Clinical features and surgical outcome of clinical and subclinical pituitary apoplexy

The clinical features of pituitary hemorrhage vary from asymptomatic to catastrophic. Clinical symptomatic pituitary apoplexy is a well-described syndrome characterized by sudden headaches, visual impairment, hypopituitarism and, at times, impaired consciousness. Subclinical pituitary apoplexy is characterized by minimal atypical clinical manifestations and, as a result, may be misdiagnosed or inappropriately treated. The purpose of the study was to evaluate the clinical manifestations, surgical outcome and post-operative pituitary function in patients who had clinical or subclinical pituitary apoplexy. We retrospectively identified 65 patients (30 men, 35 women; age range 21–87 years, mean age 48.4 years) who underwent transsphenoidal surgery. Of these, 25 patients were diagnosed as having clinical apoplexy, while the remaining 40 patients were classified as having subclinical pituitary apoplexy. The follow-up period ranged from 21 to 73 months (mean 44 months). Vision improved in 14 of 22 patients with clinical apoplexy (64%) and in 26 of 28 patients with subclinical apoplexy (93%) (p = 0.017); the total resection rate was 57% and 42%, respectively (p = 0.285). After 2 years of follow-up, hormone replacement therapy was needed in only 26% and 36% of patients, respectively (p = 0.149). Our findings suggest that the incidence of subclinical pituitary apoplexy is higher than that of clinical pituitary apoplexy. Both the tumor resection rate and mean age were higher in those with clinical pituitary apoplexy, while those who had subclinical pituitary apoplexy demonstrated better visual improvement. During long-term follow-up, the need for hormonal replacement decreased in both groups.     

Giant necrotic pituitary apoplexy

Apoplexy of the pituitary gland is a rare complication of pituitary adenomas, involving hemorrhage with or without necrosis within the tumor. This condition may be either asymptomatic or may present with severe headache, visual impairment, ophthalmoplegia, and pituitary failure. Transsphenoidal surgery is the treatment of choice, and early intervention is usually required to ensure reversal of visual impairment. Reports of pituitary apoplectic lesions exceeding 60.0 mm in diameter are very rare. A 39-year-old man with long-standing history of nasal congestion, decreased libido and infertility presented with a sudden onset of severe headache and diplopia. MRI of the head demonstrated a massive skull base lesion of 70.0 × 60.0 × 25.0 mm, compatible with a giant pituitary macroadenoma. The lesion failed to enhance after administration of a contrast agent, suggesting complete necrotic apoplexy. Urgent surgical decompression was performed, and the lesion was resected via a transnasal transsphenoidal approach. Pathological analysis revealed evidence of necrotic pituitary apoplexy. At the 2 month follow-up, the patient had near-complete to complete resolution of his visual impairment. To the authors’ knowledge, this report is unique as the patient demonstrated complete necrotic apoplexy and it underlines the diagnostic dilemma in such a case.     

Intrasellar dermoid cyst mimicking pituitary apoplexy: A case report and review of the literature

Intrasellar dermoid cysts are extremely unusual lesions, with only four cases reported to date, and have not been previously reported in association with sudden-onset symptoms. Here, we present the case of an intrasellar dermoid cyst with sudden-onset symptoms mimicking pituitary apoplexy in an elderly woman. A 69 year-old woman presented with sudden onset of headache, dizziness, and decreased visual acuity. Magnetic resonance imaging of the sellar region showed an intrasellar lesion, which showed mixed hyper- and hypointense signal on T1-weighted and T2-weighted images and enhanced peripherally. Endocrine workup showed pituitary hormones within normal levels. According to these findings, the initial diagnosis of nonsecreting pituitary macroadenoma apoplexy was made. Intraoperatively, a large amount of whitish-yellow purulent material was found in the mass and the lesion was partially removed, owing to tight adhesion between remanent mass and surrounding neurovascular structures. Pathology showed a dermoid cyst with abundant neutrophil infiltrations.     

Age,drugs, or disease: What alters the macrostructure of sleep in Parkinson’s disease?

ObjectiveTo describe the alterations in the macrostructure of sleep in a large cohort of sleep-disturbed patients with Parkinson’s disease (PD) and investigate influencing factors.MethodsA cohort of sleep-disturbed but otherwise unselected PD patients (n = 351) was investigated with video-supported polysomnography. We analyzed the influence of age, disease duration, disease severity, and dopaminergic medication on subjective sleep perception, sleep efficiency, the amount of slow wave sleep, awakenings, periodic leg movements in sleep (PLMS), and REM sleep behavior disorder (RBD).ResultsSleep efficiency and slow wave sleep decreased with age (p = 0.003 and p = 0.041, respectively). The number of awakenings and the frequency of RBD increased with age (p = 0.028 and p = 0.006, respectively). Higher Hoehn & Yahr stages were associated with more PLMS (p = 0.017). A higher daily dose of levodopa corresponded to more RBD (p < 0.001). Neither disease duration nor levodopa dosage had any influence on sleep efficiency, slow wave sleep, awakenings, or PLMS. Dopamine agonists increased awakenings (p < 0.001) and lowered PLMS (p < 0.001). Subjective sleep perception was not influenced by any of the factors analyzed. The only path model that could be replicated identified disease severity and dopamine agonists as interdependent factors influencing awakenings and PLMS.ConclusionAge leads to less sleep and a higher risk for RBD, and disease severity increases motor phenomena such as PLMS; dopamine agonists reduce PLMS but increase awakenings. No single factor analyzed influenced subjective sleep perception in this cohort of sleep disturbed PD patients.     

Fractionated stereotactic radiosurgery using the Novalis system for the management of pituitary adenomas close to the optic apparatus

Radiosurgery has been proven to be an effective treatment for residual or recurrent pituitary adenomas after surgery. However, it causes severe complications when the optic apparatus is irradiated over the tolerance dose. In this study, we analyzed the feasibility of fractionated stereotactic radiosurgery to treat pituitary tumors close to the optic apparatus. Thirty-four patients from June 2006 to June 2011 with recurrent or residual pituitary adenomas close to (<3 mm) the optic apparatus were treated with fractionated stereotactic radiosurgery. Three fractions with a total dose of 2100 cGy were applied to the tumors. Imaging, examination of vision, and estimation of hormone level were regularly performed before and after radiosurgery. The mean tumor volume before fractioned stereotactic radiosurgery was 5.06 ± 3.08 cm³ (range: 0.82–12.69 cm³). After a mean follow up of 36.8 ± 15.7 months (range: 16–72 months), tumor size was reduced in seven (20.6%) patients and remained the same in the other 27 (79.4%) patients. Vision was improved in one patient and remained stable in the rest. Only one patient developed transient post-treatment diplopia. This study suggests that fractionated stereotactic radiosurgery is safe for treating pituitary adenomas close to the optic apparatus. Studies with more patients and longer follow-up are required to draw definite conclusions.     

Efficacy and safety of dopamine agonists in restless legs syndrome

ObjectiveRestless legs syndrome (RLS) is a common neurological disorder causing considerable impairment to daily living. This article is an overview of a comprehensive Cochrane meta-analysis on the efficacy and safety of dopamine agonists (DAs), the first-line treatment of RLS.MethodsCENTRAL, MEDLINE, EMBASE, PsycINFO, and CINAHL databases were searched for double-blind randomized controlled trials (RCTs) of DAs vs placebo.ResultsThirty-five placebo-controlled RCTs (total number of patients = 6954) were eligible. The likelihood of bias was considered to be low. The mean treatment duration of the RCTs was 10.3 (standard deviation 7.3) weeks, with treatment durations up to seven months. Overall, DAs showed a moderate improvement in the International RLS Severity Scale score (mean difference ?5.7 points [95% confidence interval, CI, ?6.7 to ?4.7; P < 0.00001]) and the Clinical Global Impression-Improvement response (risk ratio 1.44 [95% CI 1.34–1.54; P < 0.00001]) compared with placebo. Periodic limb movements decreased by ?22.38/h (95% CI ?27.8 to ?16.9; P < 0.00001) for DAs compared with placebo. Sleep quality and disease-specific quality of life increased slightly to moderately. Safety data confirmed the established safety characteristics of DAs. Augmentation, a specific side-effect of dopaminergic treatment of RLS, was not assessed adequately.ConclusionsThis meta-analysis showed that DAs have moderate efficacy in the treatment of RLS. Actively controlled and long-term studies are still lacking. Large-scale comparative studies are needed to identify the most efficient treatments for this chronic disorder.     

The melatonin analog 5-MCA-NAT increases endogenous dopamine levels by binding NRH:quinone reductase enzyme in the developing chick retina

NRH:quinone reductase (QR2) is present in the retinas of embryonic and post-hatched (PH) chicks. 5-Methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) is a QR2 ligand that increases cAMP levels in developing retinas, but it does not affect cAMP levels in CHO-QR2 cells. The dopamine quinone reductase activity of QR2 retrieves dopamine, which increases cAMP levels in developing retinas. The objective of the present study was to investigate whether 5-MCA-NAT increases endogenous dopamine levels in retinas from chick embryos and post-hatched chicks. Endogenous dopamine was measured by enzyme-linked immunosorbent assay (ELISA). 5-MCA-NAT increased retinal endogenous dopamine levels at all developmental stages studied and in PH chicks (−log EC50 = 11.62 ± 0.34 M). This effect was inhibited by non-selective antagonists of receptors and melatonin binding sites N-acetyl-2-benzyltryptamine (luzindole, 5 μM), but it was not inhibited by the Mel1b melatonin receptor antagonist 4-phenyl-2-propionamidotetralin (4-P-PDOT, 10 nM). The QR2 cosubstrate, N-methyl-dihydronicotinamide (NMH) (−log EC50 = 6.74 ± 0.26 M), increased endogenous dopamine levels in controls and in retinas stimulated with 5-MCA-NAT (3 nM). The QR2 inhibitor benzo[e]pyrene inhibited endogenous dopamine levels in both control (−log IC50 = 7.4 ± 0.28 M) and NMH-stimulated (at 100 nM and 1 μM benzo[e]pyrene concentrations) retinas. Theoretical studies using Molegro Virtual Docking software corroborated these experimental results. We conclude that 5-MCA-NAT increases the level of endogenous dopamine via QR2. We suggest that this enzyme triggers double reduction of the dopamine quinone, recovering dopamine in retinal development.     

The effect of atypical antipsychotics on pituitary gland volume in patients with first-episode psychosis: A longitudinal MRI study

BackgroundPituitary volume is currently measured as a marker of hypothalamic-pituitary-adrenal hyperactivity in patients with psychosis despite suggestions of susceptibility to antipsychotics. Qualifying and quantifying the effect of atypical antipsychotics on the volume of the pituitary gland will determine whether this measure is valid as a future estimate of HPA-axis activation in psychotic populations.AimsTo determine the qualitative and quantitative effect of atypical antipsychotic medications on pituitary gland volume in a first-episode psychosis population.MethodPituitary volume was measured from T1-weighted magnetic resonance images in a group of 43 first-episode psychosis patients, the majority of whom were neuroleptic-naïve, at baseline and after 3 months of treatment, to determine whether change in pituitary volume was correlated with cumulative dose of atypical antipsychotic medication.ResultsThere was no significant baseline difference in pituitary volume between subjects and controls, or between neuroleptic-naïve and neuroleptic-treated subjects. Over the follow-up period there was a negative correlation between percentage change in pituitary volume and cumulative 3-month dose of atypical antipsychotic (r = ? 0.37), i.e. volume increases were associated with lower doses and volume decreases with higher doses.ConclusionsAtypical antipsychotic medications may reduce pituitary gland volume in a dose-dependent manner suggesting that atypical antipsychotic medication may support affected individuals to cope with stress associated with emerging psychotic disorders.     

Ascorbic acid efficiently enhances neuronal synthesis of norepinephrine from dopamine

Ascorbic acid enhances synthesis of norepinephrine from dopamine in adrenal chromaffin cells by serving as a co-factor for chromaffin granule dopamine β-hydroxylase (DβH). However, there is controversy regarding in situ kinetics of the ascorbate effect in chromaffin cells, as well as whether they apply to neuronal cells. In this study we evaluated the stimulation of norepinephrine synthesis from dopamine in cultured SH-SY5Y neuroblastoma cells. These cells contained neither ascorbate nor norepinephrine in culture, but when provided with dopamine, they generated intracellular norepinephrine at rates that were stimulated several-fold by intracellular ascorbate. Ascorbate-induced increases in norepinephrine synthesis in dopamine-treated cells were linear over 60 min, despite saturation of intracellular ascorbate. Norepinephrine accumulation after 60 min of incubation with 100 μM dopamine was half-maximal at intracellular ascorbate concentrations of 0.2–0.5 mM, which fits well with the literature K_m for ascorbate of DβH using dopamine as a substrate. Moreover, these ascorbate concentrations were generated by initial extracellular ascorbate concentrations of less than 25 μM due to concentrative accumulation by the ascorbate transporter. Treatment with 100 μM dopamine acutely increased cellular superoxide generation, which was prevented by ascorbate loading, but associated with a decrease in intracellular ascorbate when the latter was present at concentrations under 1 mM. These results show that ascorbate promptly enhances norepinephrine synthesis from dopamine by neuronal cells that it does so at physiologic intracellular concentrations in accord with the kinetics of DβH, and that it both protects cells from superoxide and by providing electrons to DβH.     

Clinical features,management and recurrence of symptomatic Rathke’s cleft cyst

Rathke’s cleft cyst (RCC) is a rare lesion of the pituitary gland that is often asymptomatic. The objective of this study was to further characterise the presenting symptoms, endocrinopathy and potential for recurrence of this lesion in an Australian population. The files of 12 patients with pathologically confirmed RCCs were reviewed retrospectively. Common presentations included headache, endocrinopathy, and visual disturbance. Uncommon presentations included 1 patient with pituitary apoplexy. The cysts varied in size from 6 mm to 20 mm; 8 had a suprasellar component. 1 patient had evidence of a RCC with xanthogranulomatous change. RCC recurrence was noted on follow-up MRI in 5 patients. In conclusion, RCCs are rare lesions that can present with an array of clinical symptoms. The relatively high rate of recurrence may indicate a link between this pathology and craniopharyngioma, although many patients with recurrent RCC do not require repeat resection and remain asymptomatic.     

Dopamine elevates intracellular zinc concentration in cultured rat embryonic cortical neurons through the cAMP-nitric oxide signaling cascade

Zinc ion (Zn^2 +), the second most abundant transition metal after iron in the body, is essential for neuronal activity and also induces toxicity if the concentration is abnormally high. Our previous results show that exposure of cultured cortical neurons to dopamine elevates intracellular Zn^2 + concentrations ([Zn^2 +]_i) and induces autophagosome formation but the mechanism is not clear. In this study, we characterized the signaling pathway responsible for the dopamine-induced elevation of [Zn^2 +]_i and the effect of [Zn^2 +]_i in modulating the autophagy in cultured rat embryonic cortical neurons. N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), a membrane-permeable Zn^2 + chelator, could rescue the cell death and suppress the autophagosome puncta number induced by dopamine. Dopamine treatment increased the lipidation level of the endogenous microtubule-associated protein 1A/1B-light chain 3 (LC3 II), an autophagosome marker. TPEN added 1 h before, but not after, dopamine treatment suppressed the dopamine-induced elevation of LC3 II level. Inhibitors of the dopamine D1-like receptor, protein kinase A (PKA), and NOS suppressed the dopamine-induced elevation of [Zn^2 +]_i. PKA activators and NO generators directly increased [Zn^2 +]_i in cultured neurons. Through cell fractionation, proteins with m.w. values between 5 and 10 kD were found to release Zn^2 + following NO stimulation. In addition, TPEN pretreatment and an inhibitor against PKA could suppress the LC3 II level increased by NO and dopamine, respectively. Therefore, our results demonstrate that dopamine-induced elevation of [Zn^2 +]_i is mediated by the D1-like receptor-PKA-NO pathway and is important in modulating the cell death and autophagy.     

Visual acuity and pattern of visual field loss at presentation in pituitary adenoma

Our purpose was to analyse the demographics, prevalence and pattern of visual field defects in patients with pituitary adenoma. We prospectively recruited 103 consecutive patients (206 eyes) presenting to a neurosurgical unit with pituitary adenoma. Ophthalmological examination and standard automated perimetry (Humphrey, 24-2 threshold) was performed. Severity of visual field defects was also assessed. The mean population age was 53.9 years (standard deviation = 15). Visual loss was the most common reason for presentation (39%) followed by endocrine abnormality (21%) and headache (15%). Patients with endocrine abnormality on presentation were 10.9 years younger than those presenting with visual loss (p = 0.001). Bitemporal defects were the most prevalent pattern (n = 22, 41%) followed by homonymous defects (n = 7, 13%). Of the patients with visual field loss, 33% had unilateral visual field defects. The mean visual acuity in those with bitemporal defects was 6/7.5 with half of these patients having 6/6 vision in both eyes. In conclusion, the majority of patients with pituitary adenoma have visual acuity better than 6/7.5 despite having visual field defects. While a bitemporal pattern of visual field loss is the most common, a significant proportion of patients had unilateral and altitudinal defects. Assessment of the visual field is essential to rule out chiasmal compression.     

Lymphocytic hypophysitis in males

Lymphocytic hypophysitis (LH) is a rare inflammatory disorder of the pituitary gland that typically affects women in the peripartum period. We describe two male patients (ages 43 years and 36 years), who presented with headaches, visual disturbance and hypopituitarism. MRI revealed a heterogeneous pituitary lesion that extended into the suprasellar region and with a thickened pituitary stalk. In both patients a histopathological diagnosis of LH was made after endoscopic transsphenoidal surgery. LH in males, although rare, should be considered as a differential diagnosis in those with hypopituitarism and a heterogeneous pituitary fossa mass, extending into pituitary stalk.     

Endoscopic endonasal approach to pituitary adenomas: Impact on adenohypophyseal function. Study of 231 cases

PurposeTo identify presurgical and surgical factors associated with the development of hypopituitarism and its recovery after endoscopic endonasal transsphenoidal (EET) resection of pituitary adenomas (PAs).MethodsRetrospective study of patients with PAs operated by the same neurosurgeon through an EET approach in two Spanish tertiary hospitals in ten years.Results242 pituitary surgeries performed in 231 patients were analyzed. In the 154 surgeries performed in 146 patients with non-functioning PAs (NFPAs), 46.8% (n = 72) presented presurgical hypopituitarism. After PAs resection, 41 of these (56.9%) normalized pituitary function and 11 of 82 patients with preoperative normal function (13.4%) developed new pituitary deficits. Patients with preoperative visual impairment (OR = 3.9, p = 0.046) and operated in the first four years of the neurosurgeon's learning curve (OR = 5.7, p = 0.016) presented a higher risk of developing postoperative hypopituitarism.Of the 88 surgeries in 85 patients with functioning PAs (FPAs), 23.9% presented presurgical hypopituitarism, and 47.6% of those recovered after surgery. 9% of the cases with preoperative normal function developed new pituitary deficit/s. Diabetic patients presented a higher risk of persistence of hypopituitarism (OR = 10.5, p = 0.024). Patients with presurgical visual impairment (OR = 30.0, p = 0.010) and PAs >3 cm (OR = 14.0, p = 0.027) had higher risk of developing new pituitary deficits.ConclusionApproximately 50% of patients with PAs and preoperative hypopituitarism recover pituitary function after EET surgery. 10% of patients with normal function develop new deficits. Patients with NFPAs with visual involvement and operated in the first four years of neurosurgeon's learning curve, and FPAs patients with presurgical visual impairment and tumor size >3 cm have a higher risk of postoperative hypopituitarism.     

Long-term use of pramipexole in the management of restless legs syndrome

ObjectiveFew studies have examined the long-term use of dopamine agonists for restless legs syndrome (RLS). We report a cohort study of 50 patients initially prescribed pramipexole between 1998 and 2002. The objective was to determine duration of treatment, long-term efficacy, development of side effects and augmentation over an extended period.MethodsWe performed a long-term analysis on a previously reported group of patients initially followed for a mean of 27.2 months. Data were collected using retrospective chart reviews, written surveys and systematic telephone interviews.ResultsPramipexole was used for a mean of 8 years (range 0.6–12 years). Nine (18%) discontinued pramipexole because of poor efficacy (four), impulse control disorders (ICD) (two), augmentation (one) and resolved symptoms (two). Pramipexole was reported completely effective in 40% (compared to 67% at the end of the initial study), partially effective in 58% and ineffective in 2%. The median daily dose increased from 0.38 mg after initial stabilization to 1.0 mg at the end of the study. As many as 74% of patients experienced side effects. A total of 56% reported daytime sleepiness including 10% reporting sleep attacks while driving and 10% developed ICDs. Augmentation developed in 42% of patients, after a mean of 16.5 months, and no later than 4.1 years after commencing treatment. A total of 28% needed additional non-dopaminergic medications.ConclusionThe efficacy of pramipexole dropped with time, with increase in dose and addition of other agents, although the majority of patients remained on the drug. Problems included the development of augmentation within the first 4 years of therapy and side effects such as sleepiness increasing with time and the development of ICDs. The study highlights the need for further research into alternative non-dopaminergic treatments for RLS.     

Pituitary dysfunction after aneurysmal subarachnoid hemorrhage in Japanese patients

To elucidate the pituitary function of Japanese patients after aneurysmal subarachnoid hemorrhage (aSAH) and implicative factors related to growth hormone deficiency (GHD) after aSAH. We evaluated basal pituitary hormone levels among 59 consecutive aSAH patients with a modified Rankin Scale (mRS) ⩽4 at 3 months after aSAH onset. Patients with low insulin-like growth factor 1 (IGF-1) SD score (SDS) or who seemed to develop pituitary dysfunction underwent provocative endocrine testing during a period of 3–36 months after SAH onset. The relationship between IGF-1 SDS and clinical factors of the patients such as severity of SAH, aneurysm location, and treatment modalities, were assessed. Six patients (10.2%) demonstrated their IGF-1 SDS less than −2. Multiple logistic regression analyses revealed that patients who underwent surgical clipping had a significantly lower IGF-1 SDS (<−1 SD) than patients who underwent endovascular embolization with an odds ratio of 5.83 (p = 0.032). Thirty-three patients took provocative tests and five (15.6%) patients were identified as having GHD. The mean IGF-1 SDS of these five GHD patients was 0.08 SD. The aneurysms in all GHD patients were located in internal carotid artery (ICA) or anterior cerebral artery (ACA). To the best of our knowledge, this is the first report describing the prevalence of GHD in Japanese patients after aSAH, and it was not as high as that of previous European studies. We recommend that screening pituitary dysfunction for aSAH survivors with their aneurysms located in ICA or ACA.     

A2A receptor antagonists do not induce dyskinesias in drug-naive or l-dopa sensitized rats

l-Dopa, the precursor to dopamine, is currently the gold standard treatment for Parkinson's disease (PD). However, chronic exposure is associated with l-dopa-induced dyskinesias (LIDs), a serious side effect characterized by involuntary movements. Adenosine A_2A receptor antagonists have been studied as a novel non-dopaminergic PD treatment. Because A_2A receptor antagonists do not act on dopamine receptors, it has been hypothesized that they will not induce dyskinesias characteristic of l-dopa. To test this hypothesis in a rodent model, the A_2A receptor antagonists SCH 412348 (3 mg/kg), vipadenant (10 mg/kg), caffeine (30 mg/kg), or istradefylline (3 mg/kg) were chronically (19–22 days) administered to Sprague Dawley rats, and dyskinetic behaviors were scored across this chronic dosing paradigm. Unlike l-dopa, there was no evidence of dyskinetic activity resulting from any of the four A_2A receptor antagonists tested. When delivered to animals previously sensitized with l-dopa (6 mg/kg), SCH 412348, vipadenant, caffeine or istradefylline treatment produced no dyskinesias. When administered in combination with l-dopa (6 mg/kg), SCH 412348 (3 mg/kg) neither exacerbated nor prevented the induction of LIDs over the course of 19 days of treatment. Collectively, our data indicate that A_2A receptor antagonists are likely to have a reduced dyskinetic liability relative to l-dopa but do not block dyskinesias when coadministered with l-dopa. Clinical studies are required to fully understand the dyskinesia profiles of A_2A receptor antagonists.     

Low nigrostriatal reserve for motor parkinsonism in nonhuman primates

ObjectiveNigrostriatal reserve refers to the threshold of neuronal injury to dopaminergic cell bodies and their terminal fields required to produce parkinsonian motor deficits. Inferential studies have estimated striatal dopamine reserve to be at least 70%. Knowledge of this threshold is critical for planning interventions to prevent symptom onset or reverse nigrostriatal injury sufficient to restore function in people with Parkinson disease. In this study, we determine the nigrostriatal reserve in a non-human primate model that mimics the motor manifestations of Parkinson disease.MethodsFifteen macaque monkeys received unilateral randomized doses of the selective dopaminergic neuronal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We compared blinded validated ratings of parkinsonism to in vitro measures of striatal dopamine and unbiased stereologic counts of nigral neurons after tyrosine hydroxylase immunostaining.ResultsThe percent of residual cell counts in lesioned nigra correlated linearly with the parkinsonism score at 2 months (r = ? 0.87, p < 0.0001). The parkinsonism score at 2 months correlated linearly with the percent residual striatal dopamine (r = ? 0.77, p = 0.016) followed by a flooring effect once nigral cell loss exceeded 50%. A reduction of about 14 to 23% of nigral neuron counts or 14% to 37% of striatal dopamine was sufficient to induce mild parkinsonism.ConclusionsThe nigral cell body and terminal field injury needed to produce parkinsonian motor manifestations may be much less than previously thought.     

One year open-label safety and efficacy trial with rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome

BackgroundLong-term efficacy and tolerability data are not yet available for patch formulations of dopamine agonists in restless legs syndrome.MethodsEfficacy and safety of rotigotine (0.5–4 mg/24 h), formulated as a once-daily transdermal system (patch), were investigated in an open extension (SP710) of a preceding 6-week placebo-controlled trial (SP709, 341 randomized patients) in patients with idiopathic restless legs syndrome. For efficacy assessment the international RLS severity scale (IRLS), the RLS-6 scales, the clinical global impressions (CGI) and the QoL-RLS questionnaire were administered. In addition, long-term tolerability and safety were assessed.ResultsOf 310 patients who finished the controlled trial, 295 (mean age 58 ± 10 years, 66% females) with a mean IRLS score of 27.8 ± 5.9 at baseline of SP709 were included. We report results after one year of this ongoing long-term trial. Two hundred twenty patients (retention rate = 74.6%) completed the 12-month follow-up period. The mean daily dose was 2.8 ± 1.2 mg/24 h with 4 mg/24 h (40.6%) being the most frequently applied dose; 14.8% were sufficiently treated with 0.5 or 1.0 mg/24 h. The IRLS total score improved by −17.4 ± 9.9 points between baseline and end of Year 1 (p < 0.001). The other measures of severity, sleep satisfaction and quality of life supported the efficacy of rotigotine (p < 0.001 for pre-post-comparisons of all efficacy variables). The tolerability was described as “good” or “very good” by 80.3% of all patients. The most common adverse events were application site reactions (40.0%), which led to withdrawal in 13.2%. Further relatively frequent adverse events were nausea (9.5%) and fatigue (6.4%). Two drug-related serious adverse events, nausea and syncope, required hospitalization. Symptoms of augmentation were not reported by the patients.ConclusionRotigotine provided a stable, clinically relevant improvement in all efficacy measures throughout one year of maintenance therapy. The transdermal patch was safe and generally well tolerated by the majority of patients. Comparable to any transdermal therapy, application site reactions were the main treatment complication.     

Single low doses of MPTP decrease tyrosine hydroxylase expression in the absence of overt neuron loss

Parkinson's disease (PD) is the second most common age-related neurodegenerative disease. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a prototypical neurotoxicant used in mice to mimic primary features of PD pathology including striatal dopamine depletion and dopamine neuron loss in the substantia nigra pars compacta (SNc). In the literature, there are several experimental paradigms involving multiple doses of MPTP that are used to elicit dopamine neuron loss. However, a recent study reported that a single low dose caused significant loss of dopamine neurons. Here, we determined the effect of a single intraperitoneal injection of one of three doses of MPTP (0.1, 2 and 20 mg/kg) on dopamine neurons, labeled by tyrosine hydroxylase (TH⁺), and total neuron number (Nissl⁺) in the SNc using unbiased stereological counting. Data reveal a significant loss of neurons in the SNc (TH⁺ and Nissl⁺) only in the group treated with 20 mg/kg MPTP. Groups treated with lower dose of MPTP (0.1 and 2 mg/kg) only showed significant loss of TH⁺ neurons rather than TH⁺ and Nissl⁺ neurons. Striatal dopamine levels were decreased in the groups treated with 2 and 20 mg/kg MPTP and striatal terminal markers including, TH and the dopamine transporter (DAT), were only decreased in the groups treated with 20 mg/kg MPTP. These data demonstrate that lower doses of MPTP likely result in loss of TH expression rather than actual dopamine neuron loss in the SN. This finding reinforces the need to measure both total neuron number along with TH⁺ cells in determining dopamine neuron loss.