Creation of a gene expression classifier for predicting Parkinson's disease rate of progression.

Parkinson's disease (PD) etiology is heterogeneous, genetic, and multi-factorial, resulting in a varied disease from a mild slow progression to a more severe rapid progression. Prognostic information on the nature of the patient's disease at diagnosis aids the physician in counseling patients on treatment options and life planning. In a cohort of PD patients from the PPMI study, the relative gene expression levels of SKP1A, UBE2K, ALDH1A1, PSMC4, HSPA8 and LAMB2 were measured in baseline blood samples by real-time quantitative PCR. At baseline PD patients were up to 2 years from diagnosis, H&Y scale ≤ 2 and PD treatment naïve. PD-Prediction algorithm comprised of ALDH1A1, LAMB2, UBE2K, SKP1A and age was created by logistic regression for predicting progression to ≤ 70% Modified Schwab and England Activities of Daily Living (S&E-ADL). In relation to patients negative for PD-Prediction (n = 180), patients positive (n = 30) for Cutoff-1 (at 82% specificity, 80.0% sensitivity) had positive hazard ratio (HR+) of 10.6 (95% CI, 2.2-50.1), and positive (n = 23) for Cutoff-2 (at 93% specificity, 47% sensitivity) had HR+ of 17.1 (95% CI, 3.2-89.9) to progress to ≤ 70% S&E-ADL within 3 years (P value < 0.0001). Likewise, patients positive for PD-Prediction Cutoff-1 (n = 49) had HR+ 4.3 (95% CI, 1.6-11.6) for faster time to H&Y 3 in relation to patients negative (n = 170) for PD-Prediction (P value = 0.0002). Our findings show an algorithm that seems to predict fast PD progression and may potentially be used as a tool to assist the physician in choosing an optimal treatment plan, improving the patient's quality of life and overall health outcome.

Repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training is a safe and effective modality for the treatment of Alzheimer's disease: clinical experience.

Alzheimer's disease (AD) is the most common type of dementia among the elderly. Common treatments available and non-pharmacological interventions have their limitations, and new therapeutic approaches are critically needed. Transcranial magnetic stimulation (TMS) is a non-invasive technique that generates an electric current-inducing modulation in cortical excitability. The previous clinical trials showed that combinations of rTMS and cognitive training (rTMS-COG), as provided by the NeuroAD medical device system, offer a novel, safe, and effective method improving mild-to-moderate AD patients. In this article, we present our experience with rTMS-COG treatment, in clinical settings, of 30 mild-to-moderate AD patients that received rTMS-COG commercial treatments in two clinics for 1-h daily sessions, 5 days per week, for 6 weeks (30 sessions). Five patients returned for a second treatment. ADAS-Cog and MMSE scores were measured pre- and post-treatments. The main analyses were conducted on patients who received 1 treatment (n = 30). Data received from the five returning patients were analyzed separately. The effect of rTMS-COG treatment was statistically significant regarding both ADAS-Cog (-2.4 point improvement, PV <0.001) and MMSE (+1.7 points improvement, PV <0.001) scores. About 80 % of patients gained some cognitive improvement following NeuroAD treatment, with more than 60 % improving by more than two points, for a minimum of 9 months. The Neuronix NeuroAD System was shown to be a safe and effective non-invasive modality for cognitive improvement of Alzheimer patients, with measurable outcomes lasting, in some of them, for up to 1 year, following completion of the 6-week daily intervention course (a carryover effect).

Selecting deep brain stimulation or infusion therapies in advanced Parkinson's disease: an evidence-based review.

Motor complications in Parkinson's disease (PD) result from the short half-life and irregular plasma fluctuations of oral levodopa. When strategies of providing more continuous dopaminergic stimulation by adjusting oral medication fail, patients may be candidates for one of three device-aided therapies: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, or continuous duodenal/jejunal levodopa/carbidopa pump infusion (DLI). These therapies differ in their invasiveness, side-effect profile, and the need for nursing care. So far, very few comparative studies have evaluated the efficacy of the three device-aided therapies for specific motor problems in advanced PD. As a result, neurologists currently lack guidance as to which therapy could be most appropriate for a particular PD patient. A group of experts knowledgeable in all three therapies reviewed the currently available literature for each treatment and identified variables of clinical relevance for choosing one of the three options such as type of motor problems, age, and cognitive and psychiatric status. For each scenario, pragmatic and (if available) evidence-based recommendations are provided as to which patients could be candidates for either DBS, DLI, or subcutaneous apomorphine.

Decreased amplitude of detrusor overactivity by repetitive swallowing.

PURPOSE: We determined whether swallowing has an effect on the degree of urinary urgency and on the amplitude of detrusor contraction during filling cystometry in patients with detrusor overactivity. MATERIALS AND METHODS: Included in study were 20 consecutive patients with detrusor overactivity. During urodynamics the mean peak pressure of each contraction was documented and compared. At the beginning of wave 2 patients were asked to perform 5 repetitive swallows. After each wave patients were asked to grade the severity of urgency on a visual analog scale. RESULTS: The mean ± SD peak of the detrusor contraction was 39 ± 15 vs 95 ± 26 cm H(2)O with vs without swallowing (p <0.01). All patients reported that during swallowing the degree of urgency decreased. The mean visual analog scale score for urgency was significantly lower during repetitive swallowing than without swallowing (mean 3.4 ± 1.5 vs 7.7 ± 2.2, p <0.01). CONCLUSIONS: The repetitive swallowing maneuver inhibits urinary urgency and detrusor overactivity. The maneuver can be used during bladder training program or when micturition is not desirable.

The effects of immediate and short-term retest on the latencies and amplitudes of the auditory event-related potentials in healthy adults.

OBJECTIVE: To evaluate the immediate and short-term effects of repeated within session trials on N1, P2, N2 and P3 latencies and P2, N2 and P3 amplitudes in healthy adults. MATERIALS AND METHODS: ERPs were elicited by the auditory oddball paradigm and recorded over Fz, Cz and Pz in 18 healthy adults over two sessions, one to three days apart, and two within session trials with one to three minutes trial-retrial interval. The ERPs' latencies and amplitudes were blindly calculated and were analyzed by Analysis of Variance (ANOVA) with repeated measures. RESULTS: Significant decreases of N2 amplitude at Fz, P3 amplitude at Cz and P3 latency at Pz were recorded in the second-compared to the first within session trial (p=0.034, 0.041, 0.046, respectively). There were no significant inter-session differences regarding N1, P2, N2 and P3 latencies or amplitudes. There was no significant interaction between session and trial. A statistically significant difference was found between the first session's mental count errors (p=0.039) but there were no significant differences between the second session's trials (p=0.581) or between sessions (p=0.328). CONCLUSIONS: N1, P2, N2 and P3 latencies and amplitudes are stable at short-term intervals of one to three days, but one to three minutes' retrial interval may affect P3 latency and N2 and P3 amplitudes. We suggest that when primary novelty-induced cognitive processes are evaluated, single trial sessions or more than three-minute inter-trials interval should be employed in order to mitigate habituation.

Admission of Parkinsonian patients to a neurological ward in a community hospital.

Hospitalization is a significant factor contributing to health care costs related to management of Parkinson's disease (PD) patients. We reviewed reasons for admission of PD patients to our Neurological Department over a 6-year period. Thereafter, we applied an "open door" policy to try to diminish the number of hospitalizations. Case records including patient data, disease duration, staging, reasons for admission, and motor, mental and general medical status of PD patients admitted to the Neurology Department over a 6-year period were reviewed. Out of 1,920 admissions, 143 were PD patients. All PD admissions were through the emergency department (non-elective). Motor complications were the reason for admission in 37%, psychosis in 24%, general medical problems in 14%, and a combination of motor and psychiatric in 25%. Drug-induced psychosis was the most significant cause of repeated and prolonged admissions (29% of patients). As motor and psychiatric complications are the commonest causes for admission, improved community-based care to "fine tune" medication appeared to be a priority. After analyzing our results, we instituted an "open door" policy, where patients are free to come to the Parkinson's clinic without appointment. This policy should improve control of PD symptoms and diminish hospitalizations.

Hallucinations and psychosis in Parkinson's disease.

Although Parkinson's disease (PD) is considered mainly a movement disorder, robust information accumulated during the last 30 years has shown that about 30% of PD patients may also suffer from psychosis, which deeply affects their quality of life and eventually brings them to permanent hospitalization in nursing homes. PD psychosis (PDPsy) mainly occurs after 10 or more years of treatment. The main features of PDPsy include recurrent and continuous hallucinations and delusions for at least 1 month. In addition, a recent consensus of the National Institute of Neurological Disorders and Stroke and National Institute of Mental Health Working Group also included illusions and a false sense of presence as "minor symptoms" supporting the diagnosis. In addition, accumulated clinical data have shown that "minor symptoms" and benign hallucinations also imply a bad prognosis with time. In the diagnostic criteria for PDPsy, it is considered that patients suffer from PD for at least more than 1 year before psychosis develops. If this is not the case, there is an unsolved problem of an overlapping diagnosis with Dementia with Lewy Bodies. Most clinicians consider that the main cause of psychosis is chronic exposure to dopaminergic medication. However, from an operational point of view there remain difficulties in defining a specific time of exposure and dose of treatment and the occurrence of PDPsy. Specific rating scales have been developed for the evaluation of PDPsy, such as the Parkinson Psychosis Rating Scale. The Scale for the Assessment of Positive Symptoms usually applied in schizophrenic patients has also proved useful for scoring psychotic symptomatology in PD. Clozapine in low doses has been proven to be the most effective antipsychotic medication for PDPsy. However, its use may cause neutropenia. Therefore, new atypical antipsychotic drugs with serotonin 5-HT2A receptor inverse agonist properties have been developed. Recently, pimavanserin--a 5-HT2A inverse agonist--has been studied. We hope that soon we will have the possibility to include new agents for the management of PDPsy.

Phenytoin intoxication in a clozapine-related prolonged seizure.

Phenytoin is a first-line drug for the treatment of status epilepticus. We report a case of phenytoin intoxication after intravenous phenytoin loading in a patient with clozapine-related seizures. To our knowledge, this is the first description of phenytoin intoxication due to CYP2C9 inhibition by clozapine. This case report is important because it supports the use of a lower intravenous loading dose of phenytoin in patients with clozapine-related status epilepticus.

Delayed post-ictal event-related potentials do not differentiate between generalized tonic-clonic seizures and syncope.

BACKGROUND: The differentiation between generalized tonic-clonic seizure (GTCS) and syncope is an important clinical problem. Corroborative investigations, which are requested when history is unclear or insufficient, have limited diagnostic value. The aim of our study was to determine whether auditory event-related potentials (ERPs) can be utilized in post-event differentiation between GTCS and syncope. MATERIALS AND METHODS: ERPs were recorded in 18 patients with a single seizure and in 21 patients following syncope, either on one or two occasions. ERP latencies and amplitudes were compared between groups and sessions. RESULTS: No significant differences of P3, N2, P2 and N1 latencies and P3, N2 and P2 amplitudes were found between patients following a single GTCS as compared to patients following syncope on either session. CONCLUSION: Post-event ERPs are insufficient to differentiate between GTCS and syncope. Further investigations are needed to evaluate the influence of different post-event intervals and ERP paradigms on ERP parameters in patients with GTCS.

Erythropoietin delays disease onset in an amyotrophic lateral sclerosis model.

Erythropoietin (Epo) has been shown in the recent years to have neuroprotective activity in a variety of settings. In this study, we investigated its impact on the progression of paralysis in a mouse model simulating the human disorder amyotrophic lateral sclerosis (ALS). We found that Epo can delay the onset of motor deterioration in transgenic SOD G93A mice without prolonging their survival. Notably this effect was selective for the females only. These initial findings encourage further investigation of this biological avenue in the search for improved remedies for this fatal disease.

Excessive daytime sleepiness in patients with Parkinson's disease: a polysomnography study.

To investigate excessive daytime sleepiness (EDS) in patients with Parkinson's disease (PD), the reasons for which have not yet been clarified, polysomnography (PSG) and the Multiple Sleep Latency Test (MSLT) were performed in 46 patients with PD, and, in addition, PSG was performed in 30 healthy controls. Assessment included Epworth Sleepiness Score (ESS), Mini-Mental State Examination (MMSE), and Hamilton Test (HT) for depression. Fifty percent of PD patients reported EDS (ESS, 10 +/- 4.5 vs. 6.9 +/- 3.7; P = 0.01). Compared with controls, PD patients as a group had lower sleep efficiency (65 +/- 22 vs. 77 +/- 14; P = 0.03), a longer Stage 2 (73 +/- 12 vs. 67 +/- 12; P = 0.03), and a shorter rapid eye movement stage (8 +/- 8 vs. 17 +/- 8; P < 0.001). Clinical data and sleep characteristics were similar in PD with/without EDS. Of interest, patients treated with clonazepam (CLNZ) had lower EDS than those without CLNZ (ESS, 7.9 +/- 4.7 vs. 11.3 +/- 4.0; P = 0.03). These patients suffered less periodic leg movement during sleep (2.1 +/- 2.7 vs. 12.4 +/- 28; P = 0.04), which might explain the finding. No correlation was found between ESS, MSLT, and all other clinical features analyzed. In PD patients, according to the data obtained, severity of EDS does not depend on any specific clinical factor and the etiology is probably multifactorial. Paradoxically, PD patients treated with CLNZ were less sleepy than patients not treated with CLNZ.

Palpitations: could they be neurogenic? A case report.

BACKGROUND: Palpitations usually occur in patients with arrhythmias of cardiac origion, in conditions associated with increased catecholamine levels, and in psychiatric disorders. A rare etiology of palpitations is seizures with autonomic features. REVIEW SUMMARY: We report a 24-year-old man with a several-week history of episodic palpitations, weakness, dizziness, and presyncopal phenomena. Subsequent events included loss of consciousness, with postevent confusion and tonic movements. A low-grade astrocytoma was diagnosed in the right frontal lobe. CONCLUSION: This case emphasizes the importance of detailed history in the diagnosis of epilepsy.

Anxiety in the first attack of vertigo.

BACKGROUND: Although psychiatric disturbances have been reported in chronic vestibular disorders, little is known about the psychological impact of an acute vertigo attack. METHODS: We conducted a comparative questionnaire study in 30 patients with a first attack of vestibular dysfunction and in 35 patients with a nonvestibular neurologic deficit of acute onset. RESULTS: Patients with vertigo reported more anxiety than patients with nonvestibular neurologic deficits (P = 0.002), despite the fact that premorbid anxiety was similar in both groups (P = 0.5). No difference in anxiety levels was found between vertigo patients who vomited and those who were free of vegetative symptoms (P = 0.97). Vertigo patients felt more disabled than nonvertigo patients (P = 0.06), irrespective of the objective restrictions caused by the disease. The rate of depression did not differ between the groups of patients (P = 0.09). CONCLUSION: Patients with acute vertigo experience extreme anxiety, and this contributes to their feeling of disproportionate disability. The reason for emotional disturbances in vestibular dysfunction is probably the result of physiological connections between the vestibular and limbic system and deserves further neuroanatomic investigation.

Phenotypic presentation of frontotemporal dementia with Parkinsonism-chromosome 17 type P301S in a patient of Jewish-Algerian origin.

A 39-year-old old Jewish woman of Algerian origin developed a rapidly progressive neurocognitive disorder characterized by asymmetric rigidity, spasticity with bilateral Babinski's sign, bradykinesia, altered speech that progressed to mutism, and severe bradyphrenia. She partially responded to levodopa. The family history revealed 4 affected first-degree relatives (3 had already died). Genetic studies carried out in the proband and her living affected sister showed a P301S mutation in chromosome 17.

H reflex threshold in Parkinson's disease patients for different stimulus duration.

Electrical stimulus, with duration starting at 0.1 ms and gradually increased to 1.0 ms, was used for eliciting the H reflex in 14 normal subjects and 19 patients with Parkinson's disease (PD). In 71.1% of normal subjects and in 13.2% of PD patients the H reflex to M response threshold ratio (H/M TR) was <1 and the H reflex was obtained before the M response for all duration stimuli. For all stimulus durations a significant difference between the H/M TR in normal subjects and PD patients was found (t test 0.002-0.007). The duration effect was found to be highly significant-H/M TR for short stimulus duration was greater than for long stimulus durations (p<0.001). The optimal stimulus duration for evaluating H reflex behavior in PD patient was 0.2 ms. These very significant differences in behavior of the H reflex in PD patients could be used as another parameter in the assessment of extrapyramidal rigidity in PD patients.

Comparison of the Unified Parkinson's Disease Rating Scale and the Short Parkinson's Evaluation Scale in patients with Parkinson's disease after levodopa loading.

The Short Parkinson's Evaluation Scale has been compiled and validated previously (Clinical Neuropharmacology, 1997). In the present study, we have assessed and compared the motor scoring of the Unified Parkinson's Disease Rating Scale and the Short Parkinson's Evaluation Scale in 23 patients (mean age, 61.8 years) with Parkinson's disease. Patients were 12 hours off medication at the beginning of the series. They were then given levodopa, 125 mg and 250 mg, on different days and were evaluated each 30 minutes for 2 hours. In addition, patients' motor skills (finger tapping and walking velocity) were measured at each time. Analysis of variance with repeated measures was applied. The results presented show that both scales have the same ability to measure levodopa-dose effect within time. In addition, Spearman's correlation coefficients showed a negative correlation between finger tapping and upper-limb impairment and a positive correlation between walking velocity and lower-limb impairment in both scales. In summary, the present results suggest that Short Parkinson's Evaluation Scale is a useful tool in assessing the effect of medication, having the advantage of being easier and quicker.