Cortical thickness in de novo patients with Parkinson disease and mild cognitive impairment with consideration of clinical phenotype and motor laterality.

BACKGROUND AND PURPOSE: Parkinson's disease (PD) is a progressive neurodegenerative disorder with motor and non-motor symptoms, including cognitive deficits. Several magnetic resonance imaging approaches have been applied to investigate brain atrophy in PD. The aim of this study was to detect early structural cortical and subcortical changes in de novo PD whilst distinguishing cognitive status, clinical phenotype and motor laterality. METHODS: Eighteen de novo PD with mild cognitive impairment (PD-MCI), 18 de novo PD without MCI (PD-NC) and 18 healthy control subjects were evaluated. In the PD-MCI group, nine were tremor dominant and nine were postural instability gait disorder (PIGD) phenotype; 11 had right-sided symptom dominance and seven had left-sided symptom dominance. FreeSurfer was used to measure cortical thickness/folding, subcortical structures and to study group differences as well as the association with clinical and neuropsychological data. RESULTS: Parkinson's disease with MCI showed regional thinning in the right frontal, right middle temporal areas and left insula compared to PD-NC. A reduction of the volume of the left and right thalamus and left hippocampus was found in PD-MCI compared to PD-NC. PD-MCI PIGD showed regional thinning in the right inferior parietal area compared to healthy controls. A decreased volume of the left thalamus was reported in PD-MCI with right-sided symptom dominance compared to PD-NC and PD-MCI with left-sided symptom dominance. CONCLUSIONS: When MCI was present, PD patients showed a fronto-temporo-parietal pattern of cortical thinning. This cortical pattern does not appear to be influenced by motor laterality, although one-sided symptom dominance may contribute to volumetric reduction of specific subcortical structures.

'INDOTEST' in atypical hemicrania continua.

Hemicrania continua (HC) is an indomethacin-responsive headache characterized by a chronic, strictly unilateral, side-locked without side-shifting, persistent headache. We report three cases of HC with atypical features in which an acute administration of indomethacin 50 mg IM (INDOTEST) was performed. In all three cases INDOTEST predicted chronic responsiveness to indomethacin. Thus, in cases of HC with atypical features, INDOTEST could help for a correct diagnosis and therapy.

A case of sarcoidosis presenting as a non-specific intramedullary lesion.

Neurosarcoidosis occurs in 5-15% of sarcoidosis cases. Approximately 50% of patients with neurosarcoidosis present with a neurological disease at the time sarcoidosis is first diagnosed. Spinal sarcoidosis is rare. We report the case of a 61-year-old man with a highly aspecific intramedullary lesion as the first manifestation of sarcoidosis. One year after the onset of neurological symptoms, the high levels of angiotensin-converting enzyme and the results of a total body gallium scan and bronchoalveolar lavage supported the diagnosis of sarcoidosis. Isolated single reports indicate that spinal neurosarcoidosis may be the initial manifestation of sarcoidosis. In our case, magnetic resonance imaging of the dorsal spine showed a largely aspecific lesion. Neurosarcoidosis should be considered in the differential diagnosis of intramedullary cord lesion with leptomeningeal enhancement; a systematic search for evidence of sarcoidosis should be mandatory in all cases for a correct diagnosis and early treatment.

Oxidative damage and cytogenetic analysis in leukocytes of Parkinson's disease patients.

BACKGROUND: Postmortem studies suggest excessive free radical toxicity in the substantia nigra of patients with PD. Increased lipid peroxidation and oxidative DNA damage have been reported in the CNS. Markers of oxidative stress have been identified in the blood of patients with PD. OBJECTIVE: To assess the presence of spontaneous chromosome and primary or oxidative DNA damage in peripheral blood leukocytes of patients with untreated PD. METHODS: Patients with de novo PD (20) and control subjects (16), matched for age, sex, and smoking habits, underwent cytogenetic analysis using the human lymphocyte micronucleus assay coupled with the fluorescence in situ hybridization technique and the Comet assay. RESULTS: Compared with controls, patients with PD showed an increase in the incidence of spontaneous micronuclei (p < 0.001); single strand breaks (p < 0.001); and oxidized purine bases (p < 0.05). Fluorescence in situ hybridization analysis showed micronuclei harboring acentric fragments. CONCLUSIONS: There is chromosomal, primary DNA damage and oxidative DNA damage demonstrable in lymphocytes of patients with untreated PD.

Cabergoline improves motor disability without modifying L-dopa plasma levels in fluctuating Parkinson's disease patients.

Studies on the influence of some dopamine agonists, particularly bromocriptine, on the pharmacokinetics of L-dopa have furnished contrasting results. Thus, any possible pharmacokinetic interaction should be taken into consideration when adding a new dopamine agonist to L-dopa treatment. In 12 Parkinson's disease (PD) patients with motor fluctuations, cabergoline was added in an 8-week study to their usual L-dopa/carbidopa therapy. Cabergoline was administered once a day at increasing doses of 0.5, 1, 2, and 3mg/day for a period of one week per dose, and 4mg/day for three weeks. Motor performance was assessed weekly evaluating the motor examination of the Unified Parkinson's Disease Rating Scale (UPDRS) and the patients' diaries of daily on-off time. Blood levels of both L-dopa and 3-O-methyldopa (3-OMD) were assayed by HPLC in two different days, over an 8-hour period, before initiating cabergoline and at the end of the study. The results of this study confirm that cabergoline is effective in the management of PD motor fluctuations without modifying L-dopa and 3-OMD pharmacokinetics.

Mexiletine in the treatment of torticollis and generalized dystonia.

Mexiletine is an antiarrhythmic drug that has been reported to exert antidystonic properties. We performed an open-label study to collect further evidence of the antidystonic effect of mexiletine in spasmodic torticollis (ST) and to evaluate its possible use in generalized dystonia. We administered mexiletine to six patients with dystonia (three with generalized dystonia and three with ST) who had failed to respond to previous pharmacotherapy. The drug was started at a dose of 200 mg/d by mouth and increased up to a maximum dose of 800 mg/d. Patients were evaluated at regular intervals over a 6-week period with use of the Fahn & Marsden Dystonia Scale and the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and videotaped. At the end of the trial, the videotapes were reviewed and scored by a blind observer. Patients were then followed for at least 1 year and evaluated every 3 months at the dose reached during the study period. No adverse effects were reported in five patients; in one patient, dizziness developed at the dosage of 800 mg/d, requiring a reduction of the dose. At the end of a 6-week period, a significant improvement in the rating scale for dystonia and in videotape ratings was observed after mexiletine treatment (p < 0.01). Our data indicate that mexiletine is a useful drug in dystonia treatment.

Diurnal motor variations to repeated doses of levodopa in Parkinson's disease.

Patients with Parkinson's disease (PD) in long-term levodopa therapy often complain of worsening of motor symptoms in the afternoon and evening. The pathophysiology of this phenomenon is not known. We evaluated the motor response to repeated doses of levodopa during a 12-hour period in 52 parkinsonian patients (19 de novo, 20 stable, and 13 wearing-off). On the day of the study, all patients received standard doses of levodopa/carbidopa at 8:00 a.m., 12:00 noon, and 4:00 p.m. Motor measurements such as tapping test, walking time, and tremor score, and blood samples for levodopa and 3-O-methyldopa (3OMD) plasma analysis, were performed hourly. Mean motor scores and pharmacokinetic data, evaluated for a period of 3 hours after each levodopa dose, were compared. In de novo patients, we did not observe diurnal changes in motor score, whereas a progressive daytime worsening was visible in stable and wearing-off patients. No significant difference in levodopa pharmacokinetics after each levodopa dose was observed within each patient group, whereas 3OMD plasma levels significant increased with repeated levodopa administrations. However, no significant correlation between motor scores and 3OMD plasma levels was observed, suggesting that the diminishing motor response to afternoon and evening doses of levodopa in patients in long-term levodopa therapy does not relate to the pharmacokinetics of the drug. It is possible that this phenomenon may be an expression of the occurrence of tolerance to repeated doses of levodopa.

Prevalence of headache syndromes in panic disorder.

We investigated the prevalence of headache in a group of patients attending a psychiatric clinic because suffering from panic disorder, according to DSM-IV criteria. The psychopathological assessment was performed with the 'Panic Disorder/Agoraphobia Questionnaire' and the presence of headache was evaluated according to the criteria of the International Headache Society. The results showed that two-thirds of patients met the criteria for a diagnosis of headache, with migraine without aura being the most frequent form, followed by tension headache, while two patients only were affected by migraine with aura. When we compared panic patients with and without headache, those with headache had a longer duration of panic disorder, a higher number of attacks and a heavier family loading for panic disorder and headache. This suggests that the comorbidity of headache with panic disorder renders this condition more severe and possibly responsive to different treatments compared to panic disorder alone.

Late whiplash syndrome: a clinical and magnetic resonance imaging study.

Cervical hyperextension injuries are common and are associated with significant morbidity. Clinically two syndromes are described: "acute" whiplash syndrome and "late" whiplash syndrome (in which the patients are still symptomatic after six months despite normal physical and radiological examination). In order to clarify the pathology of the persistent pain in late whiplash syndrome we performed a cervical spine magnetic resonance imaging (MRI) in 33 consecutive patients suffering from this condition. Twenty-six patients (78.8%) showed MRI abnormalities, the most common MRI finding (57.6%) was pre-existent spondylosis. Indeed, the group of patients with spondylosis and other MRI changes had higher clinical scores than those without MRI abnormalities as measured by a three-point grading system based upon the symptoms and signs shown. Several MRI changes, most of them already demonstrable by standard X-ray were seen among 33 patients suffering from late whiplash syndrome. Although no one of these findings appears to be specific and certainly related to the previous neck injury, they could represent a risk factor for a longer pain duration.

A whole-brain analysis in de novo Parkinson disease.

BACKGROUND AND PURPOSE: Widespread cerebral changes are observed in advanced stages of Parkinson disease (PD), suggesting that PD is a multisystem disorder. We investigated with MR imaging whether global brain changes are present in early clinical stages of PD and correlated the findings with the type of clinical presentation. MATERIALS AND METHODS: T1-weighted images and mean diffusivity and fractional anisotropy (FA) maps calculated from diffusion tensor imaging (DTI) were obtained in 27 patients with de novo drug-naïve PD, who were classified according to the clinical features in tremor-dominant type (n = 13), akinetic-rigid type (n = 11), and mixed type (n = 3). Sixteen healthy subjects provided control data. With SIENAX software, total brain, gray matter (GM), and white matter (WM) volumes were computed from T1-weighted images, whereas brain histograms were obtained from mean diffusivity and FA maps. RESULTS: Total brain, GM and WM volumes were not significantly different in patients as a whole or subgroups and controls. As compared with controls, patients with PD as a whole and patients with the akinetic-rigid type showed an increase (P

White matter MRI hyperintensities in a hundred and twenty-nine consecutive migraine patients.

The most frequently reported abnormal MRI finding in migraine is the presence of high signal white matter foci (WMF) on long TR images. Recently, WMF have been distinguished in periventricular WMF (PVF), when contiguous to ventricles, and deep WMF (DF), when far from these. DF, but not PVF, appear positively correlated with cerebrovascular risk factors and are called leukoaraiosis. In this study the MRI examination was performed in 129 consecutive migraine patients (83 of them had migraine without aura and 46 migraine with aura). In 19.3% of the migraineurs studied we observed WMF on T2 weighted images strictly localized in the deep white matter (DF). No PVF were observed. These findings were independent of the type of migraine and did not correlate with age, sex, disease duration, or frequency of attacks. The presence in a subgroup of migraineurs of leukoaraiosis (DF), for which a vascular genesis has been hypothesized, suggests that migraine could represent, a cerebrovascular risk factor in these patients.

Long-term follow-up after flunarizine or nimodipine discontinuation in migraine patients.

Various open and controlled studies have confirmed the antimigraine action of flunarizine, while the antimigraine properties of nimodipine are still open to controversy. Moreover, only a few studies include an additional follow-up after discontinuation of migraine prophylaxis with either drug. We carried out a single blind evaluation of the efficacy and tolerance of flunarizine (25 patients) in comparison with nimodipine (25 patients) and the long-term effect after discontinuation of a 6-month treatment. Both medications significantly reduced migraine frequently and severity. Flunarizine was more efficacious than nimodipine in reducing migraine frequency (p < 0.001), pain severity (p < 0.05), migraine index (p < 0.05) and corrected migraine index (p < 0.05). The positive effect lasted 8.4 +/- 4.0 months after discontinuation of flunarizine and 4.9 +/- 3.5 months after nimodipine (p < 0.05). Our results suggest that flunarizine is more effective than nimodipine in the prophylactic treatment of migraine. The positive effect after drug discontinuation lasts longer with flunarizine, compared to nimodipine.

Amitriptyline and dexamethasone combined treatment in drug-induced headache.

Frequent or regular intake of antimigraine drugs, including analgesics, constitutes a common cause of chronic daily headache. Discontinuation of symptomatic medication can produce an increase in head pain accompanied by withdrawal symptoms. We report the favourable outcome of treating a group of outpatients with the combination of amitriptyline, dexamethasone and sumatriptan. Dexamethasone (4 mg/day) was given intramuscularly for 2 weeks, amitriptyline orally at night (50 mg/day) for at least 6 months, and sumatriptan subcutaneously to treat acute headache attacks. Eighteen out of 20 patients abstained from drug abuse. Eleven of these 18 patients showed a marked reduction in headache frequency (at least 75% in relation to the basal value), and were considered "very good responders". The other seven patients experienced at least 50% reduction in headache frequency compared to baseline. This preliminary report suggests that drug-induced headache can be treated effectively in outpatients using dexamethasone, amitriptyline and sumatriptan in combination with significant benefit in everyday life conditions.

Acute and chronic effects of clozapine in essential tremor.

Patients with essential tremor (ET) may not respond to commonly used drugs. Clozapine, an atypical neuroleptic drug, has been reported to improve postural Parkinson's disease tremor clinically resembling ET. The effects of a single dose of 12.5 mg clozapine and placebo were evaluated in a randomized, double-blind, crossover study in 15 drug-resistant patients with ET. Patient responders with more than 50% improvement after a single dose of clozapine subsequently received the drug (39+/-9 mg up to 50 mg) unblinded for a period of 15.8+/-7.7 months. Tremor was effectively reduced by a single dose of clozapine in 13 of 15 patients (p <0.01). Sedation was the only side effect reported during the clozapine test; however, the time course of sedation and of the antitremor effect were not coincident. A significant reduction of tremor was reported with chronic clozapine treatment (p <0.01) with no tolerance to drug antitremor effect, whereas sedation markedly decreased after 6-7 weeks of therapy. No clozapine-induced hematologic side effects were observed in our cohort of patients during long-term treatment. Our results suggest that in selected drug-resistant ET cases, clozapine should be considered before resorting to neurosurgical options.

Flunarizine in migraine prophylaxis: predictive factors for a positive response.

The efficacy of flunarizine in migraine prophylaxis is confirmed in both open and controlled trials. However, it is unknown what factors may influence a good response to prophylaxis with flunarizine. The aim of this study was to determine the possible predictive factors for therapeutic responsiveness to 3 months' treatment with flunarizine. One-hundred headache patients treated with flunarizine were evaluated. We considered "responders" those patients who recorded a reduction in migraine frequency of 75% after treatment. Statistical analysis revealed four factors which might influence therapeutic responsiveness in our patients. Positive factors were a family history (p<0.01) and high intensity of pain (p<0.01); negative factors were frequent attacks (p<0.01) and a history of analgesic abuse (p<0.001). Patients with no previous history of analgesic abuse, low frequency of attacks at baseline, higher levels of migraine pain, and positive family history constitute the prototype of flunarizine long-term treatment responders.

Clinical outcome and magnetic resonance imaging of carbon monoxide intoxication. A long-term follow-up study.

The clinical and neuroradiological outcome of carbon monoxide (CO) intoxication was evaluated prospectively in 30 patients over a follow-up period of 3 years. Among the patients studied, 22 had been acutely exposed to CO while 8 were chronically exposed. One month after CO poisoning, 12 of the 22 patients with acute intoxication showed magnetic resonance imaging (MRI) abnormalities: 6 also had neurological sequelae and 6 were asymptomatic. The remaining 10 patients showed neither MRI abnormalities nor neurological sequelae. During the 3-year follow-up, 4 of the patients with both MRI abnormalities and neurological sequelae improved in both clinical features and MRI findings. One of the 6 asymptomatic patients with MRI abnormalities developed a progressive cognitive impairment 2 months after acute intoxication, with a concomitant severe worsening of the MRI lesions. Among the 10 patients with neither MRI abnormalities nor neurological sequelae, only 1 developed neurological sequelae after a clear period of 4 months. In the group of patients who experienced chronic CO intoxication, only 1 presented with a neuropsychiatric syndrome which improved at follow-up. Brain MRI showed white matter lesions which remained unchanged at control scan after 1 year. In conclusion, we observed that some patients with severe CO poisoning and neurological sequelae may fully regain normal functions after approximately 1 year. The presence of MRI lesions 1 month after CO poisoning did not accurately predict the subsequent outcome. The observation of a clear period longer than the usual 2-40 day interval in 2 patients should be considered for careful planning of follow-up and for prognosis in CO-poisoned patients.

Proton magnetic resonance spectroscopy (1H-MRS) of motor cortex and basal ganglia in de novo Parkinson's disease patients.

Proton MR spectroscopy (1H-MRS) has been previously performed in Parkinson's disease (PD) and parkinsonian syndromes to evaluate in vivo concentrations of basal ganglia and cerebral cortex metabolites such as N-acetylaspartate (NAA), choline (Cho), and creatine (Cr). However, this technique has never been used to evaluate motor cortex in untreated PD patients. In this study, single-voxel 1H-MRS of basal ganglia and motor cortex was carried out in 10 de novo patients with PD and 10 age-matched healthy controls. A significant reduction in the NAA/Cr ratio was observed in the motor cortex of PD patients compared with controls (p)<(0.01). Basal ganglia spectra did not allow any evaluation due to the presence of artefacts related to inorganic paramagnetic substances. The motor cortex reduction of the NAA/Cr ratio in de novo PD patients may reflect an altered neuronal functioning due to a loss of thalamocortical excitatory inputs and may represent an in vivo marker for the diagnosis of PD.

Cytogenetic analysis oxidative damage in lymphocytes of Parkinson's disease patients.

Several lines of evidence support the presence of DNA damage in somatic cells of Parkinson's disease (PD) patients due to the formation of free radical species. In order to detect spontaneous chromosome and primary or oxidative DNA damage, we performed the human lymphocyte micronucleus assay (HLMNA) and comet assay in 19 PD patients and 16 healthy controls. Compared with controls, PD patients showed a significant increase in: (I) spontaneous micronucleus (MN) frequency (p<0.001); (2) single strand break (SSB) levels (p<0.001); and (3) oxidized purine base levels (p<0.05). The chromosome damage and the increased levels of oxidized purine bases observed in our patients support the hypothesis of oxidative stress as a relevant factor in the pathogenesis of PD.