Gilad Yahalom

Chronic Kidney Disease and Clinical Outcome in Patients With Acute Stroke

Background and Purpose— Chronic kidney disease (CKD) is increasingly recognized as an independent risk factor for cardiovascular disease and stroke. Our aim was to examine the association between estimated glomerular filtration rate (GFR) and stroke outcome and to assess whether CKD and its severity affect stroke outcome in a large cohort of unselected patients with acute stroke. Methods— We examined the association between baseline estimated GFR and CKD and 1-year outcomes in 821 consecutive patients with acute stroke (ischemic or hemorrhagic). GFR was estimated by 2 methods: the Modification of Diet in Renal Disease and the Mayo Clinic quadratic equation. An estimated GFR rate ≤60 mL/min/1.73 m2 defined CKD. Results— Odds ratios (95% CI) for death across levels of estimated GFR based on both equations were estimated. CKD was present in 36% (n=291) of patients based on the Modification of Diet in Renal Disease equation and 18% (n=147) based on the Mayo Clinic equation. The adjusted ORs for mortality after 1-year based on the Modification of Diet in Renal Disease equation were 0.7 (95% CI, 0.4 to 1.2) associated with GFR 45 to 60 and 3.2 (1.7 to 6.4) associated with GFR 15 to 44 as compared with GFR >60 mL/min/1.73 m2, whereas those based on the Mayo Clinic equation were 2.3 (1.1 to 4.7) and 3.3 (1.6 to 7.1), respectively. The adjusted ORs for Barthel Index ≤75 or death after 1 year were 0.8 (0.5 to 1.5) and 2.1 (0.9 to 4.8) by the Modification of Diet in Renal Disease equation and 1.9 (0.8 to 4.4) and 3.9 (1.5 to 11.0) by the Mayo Clinic equation, respectively. Conclusions— CKD is a strong independent predictor of mortality and poor outcome in patients with acute stroke. The estimation of the prevalence of CKD and of the GFR cutoffs associated with poor outcome depend on the equation used to estimate GFR.

Neurological outcome in cerebrotendinous xanthomatosis treated with chenodeoxycholic acid: early versus late diagnosis.

ObjectiveTo present the long-term neurological outcome of Jewish Israeli patients with cerebrotendinous xanthomatosis (CTX) after several years of chenodeoxycholic acid (CDCA) treatment. MethodsA cross sectional observational study of all patients with a diagnosis of CTX followed in a referral outpatient clinic during the years 2003–2012. ResultsEighteen patients (10 men) from 11 families were enrolled. Sixteen patients were included in the analysis (2 patients had low compliance for treatment). The mean ± SD age at last evaluation was 35.0 ± 9.2 years (range, 16–45 years). After their diagnosis, at age 22.6 ± 10.8 years, all patients were treated with CDCA. Patients who started treatment after the age of 25 years had worse outcome and were significantly more limited in ambulation (P = 0.004) and more cognitively impaired (P = 0.047). Five patients who started treatment after 25 years of age continued to deteriorate despite CDCA treatment. ConclusionsBeginning CDCA treatment as early as possible is crucial to preventing neurological damage and deterioration in CTX. After significant neurological pathology is established, the effect of treatment is limited and deterioration may continue.

Dyskinesias in patients with Parkinson's disease: effect of the leucine-rich repeat kinase 2 (LRRK2) G2019S mutation.

BACKGROUND While Parkinsons disease (PD) phenotype in leucine-rich repeat kinase 2 gene (LRRK2)-associated and sporadic PD seems similar, there is paucity of data on the possible effect of mutations in LRRK2 on response to and complications of dopaminergic therapy. OBJECTIVE To assess the impact of the LRRK2 Gly2019Ser (G2019S) carrier status on the time to the onset of levodopa-induced dyskinesias (LID). METHODS Consecutive PD patients treated with levodopa were genotyped for the LRRK2 G2019S mutation. The relationship between mutation carrier status and the time to LID onset was explored after matching carriers to non-carriers for age at PD onset, gender, and time from PD diagnosis to levodopa initiation, using Kaplan-Meier curves and the Cox proportional hazards model, using LID onset as an end-point. RESULTS Overall, 349 Israeli PD patients [222 Ashkenazi-Jewish (AJ), 60.5% males, mean age at diagnosis: 60.6 ± 13.2 years] participated in the study. Of these, 33 patients (9.5%, 30 AJ) carried the LRRK2 G2019S mutation. The prevalence of LID was non-significantly higher among carriers (22/33, 66.7%) than non-carriers (168/316, 53.2%, p = 0.15). The mean duration of therapy from levodopa initiation to the development of LID or last follow-up (in cases who were LID-free) was 5.1 ± 5.4 years for carriers and 4.4 ± 4.0 years in non-carriers (p = 0.47) and the survival curves in carriers and matched non-carriers were not significantly different (Cox proportional hazards test and log-rank test; p = 0.79). CONCLUSIONS The LRRK2 G2019S mutation status has no discernable effect on the prevalence of LID or on LID latency in Israeli levodopa-treated PD patients.

Motor progression of Parkinson's disease with the leucine-rich repeat kinase 2 G2019S mutation.

In this retrospective study, we compared motor disease progression in Ashkenazi‐Jewish (AJ) Parkinsons disease (PD) patients carrying the LRRK2*G2019S mutation with that of noncarriers.

Estimated glomerular filtration rate in a population with normal to mildly reduced renal function as predictor of cardiovascular disease

Background While moderate and severe chronic kidney disease is an established independent risk factor for cardiovascular disease (CVD), the association of estimated glomerular filtration rate (eGFR) differences within the normal to mildly reduced range (from 60 to >90 ml/min/1.73 m2) and CVD is less clear. Our aim was to examine the association of eGFR with incident CVD in a cohort of predominantly healthy subjects with normal to mildly reduced renal function. Design Retrospective cohort study. Methods We collected demographic, clinical, and laboratory parameters of subjects free of diabetes mellitus or CVD who attended annual medical screening examinations between 2001 and 2009. Main outcome measures were a new diagnosis of coronary artery disease (CAD) or cerebrovascular events (CVE). Results During a median follow up of 4.3 years, among 10,909 subjects (mean eGFR 78.5 ± 12.2 ml/min/1.73 m2), 10.3% were diagnosed with CAD (n = 1025) or CVE (n = 94). Compared with subjects in the highest eGFR quintile (≥88.8 ml/min/1.73 m2), subjects in the lowest quintile (≤68.2 ml/min/1.73 m2) had a hazard ratio (HR) of 1.64 (95% CI 1.35–2.00; p < 0.001) for a CAD outcome, but this association was no longer significant after adjustment for age and other confounders (adjusted HR 1.08; p = 0.55). Similar findings were obtained for the association of eGFR with CVE. Conclusions In a predominantly healthy population with normal to mildly reduced renal function, lower eGFR is associated with higher risk for CVD; however, this association is not independent but merely reflects the association of age and other cardiovascular risk factors with reduced eGFR.

The LRRK2 G2019S mutation status does not affect the outcome of subthalamic stimulation in patients with Parkinson's disease

BACKGROUND Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established therapy for advanced Parkinsons disease (PD). The most common genetic mutation associated with PD identified to date is the G2019S mutation of the LRRK2 gene, which is highly prevalent in the Ashkenazi Jewish population. The effect of STN-DBS surgery in patients carrying this mutation has not been systematically studied. We therefore performed a case-control study to evaluate the impact of the G2019S mutation status on the outcomes of bilateral STN-DBS. METHODS The study sample included 39 Jewish PD patients with bilateral STN-DBS. Thirteen patients (5 females) were G2019S mutation heterozygous. The control group consisted of 26 PD patients with bilateral STN-DBS, negative for the mutation, matched (2:1) for gender, age at PD onset, and disease duration at surgery. Clinical data including the Unified PD Rating Scale scores (UPDRS), levodopa equivalent daily dose (LEDD), and clinical global impression of change (CGIC) concerning both motor and neuropsychiatric outcome- were available at 3 time points (preoperative baseline, 6-12 months and 3 years postoperatively). RESULTS Implementing a linear mixed model, a significant improvement (p < 0.05) was found for the whole group concerning reduction in motor UPRDS (off state) and LEDD pre- vs. postoperatively, as expected. No difference in clinical outcome was found between carriers and matched non-carriers at baseline or at postoperative follow-up (up to 3 years). CONCLUSIONS In our study, STN-DBS outcomes were not influenced by the LRRK2 G2019S mutation, and thus knowledge of carrier status may not be relevant to the considerations of patient selection for surgery.

Repetitive deep transcranial magnetic stimulation for motor symptoms in Parkinson's disease: A feasibility study

OBJECTIVES Repetitive transcranial magnetic stimulation (rTMS), using standard coils, provided modest symptomatic benefits in patients with Parkinsons disease (PD). In our previous exploratory studies, using the newly developed Hesed coil (providing deeper rTMS; rDTMS) high frequency (HF), excitatory rDTMS over the primary motor cortex (M1), did not achieve sufficient beneficial effect for PD symptoms, while low frequency (LF) inhibitory stimulation, was mildly beneficial. To further investigate the optimal rDTMS stimulation parameters for PD patients, and to assess whether there is an added value for dual stimulation, consisting of HF rDTMS over the prefrontal cortex (PFC) along with LF M1 rDTMS. The rational for the selection of the current stimulation parameters and sites lies on the previous studies that demonstrated an inhibitory effect of 1Hz rTMS on the increased cortical activity in PD as well as dopamine release by PFC stimulation. PATIENTS AND METHODS An open comparative active study of one month duration (12 sessions) of LF rDTMS over M1 alone (n=9) or combined with HF PFC rDTMS (M1-PFC, n=10). Outcome measures included the total and motor Unified Parkinsons Disease Rating Scale scores (T-UPDRS and M-UPDRS) and other variables, were collected at baseline and on days 30 and 60. RESULTS For the M1+PFC group, T-UPDRS score improved from baseline to day 30, by 15% (median: 52 points, decreased to 44, p=0.02, effect size: 0.51) and M-UPDRS score improved by 24% (median: 37 points decreased to 28, p=0.04, effect size: 0.47). The corresponding results for the M1 group were insignificant. Additionally, the between groups comparison, was insignificant. CONCLUSION rDTMS, consisting of M1 excitation with PFC inhibition improved PD motor symptoms but was not significantly superior to M1 rDTMS alone. rDTMS stimulation protocols for M1 should be further evaluated in larger scale controlled studies.

The neuropsychological profile of patients with 3-methylglutaconic aciduria type III, Costeff syndrome.

Costeff syndrome is a rare genetic neuro‐ophthalmological syndrome consisting of early‐onset bilateral optic atrophy along with a progressive complex motor disorder with elevated levels of urinary 3‐methylglutaconic acid and 3‐methylglutaric acid. While borderline to mild cognitive deficits have been considered to be common in patients with this syndrome, a comprehensive cognitive assessment has never been performed. The aim of the current study was to explore the cognitive profile associated with Costeff syndrome. Sixteen adult patients diagnosed with Costeff syndrome were administered a neuropsychological test battery that was composed of standardized verbal tests adapted for the blind. General intelligence ranged from average to borderline, with a group mean consistent with intact general cognitive functioning (VIQmean = 85, z = −1) in the low‐average range of the general population. The auditory immediate and delayed memory indexes were in the average range and were significantly higher than the general cognitive functioning, whereas the working memory index was significantly lower than the general cognitive functioning. Adult patients with Costeff syndrome have intact global cognition and learning abilities and strong auditory memory performance.

Cardiac stress test is normal in pre‐motor Parkinson's disease

Cardiac sympathetic denervation is an early nonmotor feature of Parkinsons disease (PD). The aim of the current study was to trace evidence for cardiac dysfunction abnormalities in the premotor phase of PD. We retrospectively reviewed treadmill ergometric tests of a large cohort (n = 16,841) between 2000 and 2012, that attended the Executive Screening Survey (ESS) at Sheba Medical Center. Heart rate and blood pressure profiles as well as exercise capacity were compared between subjects who later developed PD and age‐ and sex‐matched subjects (ratio 1:2) who did not. We identified 28 subjects (24 males) who developed PD at follow‐up. The PD group was older than the group of subjects who did not develop PD on first ergometric test (64.82 ± 8.82 vs. 48.91 ± 10.60 years, P < 0.001). The time between the first ergometric test and motor symptoms onset was 4.64 ± 2.86 years. Patients who later developed PD had lower maximal heart rate (P < 0.001) and lower heart rate reserve than healthy controls (P < 0.001); however, compared with age‐ and sex‐matched subjects, subjects who developed PD had similar exercise capacity and heart rate profile during rest, exercise, and recovery, even 1 year before diagnosis. In this study, we did not detect significant signs of sympathetic dysfunction during the premotor phase of PD.

Acquired premature ejaculation in Parkinson’s disease and possible mechanisms

Premature ejaculation (PE) has been reported in 40.6–51.5% of men affected by Parkinson’s disease (PD), however, this non-motor sexual complaint has not been studied in detail. We describe eight PD patients who asked for a sexological consultation between 2008 and 2014 because of a new-onset of PE. They were diagnosed with acquired PE (APE) according to the DSM-V criteria and the International Society for Sexual Medicine (ISSM) committee. Patients’ demographic, medical and sexual related data were retrieved and studied. The average age of onset of PD was 53.3 ± 12.7 years (range 38–77 years) and the sexual problem appeared 4.0 ± 3.1 years later. The mean intravaginal ejaculation latency (IELT) before APE onset was 7.3 (range 2–20) min. Interestingly, the ejaculatory disorder appeared abruptly, characterized by a dramatically shortened IELT in all patients, while in three of the cases ejaculation occurred before vaginal penetration, hampering sexual intercourse. Some patients had 2 additional sexual problems, (four with erectile dysfunctions, five with libido changes: increased desire in four and reduced in one). In this case series of PD patients with APE, the ejaculatory dysfunction developed when patients were on antiparkinsonian medications, suggesting a possible medication effect.