Olfaction in Parkin single and compound heterozygotes in a cohort of young onset Parkinson's disease patients.

BACKGROUND: Parkin related Parkinson's disease (PD) is differentiated from idiopathic PD by absent or sparse Lewy bodies, and preserved olfaction. The significance of single Parkin mutations in the pathogenesis of PD is debated. OBJECTIVES: To assess olfaction results according to Parkin mutation status. To compare the prevalence of Parkin single heterozygous mutations in patients diagnosed with PD to the rate in healthy controls in order to establish whether these single mutations could be a risk factor for developing PD. METHODS: Parkin gene mutation testing was performed in young onset PD (diagnosed <50 years old) to identify three groups: Parkin homozygous or compound heterozygote mutation carriers, Parkin single heterozygote mutation carriers, and non-carriers of Parkin mutations. Olfaction was tested using the 40-item British version of the University of Pennsylvania smell identification test (UPSIT). RESULTS: Of 344 young onset PD cases tested, 8 (2.3%) were Parkin compound heterozygotes and 13 (3.8%) were Parkin single heterozygotes. Olfaction results were available in 282 cases (eight compound heterozygotes, nine single heterozygotes, and 265 non-carriers). In Parkin compound heterozygotes, the median UPSIT score was 33, interquartile range (IQR) 28.5-36.5, which was significantly better than in single Parkin heterozygotes (median 19, IQR 18-28) and non-carriers (median score 22, IQR 16-28) (ANOVA P < 0.001). These differences persisted after adjusting for age, disease duration, gender, and smoking (P < 0.001). There was no significant difference in UPSIT scores between single heterozygotes and non-carriers (P = 0.90). CONCLUSIONS: Patients with Parkin compound heterozygous mutations have relatively preserved olfaction compared to Parkin single heterozygotes and non-carriers. The prevalence of Parkin single heterozygosity is similar to the 3.7% rate reported in healthy controls.

Baseline [(123) I]FP-CIT SPECT (DaTSCAN) severity correlates with medication use at 3 years in Parkinson's disease.

BACKGROUND: Presynaptic dopaminergic deficiency on dopamine transporter imaging supports a clinical diagnosis of Parkinson's disease and correlates with the severity of rigidity and bradykinesia. Baseline dopaminergic deficiency predicts clinical severity, but the relationship with subsequent medication use has not been reported. METHODS: A randomly selected cross section of 83 Parkinson's disease (PD) patients who had [(123) I] FP-CIT SPECT at the time of clinical diagnosis was identified. Dopaminergic deficiency was graded 1, 2 or 3 with increasing severity using visual assessment and by semiquantitative analysis of putamen and caudate uptake. Antiparkinson medication usage and clinical severity by Hoehn and Yahr were noted annually to 3 years. RESULTS: In 83 patients (66% male, median age 65.0 years, IQ 55.4-71.8), [(123) I]FP-CIT SPECT was grade 1 in 20 (24%), grade 2 in 53 (64%) and grade 3 in 10 patients (12%). Dopamine transporter uptake ratios were inversely associated with antiparkinson medication usage (r = -0.26, P = 0.0201) and Hoehn Yahr stage (r = -0.32, P = 0.0029) at 3 years from baseline, but there was considerable variation in drug usage in individual patients. At 3 years, patients with grade 1 scans at baseline received a median dose of 325 levodopa equivalent units (LEU) (interquartile range 175-433); grade 2 scan patients 400 LEU (interquartile range 300-635); and grade 3 scan patients 460 LEU (interquartile range 252-658). CONCLUSION: The degree of reduction in presynaptic dopaminergic uptake at baseline is associated with higher antiparkinson drug dosage at follow-up, but the wide variation means that the baseline FP-CIT SPECT does not reliably predict drug use in individual cases.

Alpha-synuclein in peripheral tissues and body fluids as a biomarker for Parkinson's disease - a systematic review.

Parkinson's disease (PD) is neuropathologically characterized as an alpha-synucleinopathy. Alpha-synuclein-containing inclusions are stained as Lewy bodies and Lewy neurites in the brain, which are the pathological hallmark of PD. However, alpha-synuclein-containing inclusions in PD are not restricted to the central nervous system, but are also found in peripheral tissues. Alpha-synuclein levels can also be measured in body fluids. The aim of this study was to conduct a systematic review of available evidence to determine the utility of alpha-synuclein as a peripheral biomarker of PD. We searched PubMed (1948 to 26 May 2013), Embase (1974 to 26 May 2013), the Cochrane Library (up to 26 May 2013), LILACS (up to 26 May 2013) and CINAHL (up to 26 May 2013) for the studies of alpha-synuclein in peripheral tissues or body fluids in PD. A total of 49 studies fulfilled the search criteria. Peripheral tissues such as colonic mucosa showed a sensitivity of 42-90% and a specificity of 100%; submandibular salivary glands showed sensitivity and specificity of 100%; skin biopsy showed 19% sensitivity and 80% specificity in detecting alpha-synuclein pathology. CSF alpha-synuclein had 71-94% sensitivity and 25-53% specificity for distinguishing PD from controls. Plasma alpha-synuclein had 48-53% sensitivity and 69-85% specificity. Neither plasma nor CSF alpha-synuclein is presently a reliable marker of PD. This differs from alpha-synuclein in solid tissue samples of the enteric and autonomic nervous system, which offer some potential as a surrogate marker of brain synucleinopathy.

Phase IIa randomized double-blind, placebo-controlled study of inhaled apomorphine as acute challenge for rescuing 'off' periods in patients with established Parkinson's disease.

BACKGROUND AND PURPOSE: In this first study of inhaled apomorphine (VR040) in patients with Parkinson's disease, the primary objective was to find the minimum efficacious dose of apomorphine that was useful in rescuing patients during 'off' periods. Safety, tolerability and pharmacokinetics of inhaled apomorphine were assessed during the study. METHODS: A double-blind, placebo-controlled, randomized trial of three escalating single doses of inhaled apomorphine (0.2, 0.5 and 0.8 mg fine particle dose) versus placebo (3 : 1 active:placebo) was performed. Parkinson's motor severity assessments by a clinician, and disease state assessment by the patient, were performed at baseline during an 'off' state, and at specified times after test drug administration. Safety assessments (including vital signs, electrocardiogram and forced expiratory volume) were performed, and plasma apomorphine levels measured. RESULTS: All 24 patients completed the study, and considering the three dose levels together, inhaled apomorphine did not significantly increase the proportion of patients switching from 'off' to 'on' (0/6 at 0.2 mg, 3/6 at 0.5 mg and 2/6 at 0.8 mg vs. 1/6 for placebo), or decrease the time from 'off' to 'on' post-treatment (10 min for 0.5 mg, 40 min for 0.8 mg, vs. 20 min for placebo). However, there was a suggestion of benefit at the higher doses (5/12 switched 'on' at the 0.5 or 0.8 mg doses, vs. 1/6 for placebo). There were no serious adverse events and treatment was well tolerated. Peak plasma concentration was 1-3 min post-dose, and plasma level dose proportionality was observed. CONCLUSIONS: Inhaled apomorphine was safe and well tolerated at the doses tested for an acute challenge to rescue 'off' periods, but efficacy at these doses was limited. A follow-up study at higher doses is appropriate given these initial findings.

Inhaled dry powder apomorphine (VR040) for 'off ' periods in Parkinson's disease: an in-clinic double-blind dose ranging study.

BACKGROUND: 'Off' periods increase as Parkinson's disease (PD) progresses and the benefits of standard therapy wane. Subcutaneous apomorphine rescues 'off' periods, but patient self-injection and adverse cutaneous effects are sometimes problematic. METHODS: We assessed safety, tolerability and efficacy of inhaled dry powder apomorphine (VR040) in a double-blind clinic-based Phase II study. Of 48 patients recruited at nine sites, 47 were randomized 2:1 inhaled apomorphine/placebo. Respirable doses (drug predicted to reach the lung), ascending through 1.5, 2.3, 3.0 and 4.0 mg until efficacy was achieved, were administered to patients in a practically defined 'off' state. The primary endpoint was the response in unified PD rating scale Part 3 (UPDRS 3), at the highest dose received by the patient. Secondary endpoints included time to 'on', the proportion of patients converting from 'off' to 'on', and duration of 'on'. RESULTS: In the 47 intent-to-treat patients with PD, mean age 60.6 years, the mean UPDRS 3 improvement was significantly greater for VR040 at 26.8 points (standard deviation 12.0), vs 14.9 (16.3) for placebo (treatment difference 11.6, 95% confidence interval 2.3-20.9, P = 0.016). Rapid apomorphine absorption (2-7 min) translated to rapid (mean 10 min) reversal from the 'off' state. Adverse effects did not differ between VR040 and placebo; no patient discontinued due to an adverse event; one serious adverse event (constipation) in the VR040 group was considered unrelated to trial medication. CONCLUSIONS: Inhaled apomorphine shows significant promise as a replacement for intermittent subcutaneous injections; further studies are appropriate to optimize efficacy and tolerability.

Duration of L-dopa and dopamine agonist monotherapy in Parkinson's disease.

The expected duration of initial antiparkinson monotherapy before the need for supplementation is not clearly defined for routine practice. The aim of this study was to define the length of L-dopa (L-3, 4-dihydrophenylalanine) and dopamine agonist monotherapy. The duration of monotherapy and discontinuation rates were investigated in a natural observational setting by plotting Kaplan-Meier survival curves. Out of 345 patients, 180 (52.2%) received L-dopa and 165 (47.8%) received a dopamine agonist as initial monotherapy. Half of the patients starting L-dopa received supplementary therapy with- in 3.6 years (95% confidence interval, 3.2-4.6), significantly longer than for dopamine agonist monotherapy (half required a second agent at 2.3 years [2.0-2.9]; P = 0.00017). Discontinuation of L-dopa therapy was 1%. Dopamine agonists were stopped (due to side-effects like impulse control disorders [6%], somnolence [4%] and light-headedness [3%]) in 20% over four years. The duration and tolerability of L-dopa and dopamine agonists as initial Parkinson's disease monotherapy are defined in this study; this may form part of the information exchange with patients.

Olfaction in patients with suspected parkinsonism and scans without evidence of dopaminergic deficit (SWEDDs).

BACKGROUND: Positron emission tomography and single photon emission computed tomography scanning have 87-94% sensitivity and 80-100% specificity to differentiate patients with Parkinson's disease (PD) from control subjects and patients with essential (ET) or atypical tremor. More than 10% of patients diagnosed as early PD can have scans without evidence of dopaminergic deficiency (SWEDDs). This study investigated whether smell tests can help identify possible cases with SWEDDs. METHODS: The 40 item University of Pennsylvania Smell Test (UPSIT) was used to evaluate the sense of smell in 21 SWEDDs patients. Twenty-six ET patients, 16 patients with a diagnosis of idiopathic adult onset dystonia (D), 191 non-demented PD patients and 136 control subjects were also tested. Multiple regression analyses were used to compare the mean UPSIT score in the SWEDDs group with the other four groups (ET, D, PD and controls) after adjusting for the effects of relevant covariates. RESULTS: The mean UPSIT score for the SWEDDs group was greater than in the PD group (p<0.001) and not different from the mean UPSIT in the control (p = 0.7), ET (p = 0.4) or D (p = 0.9) groups. Smell tests indicated a high probability of PD in only 23.8% of SWEDDs as opposed to 85.3% of PD patients. CONCLUSIONS: In a patient with suspected PD, a high PD probability on smell testing favours the diagnosis of PD, and a low PD probability strengthens the indication for dopamine transporter imaging.

Possible modulation of concurrent Parkinson's disease in the management of metastatic GIST: a review of two cases.

Imatinib, a tyrosine kinase inhibitor, is the mainstay of treatment for resected high-risk (adjuvant and metastatic) gastrointestinal stromal tumour (GIST) - a rare form of sarcoma. There has been recent research into the neuroprotective role and modulation of dopaminergic neurones by imatinib through the abl pathway in Parkinson's disease (PD). We describe two patients from a single cancer centre with concurrent diagnoses of PD and metastatic GIST receiving imatinib and standard PD management. The cases highlight a potential reduction in PD progression using Unified Parkinson's Disease Rating Scale. Further research into repurposing of imatinib for PD may provide additional management options for this neurodegenerative illness.

Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease.

A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis.

Tolerability of the low-affinity, use-dependent NMDA antagonist AR-R15896AR in stroke patients: a dose-ranging study.

BACKGROUND AND PURPOSE: AR-R15896AR is a use-dependent, low-affinity blocker of the NMDA ion channel with neuroprotective effects in animal models of focal cerebral ischemia. This study aimed to establish the highest safe and tolerated loading and maintenance dosing regimen of AR-R15896AR in acute ischemic stroke patients and to determine the associated plasma concentrations of AR-R15896AR. METHODS: This was a 4-part, multicenter, randomized, double-blind, placebo-controlled study in 175 patients (mean age, 69 years) within 24 hours of acute stroke symptom recognition. Ascending 60-minute intravenous infusion loading doses of AR-R15896AR were initially examined (100, 150, 200, 250, or 300 mg or placebo in 3:1 randomization, n=36 treated); in part 2, 250, 275, or 300 mg was compared with placebo (n=33). In part 3, a 250-mg loading dose was followed by 9 maintenance doses of 60, 75, 90, 105, or 120 mg every 8 hours versus placebo in 3:1 randomization (n=59); subsequently, in part 4, maintenance doses of 90, 105, and 120 mg after the 250-mg loading dose were directly randomized against placebo (n=42). Safety, tolerability, and pharmacokinetics were the primary end points; NIHSS at 1 week and Barthel and modified Rankin scores at 1 month were also recorded, but the study was neither designed nor powered to assess efficacy. RESULTS: Rates for mortality and serious adverse events (SAE) were similar in active and placebo groups (9% mortality and 23% SAE for all active combined versus 11% mortality and 33% SAE for placebo). Adverse events associated with AR-R15896AR were dizziness, vomiting, nausea, stupor, and some agitation/hallucination. Withdrawal from treatment occurred only in response to loading doses with AR-R15896AR: placebo, 3 of 46 (7%); 250 mg, 11 of 89 (12%); 275 mg, 1 of 8 (12.5%); and 300 mg, 3 of 15 (20%). No significant difference in outcome was observed between groups. Plasma concentrations of AR-R15896AR were 1524+/-536 ng/mL at the end of the 250-mg loading infusion and were 1847+/-478 ng/mL at steady state after the 9 maintenance doses of 120 mg. CONCLUSIONS: The maximum tolerated loading infusion of AR-R15896AR in this study was 250 mg over a period of 1 hour. Subsequent maintenance infusions of 120 mg every 8 hours were well tolerated. With these doses, putative neuroprotective concentrations of 1240 ng/mL are attained by the loading dose and are satisfactorily maintained thereafter. The loading dose may be improved further by adjustment on an individual patient basis, but tolerability issues remain.

Clinical pharmacology of CNS 1102 in volunteers.

The high affinity noncompetitive N-methyl-D-aspartate receptor antagonist CNS 1102 (aptiganel hydrochloride, Cambridge NeuroScience, Cambridge, MA.) is neuroprotective in preclinical models of stroke when administered as pretreatment or up to 60 minutes postischemia, and has potential for treatment of acute stroke or traumatic brain injury in man. A total of 55 healthy male subjects have participated in three separate studies to determine the clinical pharmacology of CNS 1102, 43 of whom have received CNS 1102 in doses of up to 100 micrograms/kg. Administration of CNS 1102 has been studied as a 15-minute intravenous infusion, as a 15-minute loading intravenous infusion followed by a 4-hour maintenance infusion, or as a fixed-dose intravenous bolus over 90 seconds. CNS 1102 in normal volunteers is well tolerated in total doses up to 32 micrograms/kg whether as a bolus injection, 15-minute infusion or 4-hour infusion. Central nervous system affects are evident within minutes of administration, implying rapid drug penetration. CNS 1102 has a large and variable volume of distribution (mean +/- standard deviation, 6.2 +/- 1.9 l/kg), variable clearance (115 +/- 77 l/h), and plasma half-life of approximately 4.5 hours. Adjustment of doses by subject weight does not improve variability of these parameters, and fixed doses may thus be administered. CNS 1102 causes dose-dependent elevation of blood pressure, accompanied by clinical evidence of vasoconstriction. Global cerebral blood flow is maintained, whilst middle cerebral artery flow velocity increases. Symptoms of light-headedness, disorientation and paresthesia progress through euphoria, disinhibition, and hallucinations to psychomotor retardation, paranoia and catatonia as total administered dose increases.

Randomized trial of graded compression stockings for prevention of deep-vein thrombosis after acute stroke.

Graded compression stockings are commonly used to prevent deep-vein thrombosis (DVT) after stroke, but their efficacy in this setting has not been evaluated. Extrapolation of effectiveness from trials in patients undergoing elective surgery may be inappropriate. We undertook a randomized, controlled trial, with blinded data review, in a University hospital Acute Stroke Unit. Patients were allocated to graded compression stockings or to standard care alone. DVT incidence was determined at baseline and at day 7+/-2 by colour-flow Doppler ultrasound. Ninety-eight patients with acute, immobilizing stroke were randomized; 97 had full outcome data. One patient had clinically manifest DVT, and no patient had pulmonary thromboembolism. DVT was detected in 7/65 patients allocated stockings, and 7/32 controls (odds ratio 0.43, 95% CI 0.14-1.36); DVT involving femoral veins was detected in 3/65 and 2/32. In the first week after stroke, radiologically-detected DVT remains common, but is usually clinically silent. Proximal DVT is less common. Graded compression stockings produced a reduction in DVT incidence comparable to that in other patient groups, but the reduction was not statistically significant, and the magnitude of effect size requires confirmation. There is greater doubt over efficacy in early prevention of proximal DVT.

A pilot study of streptokinase for acute cerebral infarction.

We evaluated intravenous streptokinase in the treatment of cerebral infarction. Following neurological assessment and cerebral computed tomography (CT), patients aged 40-80 years with symptoms of anterior circulation acute ischaemic stroke were given 1.5 M units streptokinase or saline placebo in a double-blind randomized study. Twenty patients (10 streptokinase, 10 placebo), 11 males, 9 females, aged 57-79 years, were treated out of 512 consecutive admissions to the acute stroke unit over a 2-year period. Initial CT was normal in 11 (6 placebo, 5 streptokinase) and showed early signs of cerebral infarction in nine (4 placebo, 5 streptokinase). Median times from symptom onset to treatment were 5.2 h (placebo) and 5.8 h (streptokinase). Streptokinase treatment was associated with symptomatic hypotension in one patient. Repeat CT at 72 h demonstrated intracerebral haematoma in two patients and haemorrhagic infarction in one patient in the streptokinase group; the two cases of haematoma formation were associated with neurological deterioration and death. One patient in the placebo group had evidence of haemorrhagic infarction at 72 h. There were three deaths in each treatment group, all within the first 14 days. Patients with acute stroke can be evaluated with CT and treated with streptokinase within 6 h, but the opportunity for treatment is currently limited to few patients. Streptokinase treatment is not without risk, but potential clinical benefit justifies ongoing multicentre randomized trials.

Use of transcranial Doppler sonography to predict development of a delayed ischemic deficit after subarachnoid hemorrhage.

Blood flow velocity was recorded from the middle or anterior cerebral and extracranial internal carotid arteries using transcranial Doppler sonography (TCD) in 121 unselected consecutive patients with acute aneurysmal subarachnoid hemorrhage (SAH). Recordings were made daily or every 2nd day after SAH for a 14-day period. The highest recorded velocity was greater in the 47 patients who developed a delayed ischemic neurological deficit (186 +/- 6 cm sec-1; mean +/- standard error of the mean) than in the 74 patients who did not develop a neurological deficit (149 +/- 5 cm sec-1) (p < 0.001, Mann-Whitney test). Peak velocity recordings can thus assist in the diagnosis of delayed ischemic neurological deficit; however, peak velocity was often recorded only after the onset of neurological deficit. When only those readings made before the onset of neurological deficit were considered, there was no significant difference in peak velocity between the groups (157 +/- 8 cm sec-1 vs. 149 +/- 5 cm sec-1, respectively). Alternative TCD parameters for predicting delayed neurological deficit were therefore sought. The rate of increase in TCD velocity, recorded during the first few days after SAH, was significantly higher in the patients who later developed a neurological deficit. A maximum velocity increase of 65 +/- 5 cm sec-1 per 24-hour period was recorded in patients who later developed a neurological deficit, compared to 47 +/- 3 cm sec-1 24 hrs-1 in patients who did not develop a delayed neurological deficit (p = 0.003). A rise of more than 50 cm sec-1 24 hrs-1 identifies those patients who are most likely to develop a delayed ischemic neurological deficit after SAH. This can be applied prospectively to individual cases. Serial TCD studies in the early period after SAH are thus of value to identify patients who can be selected for prophylactic therapy, which may prevent or ameliorate development of delayed ischemic neurological deficits.

Effects of prolonged infusions of the NMDA antagonist aptiganel hydrochloride (CNS 1102) in normal volunteers.

Blockade of the N-methyl D-aspartate (NMDA) receptor by the ion-channel-blocking drug aptiganel hydrochloride (CNS 1102, Cerestat) is neuroprotective in focal cerebral ischemia. Short intravenous infusions of up to 30 microg/kg have been well tolerated by healthy male volunteers. We undertook a randomized, double-blind, placebo-controlled study in 20 male volunteers to examine the safety, tolerability, and cardiovascular and psychomotor effects of a dosing paradigm similar to that envisaged for therapeutic use. Aptiganel HCl was infused over 4 h in total doses of 15, 32, 50, or 73 microg kg. Mean arterial pressure increased significantly with dose group (p < 0.01, analysis of covariance). Motor reaction time was related to maximal plasma concentration (r2 = 0.21, p < 0.001). Transient symptoms and signs of peripheral paresthesiae, light-headedness, and euphoria were seen at total doses of 32 microg/ kg. Higher doses were associated with motor retardation, perceptual disturbances, and hallucinations (one case). Clearance was 125 +/- 55 L/h, and volume of distribution was 537 +/- 1,261. Total doses of up to 32 microg/kg of aptiganel HCl infused over 4 h are well tolerated by healthy males. Aptiganel HCl causes elevation of blood pressure and is associated with central nervous system symptoms and signs similar to other noncompetitive NMDA antagonists.

On the origin of cerebrovascular microemboli associated with prosthetic heart valves.

Application of transcranial Doppler ultrasonography to asymptomatic prosthetic heart valve patients can result in the detection of transient high intensity signals, similar to those induced by the passage of emboli. However, the origin of these signals is unknown. An in vitro study has been undertaken to investigate the capacity of prosthetic heart valves to generate high intensity Doppler signals in the absence of blood. A pulse duplicator, filled with a seeded saline solution, was used to function prosthetic heart valves under mock-physiological conditions. A Björk-Shiley Monostrut valve was mounted in the aortic port while a tri-leaflet control valve was fixed in the mitral port. At stations upstream and downstream from the Björk-Shiley valve, flow was monitored using pulsed wave Doppler ultrasound (Nicolet TC-2000, 2 MHz probe). The effect of damping the harsh closure of the mechanical valve was investigated by applying a thin layer of soft adhesive tape between the valve occluder and outer ring. For all valve configurations, transient high intensity Doppler signals, characteristic of microemboli and similar to those observed in clinical studies of prosthetic heart valve patients, were detected downstream from the aortic port. The number of microemboli signals did not change significantly between sites at 20 cm and 40 cm downstream from the aortic valve. Damping the Björk-Shiley valve closure greatly reduced (by 80%) the number of microemboli signals detected. It is concluded that Doppler microemboli signals can be generated by prosthetic heart valves while functioning in the absence of the formed elements of blood, and that the number of microemboli signals produced depends upon the rate of energy dissipation at valve closure.

Ultrasound detection of cerebral emboli in patients with prosthetic heart valves.

This study was undertaken in 64 patients, 50 with mechanical and 14 with porcine prosthetic valves, to evaluate the incidence of intracranial emboli and their distribution in the basal cerebral arteries. The patients were studied using transcranial Doppler (EME TC2-64B, Uberlingen, Germany), with a monitoring time of two minutes over each of the internal carotid arteries, middle and anterior cerebral arteries, vertebral arteries and the basilar artery. Sixty-three of the 64 patients were stabilized on warfarin at the time of the study. The incidence of emboli signals was significantly higher in patients with mechanical compared to porcine cardiac valves (88% versus 14%, p < 0.01). The number of emboli signals was significantly higher in the anterior compared with the posterior circulation, with a median of eight signals in the internal carotid arteries (95% confidence interval 5-15), 2.5 in the vertebral arteries (95% confidence interval 1-5.5)(p < 0.03). It was also significantly higher in those patients who had undergone double (aortic and mitral) as opposed to those who had undergone single aortic valve replacement: 18 versus two signals per minute (confidence intervals 5-30.5 versus 0.5-3.5) (p < 0.01). It is concluded that subclinical emboli signals are readily detectable using transcranial Doppler and are common in patients with prosthetic heart valves. Their number depends on both the type and the number of the prosthesis, while their distribution in the basal cerebral arteries is consistent with their cardiac source.

Transcranial Doppler ultrasound signals associated with prosthetic heart valves: an in vitro study.

The application of transcranial Doppler (TCD) ultrasonography to asymptomatic prosthetic heart valve patients can result in detection of localized bursts of high intensity signals, similar to those caused by the passage of emboli. The origin of these signals is not known. In order to investigate this phenomenon in a simplified, more controllable environment, a TCD machine was used to record flow downstream from mechanical prosthetic heart valves in a mock circulatory loop. The model, which uses a saline solution seeded with silk particles (< 15 micrometers) as the circulatory fluid, recreates the principal hydrodynamic characteristics of the left heart and systemic circulation. Reproducibility of the system was established through repeated testing of a Monostrut valve. Three different mechanical valve types, (Monostrut, Medtronic Hall, St. Jude Medical) were tested over a range of simulated cardiac outputs, and the effect of valve size was investigated with four Omniscience tilting disc valves (21, 23, 25 and 29 mm). Average energy of the reflected Doppler signal was used to quantify the amount of high intensity Doppler signal, QTCD. TCD signals recorded in vitro were visually and aurally similar to those found in prosthetic heart valve patients. All valve types generated exponentially more QTCD with increasing simulated cardiac output. Differences amongst valve types were only significant at higher flow outputs, with the Monostrut valve producing the greatest QTCD. Larger valves consistently generated greater QTCD than smaller valves. In conclusion, TCD signals found in prosthetic heart valve patients can be reproduced, at least qualitatively, using a mock circulatory loop which does not incorporate the formed elements of blood.(ABSTRACT TRUNCATED AT 250 WORDS)

Subclinical embolism in patients undergoing cardiac valve implantation and coronary artery bypass surgery.

Patients undergoing prosthetic valve insertion and coronary artery bypass surgery were examined with transcranial Doppler ultrasound, recently shown to be capable of detecting continuing subclinical emboli in patients with embolic sources. In 30 patients examined at least 1 year after valve surgery, and in whom warfarinisation was stable within defined limits, 20 of 24 patients (83%) with mechanical valves and 3 of 6 patients (50%) with porcine valves had embolic signals. In a serial preoperative and postoperative study in a further 30 patients, of whom 29 had native or bioprosthetic valves, only the one patient with a previous mechanical mitral valve prosthesis had embolic signals preoperatively. The incidence of embolic signals increased to 9 (30%) on the first postoperative day, and 20 (67%) on day 5. In a similar serial study in 25 patients undergoing coronary bypass surgery, 8 (32%) had preoperative embolic signals, which were explicable by cardiac and/or carotid disease in 6 cases. The embolus signal incidence and count did not increase postoperatively in this group. No embolic signals were found in 15 volunteer controls. The results indicate that prosthetic valves cause continuing microembolisation, detectable by transcranial Doppler; coronary artery bypass cases may have incidental embolic signals which are unaffected by cardiac surgery. This new application of Doppler ultrasound may improve the clinical assessment of embolic risk of new prosthetic valve types and deserves further examination.

Detection of microemboli by transcranial Doppler ultrasound.

Doppler ultrasound detection of abnormally high-pitched signals within the arterial waveform offers a new method for diagnosis, and potentially for prediction, of embolic complications in at-risk patients. The nature of Doppler "microembolic" signals is of particular interest in patients with prosthetic heart valves, where a high prevalence of these signals is observed. Monitoring the middle cerebral artery with 2-MHz transcranial Doppler ultrasound (TC-2000, Nicolet Biomedical; Warwick, UK), we looked for microemboli signals in 150 patients (95 women and 55 men), and found 1 or more signals during a 30-min recording in 89% of 70 patients with Bjork-Shiley valves (principally monostrut), 54% of 50 patients with Medtronic-Hall valves, and 50% of 30 patients with Carpentier-Edwards valves (p < 0.001, chi 2). In the patients with Bjork-Shiley valves, the mean number of signals per hour was 59 (range, 42-86; 95% confidence interval), which was significantly higher than the mean in patients with Medtronic-Hall and Carpentier-Edwards valves (1.5[range, 0.5-2.5] and 1 [range, 0-5.3], respectively; both p < 0.04, multiple comparisons. Bonferroni correction). In the patients undergoing serial pre- and postoperative studies, the causative role of the valve implant was emphasized. There was no correlation between the number of emboli signals and a prior history of neurologic deficit, cardiac rhythm, previous cardiac surgery, or the intensity of oral anticoagulation, in patients with prosthetic heart valves. In Bjork-Shiley patients, dual (mitral and aortic) valves were associated with more signals than were single valves. In Medtronic-Hall patients, the signal count was greater for valves in the aortic position than it was for valves in the mitral position. Comparative studies of Doppler emboli signals in other clinical settings suggest a difference in composition or size of the underlying maternal between prosthetic valve patients and patients with carotid stenosis. These studies also suggest that the signals are of gaseous origin in valve patients. The clinical significance of continuing microembolism remains to be determined.