinson's disease. Bromocriptine, an ergot derivative, is the main clinically used dopamine agonist, and it has been established as a valuable adjunct in the treatment of Parkinson's disease. Bromocriptine is most useful in patients with a declining efficacy of levodopa treatment, in patients with diurnal oscillations in motor performance, especially in patients with wearing-off phenomena, and in patients with onset and end-of-dose dyskinesias. The question of bromocriptine dosage, required to obtain an optimal benefit and a decreased rate of late adverse reactions, is quite controversial. The trend has been to lower daily dosage of bromocriptine, i.e., low doses suffice in patients with mild, early disease. Higher doses of bromocriptine seem to be required in patients with severe parkinsonian deficits. In this retrospective study of 8 years experience with high dosage of bromocriptine in levodopa response-losing parkinsonian patients, the adjunction of bromocriptine had a clear-cut but short-lasting beneficial effect on the disability scores.(ABSTRACT TRUNCATED AT 250 WORDS)

Madopar HBS in nocturnal symptoms of Parkinson's disease.

Madopar Hydrodynamically Balanced System (HBS), a new sustained-release levodopa preparation, was used to control severe nightly disabilities in 15 outpatients suffering from Parkinson's disease in an advanced state and with long-term levodopa therapy. This medication was given ante noctem in addition to an otherwise unchanged daily regimen of levodopa administration. In 13 patients a considerable diminution in nocturnal akinesia and in the frequency of waking up was reached with a mean dosage of 308 mg of Madopar HBS. Early morning akinesia was only slightly alleviated in four patients. The nocturnal off-period pain disappeared in one patient. Adverse effects consisted of nocturnal dyskinesia in two patients and early morning dystonia in another two patients. The regular use of sleeping pills was clearly reduced after Madopar HBS therapy.

Madopar HBS in Parkinson patients with nocturnal akinesia.

Madopar Hydrodynamically Balanced System (HBS), a new sustained-release levodopa preparation, was used to control severe nightly disabilities in 15 outpatients suffering from Parkinson's disease in an advanced state and with long-term levodopa therapy. This medication was given ante noctem in addition to an otherwise unchanged daily regimen of levodopa administration. In 13 patients a considerable diminution in nocturnal akinesia and in the frequency of waking up was reached with a mean dosage of 308 mg of Madopar HBS. Early morning akinesia was only slightly alleviated in four patients. The nocturnal off-period pain disappeared in one patient. Adverse effects consisted of nocturnal dyskinesia in two patients and early morning dystonia in another two patients. The regular use of sleeping pills was clearly reduced after Madopar HBS therapy.

Von Recklinghausen neurofibromatosis (VRNF) and pregnancy. A single case study.

A case of Von Recklinghausen neurofibromatosis (VRNF) with progression during two pregnancies and obstetrical complications is described to illustrate the effect of pregnancy on VRNF and vice versa. The interaction between VRNF and pregnancy is discussed. The obstetrical complications and progression of VRNF lesions during pregnancy necessitate close follow-up of these patients by neurologist and obstetrician.

Ischialgia caused by a malignant Triton tumour of the lumbosacral plexus. A case report.

In this report we present a malignant Triton tumour of the lumbosacral plexus, not associated with Von Recklinghausen's neurofibromatosis.

A double-blind study of the efficacy of apomorphine and its assessment in 'off'-periods in Parkinson's disease.

Five patients with idiopathic Parkinson's disease with severe response fluctuations were selected for a randomized double-blind placebo-controlled study, concerning the clinical effects of subcutaneous apomorphine and its assessment in 'off'-periods. The study was designed as five n = 1 studies, in which every patient was his own control. The effect of apomorphine was studied by using the Columbia rating scale and quantitative assessments, using tapping, walking and pinboard. There was a significant positive effect of apomorphine, in a mean optimal dose of 2.7 mg, with a mean latency of onset of 7.3 min and a mean duration of response of 96 min. After pretreatment with domperidone, no significant adverse effects were observed. Tapping showed the highest correlation with rigidity and bradykinesia. Walking showed a high correlation with stability and gait. Pinboard testing did not give additional information. The first conclusion was that apomorphine proved to be a significantly effective dopamine agonist, proven now also by a double blind placebo-controlled study. Secondly it was concluded that assessment of clinical effect in parkinsonian patients can be performed best by combining the Columbia item tremor with tapping and walking scores.

'Lewy body disease': clinico-pathological correlations in 18 consecutive cases of Parkinson's disease with and without dementia.

One of the characteristic histological features of Parkinson's disease (PD), with or without dementia, is the presence of Lewy bodies (LBs) in the brainstem and neocortical and limbic structures. They are often accompanied by Alzheimer type pathology (ATP). In the present retrospective study the clinical features and post-mortem findings of 18 consecutive and unselected PD patients were compared, with special reference to the frequent but not exclusive association of LBs with ATP in Lewy body disease (LBD). LBD is the term applied to a particular pattern of neuronal degeneration associated with LBs. In this study of idiopathic PD patients ATP seems to be the major determinant of the cognitive decline in most patients. Cortical Lewy Bodies (CLBs) were present in all patients reviewed, whether or not dementia was present. It was not possible to distinguish a specific pattern in the cognitive or psychopathological symptoms of dementia that would differentiate LBD from Alzheimer's disease (AD). Although in most cases hippocampal CA2-3 ubiquitin immunoreactive neurites were observed, here again there was no correlation with the presence of dementia.

Clinical efficacy of Sinemet CR 50/200 versus Sinemet 25/100 in patients with fluctuating Parkinson's disease. An open, and a double-blind, double-dummy, multicenter treatment evaluation. The Dutch Sinemet CR Study Group.

In a multicenter study we selected 84 patients with fluctuating Parkinson's disease in order to evaluate the effects of controlled-release Sinemet 50/200 (=CR) versus standard Sinemet 25/100 (=STD) in an open-label 8-week titration period, followed by a double-blind, double-dummy 24-week treatment period. In contrast with previous double-blind studies, the efficacy of Sinemet CR proved to be significantly superior to that of Sinemet-STD according to NYUPDS and NUDS rating scales. This higher efficacy of Sinemet CR was not achieved at the expense of safety and/or tolerability. Actual total daily levodopa dosage in patients treated with Sinemet CR was increased by 33%; however, the plasma level of this dosage is calculated to be similar to that of the previous dosage of Sinemet-STD (bio-availability of Sinemet CR is 71%). Mean numbers of daily doses, off-hours, and off-periods were decreased significantly during Sinemet CR treatment. Although all other variables suggest that the number of on-hours had to be increased, statistical significance could not be reached in this respect.

[Nasolabial allergic reaction to intranasal administration of apomorphine in Parkinson disease]. / Nasolabiale allergische reactie op intranasale toediening van apomorfine bij de ziekte van Parkinson.

A patient is presented who used apomorphine, a potent dopamine agonist in the treatment of Parkinson patients. He suffered of severe dystonia of the legs, which did not respond to conservative treatment. The apomorphine was delivered bij intranasal spray. The patient developed an allergic reaction with swollen nose and lips, which disappeared within one day after discontinuation of the treatment. Subcutaneous administration caused no symptoms. Cutaneous challenge with apomorphine caused a positive reaction. We raise the hypothesis that the allergic reaction was due to the binding of apomorphine to certain proteins in cutis or nasal mucosa.