Neuro-psychiatric therapy during chronic subthalamic stimulation in Parkinson's disease.

BACKGROUND: Neuro-psychiatric (NP) disturbances are highly prevalent in patients with Parkinson's disease (PD) and contribute to worsen quality of life. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is commonly utilized as surgical treatment for advanced PD with motor complications. The effectiveness of the procedure on motor symptoms is well established whereas the effects of STN-DBS on NP symptoms are less clear. The aim of our study was to analyze the postoperative pharmacological therapy for NP symptoms in a group of STN-DBS treated PD patients. Such therapy provides indirect information about the evolution of underlying NP disturbances during the follow-up in this group of PD patients. METHODS: NP therapy (benzodiazepines, antidepressants, antipsychotics) was assessed in 48 consecutive PD patients treated by STN-DBS, preoperatively and postoperatively after 4 months, 1 year and 3 years. Motor symptoms were evaluated by the Unified PD Rating Scale (UPDRS) and levodopa equivalence daily dose (LEDD) was calculated. Cognitive, mood and anxiety assessments were performed with appropriate rating scales. RESULTS: The number of patients treated with antidepressant drugs gradually increased during the follow-up. The use of antipsychotic drugs was stable until 1 year, with a subsequent increase at 3 years. Benzodiazepines were given to fewer patients immediately after surgery. CONCLUSIONS: Pharmacological treatment supplies further information about NP symptoms in the follow-up of PD patients undergoing STN stimulation.

Antiparkinsonian therapy modifications in PD patients after STN DBS: a retrospective observational analysis.

OBJECTIVE: This study reports a retrospective analysis of 67 consecutive parkinsonian patients to assess changes in antiparkinsonian medications after Deep Brain Stimulation (DBS) of the Subthalamic Nucleus (STN). METHODS: All antiparkinsonian drugs, including levodopa, dopamine agonists, associated drugs such as COMT and MAO inhibitors, amantadine and anticholinergics, were evaluated pre- and post-operatively at 1 and 3 years follow-up. RESULTS: The levodopa mean daily dose was reduced approximately 60% after 1 year and remained stable after 3 years. Apomorphine, bromocriptine, tolcapone, entacapone and selegiline were withdrawn after STN DBS. Three years post-operatively, 9 patients (13.4%) no longer required levodopa and 6 patients (8.9%) completely stopped all dopaminergic medications. More patients were on monotherapy of either levodopa or dopamine agonist and fewer patients required a combined treatment of dopamine agonist and levodopa, compared to the pre-surgical condition. CONCLUSIONS: STN DBS treated PD patients experience a significant long-term reduction and simplification of the pharmacological treatment.

Apathy and verbal fluency in STN-stimulated PD patients. An observational follow-up study.

OBJECTIVE: To evaluate apathy and its relation to verbal fluency tasks in a consecutive series of 19 patients with Parkinson's disease (PD) submitted to deep brain stimulation of the subthalamic nucleus (DBS of STN). METHODS: 19 consecutive PD patients submitted to bilateral DBS of STN were studied for apathy pre-operatively and 17 months after surgery. The PD patients underwent a battery of cognitive tests assessing reasoning, memory and frontal executive functions, including phonemic and categorial fluency tasks. The Beck Depression Inventory (BDI) was used for depression. Apathy was assessed by means of the Apathy Scale (AS). In order to quantify changes among individual patients, the clinical criterion of more or less than 1 SD (standard z-score) was used to register a patient as improved or worsened, respectively. RESULTS: After surgery, apathy scores did not change and mood improved (p < 0.02), while a significant worsening was found in the phonemic fluency (p < 0.001). The percentage of patients with an apathy score above the recommended cut-off value (14) was 42% both before and after DBS of STN. Individual outcomes on the apathy scale (1 SD criterion) evidenced that 53% of the patients remained stable, 16% improved, while 31% worsened. This last percentage reduced to 21% (4/19) when considering only the PD patients with an apathy score > or =14 after surgery. No significant correlation was found between the apathy scores variation and any of the neurological variables considered, and, in particular, no correlation was found between apathy and verbal fluency. CONCLUSIONS: The results of the present study suggest that DBS of STN does not necessarily induce apathy even if individual patients show a moderate post-operative worsening of apathetic symptoms.

Motor and nonmotor symptom follow-up in parkinsonian patients after deep brain stimulation of the subthalamic nucleus.

OBJECTIVE: To evaluate motor and nonmotor symptoms in patients with Parkinson's disease undergoing bilateral deep brain stimulation of the subthalamic nucleus (STN DBS). METHODS: Thirty-six consecutive patients receiving bilateral STN stimulation implants were evaluated preoperatively as well as 12 and 24 months after surgery. Motor symptoms were assessed through the Unified Parkinson's Disease Rating Scale (UPDRS). Data concerning nonmotor symptoms were collected from items of the UPDRS and 2 additional questions from clinical charts regarding constipation and urological dysfunction. RESULTS: STN DBS was effective in controlling motor symptoms; concerning nonmotor symptoms, sleep quality and constipation improved after surgery as compared to baseline. Salivation, swallowing and sensory complaints were ameliorated to a comparable degree by the medication on state, whether preoperatively or postoperatively. With a lower dose of dopaminergic medication, however, the medication on state appeared to be a much larger percentage of the day postoperatively. No significant variations were detected in intellectual impairment, depression, thought disorders, motivation, falling unrelated to freezing, nausea, orthostatic hypotension and urological dysfunction. CONCLUSIONS: STN DBS effectively controls motor symptoms, while nonmotor features of advanced Parkinson's disease patients are mostly unchanged after surgery, even though some specific aspects, notably sleep complaints and constipation, are ameliorated.

Magnetic investigations of human mesencephalic neuromelanin.

Pigmentation of neurons in substantia nigra is due to neuromelanin, a pigment that stores large amounts of iron. Human mesencephalic neuromelanin has been investigated by means of magnetic susceptibility measurements as a function of temperature. Magnetic measurements provide a physico-chemical characterization of the iron cluster buried in the organic melanin matrix and support the view that iron is not simply chelated, but rather is organized in a three-dimensional network. The paramagnetism of isolated iron ions is observed, in agreement with electron paramagnetic resonance spectroscopy. Furthermore, antiferromagnetic grains with a large size distribution function are present. These grains contain N spins coupled antiferromagnetically; however, N(1/2) spins are decoupled from the grain bulk and parallelly aligned. The latter subgrains are superparamagnetic with a blocking temperature ranging between 5 K and room temperature. This behavior has not been observed in synthetic melanin, where the paramagnetic contribution is strongly enhanced. Preliminary results on pigment isolated from patients affected by Parkinson's disease, a neurodegenerative pathology involving primarily pigmented neurons in substantia nigra pars compacta, show a lower total magnetization compared to control neuromelanin. The temperature behavior of zero field cooling and field cooling magnetizations is similar for both. The significant depletion of iron content in Parkinson's disease neuromelanin could indicate a progressive Fe migration from its storage environment to the cytosol.

EPR investigations of the iron domain in neuromelanin.

The interactions between iron and neuromelanin (NM) have been studied by means of EPR spectroscopy. The variable temperature EPR spectral features of a specimen of NM extracted from normal human midbrains clearly indicate that iron is present as polynuclear oxy-hydroxy ferric aggregates as well as isolated Fe(III) centres. Ferric oxy-hydroxy phases are typical of the iron storage proteins ferritin and hemosiderin, but the comparison of the variable temperature EPR spectra of ferritin and NM highlights significant differences between the two iron(III)oxy-hydroxy domains. Moreover, further investigations on melanin models synthesised in the presence of either ferritin or a ferric salt as iron sources suggest that the same pathway of formation and inclusion of the polynuclear iron oxide is operating in NM and in the model systems, whatever is the source of iron.

Q-band EPR investigations of neuromelanin in control and Parkinson's disease patients.

New insights into the understanding of the changes induced in the iron domain of neuromelanin (NM) upon development of Parkinson's disease (PD) have been gained by electron paramagnetic spectroscopy (EPR). The results of this study are compared with a previously reported variable temperature analysis of X-band EPR spectra of a NM specimen obtained from control brain tissues. The availability of high sensitivity instruments operating in the Q-band (34.4 GHz) allows us to deal with the low amounts of NM available from PD brains. The organization of iron in NM is in the form of polynuclear superparamagnetic/antiferromagnetic aggregates, but the lack of one or more signals in the EPR spectra of NM from PD suggests that the development of the pathology causes NM to decrease its ability to bind iron. Furthermore, the detection of the Mn(II) signal in the Q-band spectra is exploited as an additional internal probe to assess minor structural differences in iron domains of PD and control NM specimens.

Restricted dissociated sensory loss in a patient with a lateral medullary syndrome: A clinical-MRI study.

BACKGROUND: Various sensory syndromes in lateral medullary infarctions are described. A small variation in the location of a lesion may lead to very different clinical features, owing to the complex anatomy of the medulla oblongata. MRI may identify the location and extent of the ischemic lesions, allowing a clear clinical-anatomical correlation. CASE DESCRIPTION: We describe a man with an ischemic lesion in the right portion of the lower medulla that presented a contralateral impairment of spinothalamic sensory modalities and an ipsilateral impairment of lemniscal modalities with a restricted distribution (left forearm and hand, right hand and fingers, respectively). The restricted and dissociated sensory abnormalities represent the only permanent neurological consequence of that lesion. CONCLUSIONS: The atypical sensory syndrome may be explained by the involvement of the medial portion of spinothalamic tract and the lateral portion of archiform fibers at the level of the lemniscal decussation.

Higher lipoprotein (a) levels in atherothrombotic than lacunar ischemic cerebrovascular disease.

To investigate the role of plasma lipid abnormalities in ischemic cerebrovascular disease related to primary vessel disease, the authors assess lipid profiles in a hospital-based cohort of 202 consecutive patients with atherothrombotic or lacunar stroke subtypes. Lipoprotein (a) was the unique lipid parameter that differs between these two subtypes being its value twofold higher in patients with atherothrombotic than in lacunar stroke. This suggests that lipoprotein (a) promotes large vessel atheromatosis rather than small vessel arteriolosclerosis and favors thrombosis on atheromatous plaques by suppressing local fibrinolysis.

High-dose intravenous methylprednisolone in the treatment of multiple sclerosis: clinical-immunologic correlations.

We conducted a double-blind trial of high-dose parenteral 6-methylprednisolone (MP) and placebo on 23 patients with acute MS. After the double-blind trial, the patients were given corticosteroids in gradually decreasing doses. The frequency of improvement was significantly higher and the bout duration significantly lower in the MP group than in the placebo group. The first signs of improvement (3 to 6 days after starting MP) were associated with a marked decrease in the rate of CNS IgG synthesis, but IgG CSF oligoclonal bands did not change. CNS IgG production slowly returned toward baseline despite progressive clinical improvement.

Deep brain stimulation of the subthalamic nucleus: clinical effectiveness and safety.

The authors report the data relative to the clinical effectiveness of bilateral deep brain stimulation of the subthalamic nucleus in 16 patients with PD 3 months after the surgery. The comparison of the Unified PD Rating Scale scores in the different conditions of medication and stimulation, and the lack of significant surgical complications, confirm the effectiveness and the safety of the subthalamic nucleus deep brain stimulation for the treatment of advanced PD.

Interferon alpha-2a treatment of relapsing-remitting multiple sclerosis: disease activity resumes after stopping treatment.

We evaluated the long-lasting effects of systemic high-dose recombinant interferon alpha-2a (rIFNA) in relapsing-remitting (RR) MS after discontinuing treatment in a single-blind randomized placebo-controlled trial with 20 RR clinically definite MS patients using either nine million IU intramuscular rIFNA (n = 12) or placebo (n = 8) every other day for 6 months. Follow-up continued for a further 6 months without IFN treatment. In rIFNA-treated patients, main outcome measures, significantly different from placebo during treatment, returned, after discontinuing treatment, to values similar to placebo or baseline. Active MRI lesions per patient increased from 0.08 +/- 0.08 to 1.2 +/- 0.4 (p < 0.02), number of patients with clinical MRI signs of disease activity from 2 of 12 to 8 to 12 (P < 0.04), lymphocyte IFN gamma production from 3.0 +/- 0.7 to 12.4 +/- 2.2 IU/mL (p < 0.01), lymphocyte tumor necrosis factor alpha production from 5.8 +/- 0.9 to 18.9 +/- 6.3 pg/mL (p < 0.05). All side effects of rIFNA treatment disappeared after discontinuing the drug. The reduction of clinical MRI signs of disease activity and the immunologic effects were temporary and restricted to the period of rIFNA administration. The depression of many immunologic and clinical MRI responses during drug administration and their simultaneous return to baseline after discontinuing the drug strongly argue all observed changes were related to drug administration.

Pain threshold and tolerance in Alzheimer's disease.

We tested both pain thresholds and pain tolerance in patients with Alzheimer's disease (AD) by means of phasic and tonic noxious stimuli. In the first case, electrical stimulation was used, whereas in the second case arm ischemia was studied. By comparing AD patients with normal subjects of the same age, we found no differences in stimulus detection and pain thresholds, whereas a clearcut increase in pain tolerance was present in AD patients. The severity of AD was assessed by means of the Mini Mental State Examination test (MMSE) and the spectral analysis of the electroencephalogram (EEG). There was a straightforward correlation between MMSE scores and pain tolerance such that the more severe the cognitive impairment the higher the tolerance to pain. In addition, analysis of the EEG power spectra indicated that patients with low alpha and high delta peaks showed an increase in pain tolerance to both electrical stimulation and ischemia. These findings show that, whereas the sensory-discriminative component of pain is maintained in AD patients, pain tolerance is altered and depends on cognitive and affective factors. Thus, pain tolerance is tightly related to the severity of the disease according to the rule, 'the more severe the MMSE and EEG changes, the higher the tolerance to pain'.

Dose-response relationship of opioids in nociceptive and neuropathic postoperative pain.

The treatment of neuropathic pain with opioid analgesics is a matter of controversy among clinicians and clinician scientists. Although neuropathic pain is usually believed to be only slightly responsive to opioids, several studies show that satisfactory analgesia can be obtained if adequate doses are administered. In the present study, we tested the effectiveness of buprenorphine in 21 patients soon after thoracic surgery (nociceptive postoperative pain) and 1 month after surgery in the same 21 patients who developed postthoracotomy neuropathic pain with a burning, electrical and shooting quality. According to a double-blind randomized study, the analgesic dose (AD) of buprenorphine needed to reduce the long-term neuropathic pain by 50% (AD50) was calculated and compared to the AD50 in the immediate postoperative period. We found that long-term neuropathic pain could be adequately reduced by buprenorphine. However, the AD50 in neuropathic pain was significantly higher relative to the AD50 in the short-term postoperative pain, indicating a lower responsiveness of neuropathic pain to opioids. We also found a strict relationship between the short-term and long-term AD50, characterized by a saturating effect. In fact, if the AD50 soon after surgery was low, the AD50 increase in the long-term neuropathic pain was threefold. By contrast, if the AD50 soon after surgery was high, the AD50 in neuropathic pain was only slightly increased. This suggests that, though neuropathic pain is indeed less sensitive to opioids, in some neuropathic patients a large amount of opioid resistance is already present in other painful conditions.

[3H]N-methylscopolamine binding to muscarinic receptors in human peripheral blood lymphocytes: characterization, localization on T-lymphocyte subsets and age-dependent changes.

The properties of the binding of the muscarinic receptor ligands, [3H]quinuclidinyl benzilate ([3H]QNB) and [3H]N-methylscopolamine ([3H]NMS) in human mononuclear cells were compared. The binding of [3H]QNB showed a high, non-specific component and lack of saturability in both intact mononuclear cells and preparations of lysed mononuclear cell membranes. Conversely the specific binding of [3H]NMS had a high affinity and was saturable at concentrations greater than 30 nM in both intact and broken cells. Classical muscarinic receptor antagonists displaced specific binding of [3H]NMS binding according to the law of mass action, while displacement curves for pirenzepine and muscarinic agonists were very shallow (nH less than 1), suggesting the presence of more than one subtype of muscarinic receptor on mononuclear cell membranes. Binding studies with [3H]NMS to purified mononuclear cell subpopulations demonstrated that muscarinic binding sites were mainly localized on thymus-derived (T) lymphocytes and large granule lymphocytes. Moreover evidence is presented of an age-dependent increase of the density of muscarinic binding sites on T-lymphocytes. The results are discussed in terms of the usefulness of the binding of [3H]NMS in studying the physiological function of muscarinic receptors on human T-lymphocytes and their possible changes in patients with neurological diseases.

Peripheral-type benzodiazepine receptors on human blood mononuclear cells are not regulated by ovarian steroids.

Peripheral-type benzodiazepine receptors (pBZr) have been shown to be sensitive to hormonal perturbations, including changes in ovarian steroids. This study examines whether estradiol and progesterone modulate pBZr binding in membranes of human blood mononuclear cells, as measured by binding of both 3H-PK 11195 and 3H-Ro 5-4864. Our findings were negative. There was no steroidal modulation of pBZr binding to these membrane preparations in vivo in normal women studied at different sex-steroid phases of the menstrual cycle, or during 8-30 weeks of pregnancy. There was also no effect of hormones on the binding sites in cultures of mononuclear cells treated with estradiol or progesterone (up to 10(-5) M) over a period between 2 and 72 h. Further, we performed in vitro competition experiments, which showed that both steroids are not active at the pBZr. Our data suggest that pBZr located in human blood mononuclear cells are insensitive to the physiological variations of circulating female hormones.

Neurophysiologic assessment of nerve impairment in posterolateral and muscle-sparing thoracotomy.

OBJECTIVE: This study was aimed at analyzing the degree of intercostal nerve impairment in posterolateral and muscle-sparing thoracotomy and at correlating the nerve damage to the severity of long-lasting postthoracotomy pain. METHODS: Neurophysiologic recordings were performed 1 month after either posterolateral or muscle-sparing thoracotomy to assess the presence of the superficial abdominal reflexes (mediated in part by the intercostal nerves), the somatosensory-evoked responses after electrical stimulation of the surgical scar, and the electrical thresholds for tactile and pain sensations of the surgical incision. RESULTS: The patients who underwent a posterolateral thoracotomy showed a higher degree of intercostal nerve impairment than the muscle-sparing thoracotomy patients as revealed by the disappearance of the abdominal reflexes, a larger reduction in amplitude of the somatosensory-evoked potentials, and a larger increase of the sensory thresholds to electrical stimulation for both tactile perception and pain. In addition, these neurophysiologic parameters were highly correlated to the postthoracotomy pain experienced by the patients 1 month after surgery, indicating a causal role for nerve impairment in the long-lasting postoperative pain. CONCLUSIONS: This study shows for the first time the pathophysiologic differences between posterolateral and muscle-sparing thoracotomy and suggests that the minor long-lasting postthoracotomy pain in muscle-sparing thoracotomy patients is partly due to a minor nerve damage. In addition, because nerve impairment is responsible for the long-lasting neuropathic component of postoperative pain, it is necessary to match specific treatments to the neuropathic pain-generating mechanisms.

Nuclear magnetic relaxation dispersion profiles of substantia nigra pars compacta in Parkinson's disease patients are consistent with protein aggregation.

Nuclear Magnetic Relaxation field-cycling relaxometry is a technique, able to report on water mobility in tissues. By means of this technique, post-mortem specimens from both controls and idiopathic Parkinson's disease patients have been investigated. Results show different relaxometric behavior between the groups, which is consistent with protein aggregation in Parkinson's disease specimens.

Autonomic responses and pain perception in Alzheimer's disease.

We analysed the effects of electrical noxious stimulation on the autonomic nervous system of Alzheimer's disease (AD) patients who were assessed by means of the Mini Mental State Examination test (MMSE). To do this, we used electrical stimuli at two different intensities: just above pain threshold and twice pain threshold. We recorded heart rate and systolic blood pressure by using conventional electrocardiography and finger photo-plethysmography. When a pain stimulus just above threshold was delivered, AD patients were found to have blunted autonomic responses compared to controls of the same age. Similarly, prestimulus expectation produced a less pronounced increase of the responses in AD patients compared to the controls. However, when the painful stimulus was increased to twice the pain threshold, the systolic blood pressure increase of AD patients did not differ from the controls, whereas heart rate increase was still slightly diminished. By contrast, pain perception was similar in the two groups when the stimulus was at pain threshold, whereas it was blunted in AD patients when the stimulus was twice the pain threshold. These findings show that in AD mild noxious stimulation produces blunted autonomic responses and normal pain perception, whereas strong noxious stimulation produces quasi-normal autonomic responses and blunted pain perception. These results indicate that AD patients have an increased threshold for both autonomic activation and pain tolerance.

Amineptine in the management of the depressive syndromes.

The antidepressant activity of amineptine was evaluated in 34 patients in a double-blind study vs clomipramine. Clinical results, assessed using the Hamilton rating scale for depression, failed to show any significant difference in the activity of the two drugs. Amineptine was however much better tolerated than clomipramine. The antidepressant activity of amineptine was further investigated in an open multicenter study carried out in 351 depressed patients. The significant reductions in the scores of the Hamilton rating scale for depression and the final clinical evaluations (87% favorable results, 69% of which excellent or good) confirmed the therapeutic efficacy of amineptine. Tolerance was excellent also in elderly, at risk patients.