Oral ENT-01 Targets Enteric Neurons to Treat Constipation in Parkinson Disease : A Randomized Controlled Trial.

BACKGROUND: Parkinson disease (PD) is associated with α-synuclein (αS) aggregation within enteric neurons. ENT-01 inhibits the formation of αS aggregates and improved constipation in an open-label study in patients with PD. OBJECTIVE: To evaluate the safety and efficacy of oral ENT-01 for constipation and neurologic symptoms in patients with PD and constipation. DESIGN: Randomized, placebo-controlled phase 2b study. (ClinicalTrials.gov: NCT03781791). SETTING: Outpatient. PATIENTS: 150 patients with PD and constipation. INTERVENTION: ENT-01 or placebo daily for up to 25 days. After baseline assessment of constipation severity, daily dosing was escalated to the prokinetic dose, the maximum dose (250 mg), or the tolerability limit, followed by a washout period. MEASUREMENTS: The primary efficacy end point was the number of complete spontaneous bowel movements (CSBMs) per week. Neurologic end points included dementia (assessed using the Mini-Mental State Examination [MMSE]) and psychosis (assessed using the Scale for the Assessment of Positive Symptoms adapted for PD [SAPS-PD]). RESULTS: The weekly CSBM rate increased from 0.7 to 3.2 in the ENT-01 group versus 0.7 to 1.2 in the placebo group (P < 0.001). Improvement in secondary end points included SBMs (P = 0.002), stool consistency (P < 0.001), ease of passage (P = 0.006), and laxative use (P = 0.041). In patients with dementia, MMSE scores improved by 3.4 points 6 weeks after treatment in the ENT-01 group (n = 14) versus 2.0 points in the placebo group (n = 14). Among patients with psychosis, SAPS-PD scores improved from 6.5 to 1.7 six weeks after treatment in the ENT-01 group (n = 5) and from 6.3 to 4.4 in the placebo group (n = 6). ENT-01 was well tolerated, with no deaths or drug-related serious adverse events. Adverse events were predominantly gastrointestinal, including nausea (34.4% [ENT-01] vs. 5.3% [placebo]; P < 0.001) and diarrhea (19.4% [ENT-01] vs. 5.3% [placebo]; P = 0.016). LIMITATION: Longer treatment periods need to be investigated in future studies. CONCLUSION: ENT-01 was safe and significantly improved constipation. PRIMARY FUNDING SOURCE: Enterin, Inc.

Hemichorea-Hemiballism as a Delayed Manifestation of Hyperglycemia: A Case Report.

Hemichorea is characterized by involuntary, continuous, non-patterned movements on one side of the body. While it is most commonly caused by strokes, it can also be caused by metabolic derangements such as hyperglycemia. We present two patients who developed hemichorea in the setting of hyperglycemia. Our first patient had a history of uncontrolled diabetes mellitus and developed chorea 2 weeks following a hyperglycemic event. The second patient developed chorea while being on steroids for hip pain and was later diagnosed to have underlying diabetes mellitus. MRI showed hyperintensity in the contralateral lentiform nucleus in both cases. The chorea did not improve despite the correction of the hyperglycemia. Both patients were started on Tetrabenazine with significant improvement. Hyperglycemia-induced hemichorea might be underdiagnosed given the prevalence of diabetes mellitus in the population. Chorea can even be the presenting symptom of diabetes mellitus and in some cases is a delayed manifestation of hyperglycemia.

Persistent hiccups following thalamic hemorrhage: A case report.

Persistent hiccups (lasting more than 48 hours) can cause physical and emotional distress. They can result in dehydration, exhaustion, malnutrition, insomnia, wound dehiscence, ventilatory desynchronization, and hemodynamic changes. Hiccups are thought to be due to a complex reflex arc involving peripheral nerves and central structures such as the brainstem, temporal lobe, basal ganglia, hypothalamus, and spinal cord levels C3-5. Medullary strokes, for instance, have been reported to cause hiccups. We report a patient with a thalamic bleed who developed persistent hiccups. A 56-year-old man was brought to the hospital in an unresponsive state. He was intubated for airway protection. CT brain showed a left thalamic hemorrhage with edema and mass effect on the 3rd ventricle, intraventricular extension of hemorrhage, and hydrocephalus. An external ventricular drain was placed successfully with adequate drainage. One week after admission, the patient developed persistent abdominal jerks. These jerks were occurring every 3-4 seconds and would last for hours with brief periods of remission. He was started on levetiracetam 1000 mg IV bid and then increased to 1500 mg IV BID without any improvement of symptoms. The patient was also placed on EEG which did not reveal any epileptiform abnormality but did show an EMG artifact. His electrolytes including sodium, and potassium, and corrected calcium levels were normal. He did not have any evidence of pneumonia or other infections. It was determined that these jerks were likely hiccups. Metoclopramide 10 mg IV was tried without any benefit. He was then started on Baclofen 10 mg PO TID which resulted in a significant improvement in hiccups. Our case suggests that thalamic lesions might also lead to persistent hiccups.

An Update on Medical and Surgical Treatments of Parkinson's Disease.

Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta and other neuronal populations. The worldwide prevalence of PD is over 7 million and has been increasing more rapidly than many other neurodegenerative disorders. PD symptoms can be broadly divided into motor (slowness, stiffness, tremor) and non-motor symptoms (such as depression, dementia, psychosis, orthostatic hypotension). Patients can also have prodromal symptoms of rapid eye movement sleep behavior disorder, hyposmia, and constipation. The diagnosis of PD is mainly clinical, but dopamine transporter single-photon emission computed tomography can improve the accuracy of the diagnosis. Dopamine based therapies are used for the treatment of motor symptoms. Non-motor symptoms are treated with other medications such as selective serotonin reuptake inhibitors (depression/anxiety), acetylcholinesterase inhibitors (dementia), and atypical antipsychotics (psychosis). Patients with motor fluctuations or uncontrolled tremor, benefit from deep brain stimulation. Levodopa-carbidopa intestinal gel is an alternative to deep brain stimulation for uncontrolled motor fluctuations. Rehabilitative therapies such as physical, occupational, and speech therapy are important during all stages of the disease. Management of PD is complex but there have been significant advancements in the treatment of motor and non-motor symptoms over the past few years. This review discusses the updates in the medical and surgical management of PD.

Uptake of telehealth in Parkinson's disease clinical care and research during the COVID-19 pandemic.

INTRODUCTION: Traditionally, medical care and research in Parkinson's disease (PD) have been conducted with in-person encounters. The recent COVID-19 pandemic has profoundly impacted the delivery of in-person clinical care and clinical research. We conducted an online survey of active clinician members of the Parkinson Study Group (PSG) to evaluate the adoption of various non-face-to-face methods in clinical practice and research in PD during the COVID-19 pandemic. METHODS: We conducted a survey using the open-access online SurveyMonkey tool (http://www.surveymonkey.com). The survey had 27 items and was designed to elucidate clinical/research care before and during the COVID-19 pandemic. The survey was sent to 414 active PSG members with weekly reminders and it remained accessible for 30 days from May 2020. RESULTS: We received 142 responses, of which 133 (93.7%) provided demographic data. The clinical use of virtual visits via synchronous video conferencing increased from 39.5% pre-COVID-19 to 94.6% during the COVID-19 pandemic. Lack of access for patients (68.2%) and patient resistance (51.4%) were the top barriers for its use. Approximately 70% respondents stated that 75-100% of their research activities were suspended during the COVID-19 pandemic. Many sites had to fill out protocol deviations (38.2%), protocol exceptions (25.5%) or change their research profile due to layoffs (16.8%). The overall use of video conferencing increased from 30.3% to 64.1%. CONCLUSION: The current results suggest a need for flexibility in conducting office visits and clinical trials in PD patients. Technology has the potential to enhance patient care and convenience, when in-person visits can be challenging.

Make Kids Stroke-Smart: A Community Based Interventional Study.

BACKGROUND: Stroke is the third leading cause of death and the major cause of long-term disability in the United States. Timely recognition of symptoms is critical. Family members are crucial in recognizing stroke symptoms since <5% patients can call Emergency Medical Services themselves due to inability to speak or dial the phone. This might be of significance, especially, in family units where children have frequent contact with multiple generations. This study was undertaken to assess and improve the knowledge about stroke amongst children. METHODS: A community-based interventional study was conducted among 305 kids ranging from second to eighth grade. A pre-test questionnaire was administered and later health education regarding stroke was imparted using audiovisual aids. Post-test was done to assess the impact of stroke education. Components of education included were: 1) What is stroke? 2) FAST mnemonic. 3) Time sensitive treatment. 4) Risk factors for stroke 5) How can they help? 6) Whom to call and where to go? The data was compiled and analyzed using Chi square test. RESULTS: There was a significant lack of knowledge in the pretest groups. The post-test showed statistically significant improvement in all the tested components irrespective of age or grade (p<0.001). CONCLUSION: Targeting the younger generation for stroke education is one way to improve community knowledge of stroke symptoms thus increasing the chances that the stroke patient may receive acute stroke therapy. Children can also be used as a conduit to transmit educational information to parents and other family members thus further raising awareness.

Psychosocial and Physiologic Characteristics of Patients with Non-epileptic Events: A Retrospective Study.

Background The main focus of this study is to aid early identification of psychogenic non-epileptic seizure (PNES) patients by identifying physical and psychosocial characteristics to reduce the health care burden, to reduce the unnecessary use of anti-epileptic medications and their side effects, and maximizing cost-effective use of video electroencephalography (VEEG). Methods We analyzed PNES subject data from VEEG monitoring performed at the Epilepsy Center at the Marshall University School of Medicine. We reviewed more than 360 episodes in 54 subjects older than 18 years (mean age ± standard deviation (SD): 48 ± 12.97 years; 83% female). Results We found that most of our PNES patients were older than 45 years of age (66.7%), females (83.3%); obese (66.6%) or overweight (18.5%); either single (33.3%), separated (7.4%), divorced (22.2%), or widowed (14.8%); of low education, unemployed (either received government assistance (83.3%) or disability benefits (57.4%)) with associated physical illness (85.2%) and psychiatric illness (96.3%).  Conclusion Our study adds to the current knowledge of the sociodemographic and sociocultural variability of PNES. It might enable early diagnosis and management of patients with PNES.

Intravenous tPA in the treatment of acute stroke related to aortic dissection.

A 61-year-old woman with no prior medical illness presented with acute onset stroke symptoms. She had no chest pain at the time of presentation. However, CT angiogram showed an extensive aortic dissection, resulting in hypoperfusion of the right cerebral hemisphere and thus causing stroke symptoms. Due to this finding, tissue plasminogen activator was not given and a negative outcome was avoided.

Impaired Retinal Vasoreactivity: An Early Marker of Stroke Risk in Diabetes.

Diabetes is a common cause of small vessel disease leading to stroke and vascular dementia. While the function and structure of large cerebral vessels can be easily studied, the brain's microvasculature remains difficult to assess. Previous studies have demonstrated that structural changes in the retinal vessel architecture predict stroke risk, but these changes occur at late disease stages. Our goal was to examine whether retinal vascular status can predict cerebral small vessel dysfunction during early stages of diabetes. Retinal vasoreactivity and cerebral vascular function were measured in 78 subjects (19 healthy controls, 22 subjects with prediabetes, and 37 with type-2 diabetes) using a new noninvasive retinal imaging device (Dynamic Vessel Analyzer) and transcranial Doppler studies, respectively. Cerebral blood vessel responsiveness worsened with disease progression of diabetes. Similarly, retinal vascular reactivity was significantly attenuated in subjects with prediabetes and diabetes compared to healthy controls. Subjects with prediabetes and diabetes with impaired cerebral vasoreactivity showed mainly attenuation of the retinal venous flicker response. This is the first study to explore the relationship between retinal and cerebral vascular function in diabetes. Impairment of venous retinal responsiveness may be one of the earliest markers of vascular dysfunction in diabetes possibly indicating subsequent risk of stroke and vascular dementia.

MRI evaluation of asymmetry of nigrostriatal damage in the early stage of early-onset Parkinson's disease.

INTRODUCTION: The motor symptoms and signs of early-onset idiopathic Parkinson's disease (PD) in Hoehn and Yahr (H&Y) stage-1 are generally unilateral. We hypothesized that there would be detectable differences in the quantitative MRI parameters in these PD patients between the hemispheres contralateral to the clinically symptomatic and non-symptomatic body side. METHODS: We tested this hypothesis by comparing transverse relaxation rates and diffusion tensor imaging (DTI) parameters in the substantia nigra and putamen between the two hemispheres contralateral to the symptomatic and non-symptomatic side in H&Y stage-1 PD patients who had onset of symptoms between ages of 40-59 years. RESULTS: There were quantifiable hemispheric asymmetries in transverse relaxation rates in the substantia nigra, as well as fractional anisotropy and mean diffusivity in the putamen in early PD, which correlated with the unilaterality of motor symptoms as evaluated using the motor portion of the Unified Parkinson's Disease Rating Scale. CONCLUSION: Transverse relaxation mapping and DTI demonstrated significant differences between the symptomatic and non-symptomatic hemispheres at the early stage of early-onset PD. These findings support the hypothesis of asymmetric neurodegeneration in the bilateral nigrostriatal pathways in the early stage of the disease.

Impaired retinal vasodilator responses in prediabetes and type 2 diabetes.

PURPOSE: In diabetes, endothelial dysfunction and subsequent structural damage to blood vessels can lead to heart attacks, retinopathy and strokes. However, it is unclear whether prediabetic subjects exhibit microvascular dysfunction indicating early stages of arteriosclerosis and vascular risk. The purpose of this study was to examine whether retinal reactivity may be impaired early in the hyperglycaemic continuum and may be associated with markers of inflammation. METHODS: Individuals with prediabetes (n = 22), type 2 diabetes (n = 25) and healthy age and body composition matched controls (n = 19) were studied. We used the Dynamic Vessel Analyzer to assess retinal vasoreactivity (percentage change in vessel diameter) during a flickering light stimulation. Fasting highly sensitive c-reactive protein (hs-CRP), a marker of inflammation, was measured in blood plasma. RESULTS: Prediabetic and diabetic individuals had attenuated peak vasodilator and relative amplitude changes in retinal vein diameters to the flickering light stimulus compared with healthy controls (peak dilation: prediabetic subjects 3.3 ± 1.8%, diabetic subjects 3.3 ± 2.1% and controls 5.6 ± 2.6%, p = 0.001; relative amplitude: prediabetic subjects 4.3 ± 2.2%, diabetic subjects 5.0 ± 2.6% and control subjects 7.2 ± 3.2%, p = 0.003). Similar findings were observed in retinal arteries. Levels of hs-CRP were not associated with either retinal vessel response parameters. CONCLUSION: Retinal reactivity was impaired in prediabetic and type 2 diabetic individuals in parallel with reduced insulin sensitivity but not associated with levels of hs-CRP. Retinal vasoreactivity measurements may be a sensitive tool to assess early vascular risk.

Retinal vasoreactivity as a marker for chronic ischemic white matter disease?

UNLABELLED: The cerebral microvasculature cannot be easily studied non-invasively. Because the retina and brain share embryological, anatomical and physiological similarities, studies of retinal blood vessels may prove to be useful as a surrogate marker for cerebrovascular disease. In epidemiological studies abnormal retinal arteriovenous ratios (AVRs) predict the risk of stroke and vascular dementia. However, the association between retinal vasoreactivity, cerebral small vessel ischemic disease, and cerebral blood vessel function remains unknown. STUDY GOALS: To examine (1) the association between cerebral ischemic white matter disease (WMD) and retinal microvessel behavior and (2) the relationship between retinal blood vessel reactivity and measures of cerebrovascular function. METHODS: Cohort study of 12 patients with ischemic WMD and 14 healthy controls. Retinal vasoreactivity was measured following high frequency flicker light stimulation. Middle cerebral artery (MCA) vasoreactivity was measured using transcranial Doppler ultrasound (TCD). Magnetic resonance imaging scans (MRIs) were reviewed for evidence of ischemic WMD. RESULTS: Patients with ischemic WMD had attenuated retinal venous (2.2% ± 0.27 SD, vs. controls 6% ± 0.7 SD, p=0.002, CI 95%) and arterial (1.9% ± 0.8 SD, vs. controls 4.9% ± 0.8 SD, p=0.004, CI 95%) vasoreactivity compared to controls. An attenuated retinal venous light flicker response was associated with a significant decrease of MCA vasoreactivity (r=0.45, p=0.05, CI 95%). Decreased AVRs, an indicator for altered retinal vessel architecture in patients with cerebral chronic ischemic WMD, were also significantly correlated with dysfunction of cerebral vasoreactivity (r=0.69, p=0.001, CI 95%). CONCLUSION: In this study functional and structural impairment of the retinal microvasculature were associated with ischemic WMD and measures of cerebral vascular function. Microvascular dysfunction in the eye may predict cerebral small vessel disease, but validation by larger studies is needed.

Comparison of retinal vasodilator and constrictor responses in type 2 diabetes.

PURPOSE: The retinal blood vessels provide a unique way to directly examine the human microvasculature, which is frequently damaged in individuals with diabetes. Previous studies have demonstrated that retinal flickering light-induced vasodilation and hyperoxia-induced vasoconstriction may operate by enhancing or reducing similar vasoregulatory factor(s), but a comparison between these two provocative stimuli in individuals with diabetes has not been studied. The purpose of the study was to examine the association between retinal flickering light-induced vasodilation and retinal hyperoxia-induced vasoconstriction in type 2 diabetic subjects and in healthy controls. METHODS: Twenty men and women with type 2 diabetes and 10 men and women without diabetes between 21 and 75 years of age were recruited. Changes in retinal artery and vein diameters to flickering light and during hyperoxia (100% oxygen) stimuli were measured on the same visit using a noninvasive retinal imaging device (Dynamic Vessel Analyzer, Imedos Inc., Germany). RESULTS: Compared with controls, diabetic subjects had impaired arterial vasodilator and vasoconstrictor responses to both flickering light and hyperoxia, respectively (both p<0.001). Merging both groups, an inverse correlation (r=-0.56; p=0.003) between the retinal artery's responses to flickering light-induced vasodilation and hyperoxia-induced vasoconstriction was demonstrated independent of glucose or insulin levels. CONCLUSION: This suggests that both responses are attenuated to a similar degree in diabetic subjects and that the attenuation to both stimuli can be observed in retinal arteries and veins. This would suggest that similar vasoregulatory factor(s) might in part help to explain the retinal diameter responses between the two stimuli. One suggested common vasoregulator of vascular tone is nitric oxide; however, other factor(s) may be involved, which contribute to this association and require further research.