Differential Findings on Anorectal Manometry in Patients with Parkinson's Disease and Defecatory Dysfunction.

Introduction: Gastrointestinal dysfunction, particularly constipation, is among the most common non-motor manifestations in Parkinson's Disease (PD). We aimed to identify high-resolution anorectal manometry (HR-ARM) abnormalities in patients with PD using the London Classification. Methods: We conducted a retrospective review of all PD patients at our institution who underwent HR-ARM and balloon expulsion test (BET) for evaluation of constipation between 2015 and 2021. Using age and sex-specific normal values, HR-ARM recordings were re-analyzed and abnormalities were reported using the London Classification. A combination of Wilcoxon rank sum and Fisher's exact test were used. Results: 36 patients (19 women) with median age 71 (interquartile range [IQR]: 69-74) years, were included. Using the London Classification, 7 (19%) patients had anal hypotension, 17 (47%) had anal hypocontractility, and 3 women had combined hypotension and hypocontractility. Anal hypocontractility was significantly more common in women compared to men. Abnormal BET and dyssynergia were noted in 22 (61%) patients, while abnormal BET and poor propulsion were only seen in 2 (5%). Men had significantly more paradoxical anal contraction and higher residual anal pressures during simulated defecation, resulting in more negative recto-anal pressure gradients. Rectal hyposensitivity was seen in nearly one third of PD patients and comparable among men and women. Conclusion: Our data affirms the high prevalence of anorectal disorders in PD. Using the London Classification, abnormal expulsion and dyssynergia and anal hypocontractility were the most common findings in PD. Whether the high prevalence of anal hypocontractility in females is directly related to PD or other confounding factors will require further research.

Nonvestibular Dizziness.

Dizziness is a common chief complaint with an extensive differential diagnosis that ranges from peripheral, central, to nonvestibular conditions. An understanding of nonvestibular conditions will aid accurate diagnosis and initiation of appropriate management. Thus, the objective of this article is to present an overview of nonvestibular etiologies that may plague a dizzy patient and the recommended treatment options.

Symptom Recognition Is Impaired in Patients With Orthostatic Hypotension.

Failure to recognize symptoms of orthostatic hypotension (OH) may result in falls, syncope, and injuries. The relationship between orthostatic changes in blood pressure and symptom occurrence and severity is not known. The goal of the present study was to define the relationship between the occurrence and severity of the symptoms of orthostatic hypotension (OH) and (1) the upright systolic blood pressure (SBP) and (2) the fall in SBP after tilting in patients with OH. We prospectively studied 89 patients with OH. Reported BP values include the lowest BP in the first 3 minutes of tilt and the change in blood pressure during tilt. Subjects were queried about symptoms of orthostatic intolerance while supine and during the first 3 minutes of tilt testing using Question 1 of the Orthostatic Hypotension Questionnaire. Mean tilted SBP was 101.6±26.1 mm Hg and mean SBP fall 47.9±18.1 mm Hg. Mean symptom scores when upright were: light-headedness (2.3/10±2.7), dizziness (1.6/10±2.5), and impending blackout (0.8/10±1.9). The majority of patients were asymptomatic or mildly symptomatic and no discrete cutoff for symptoms was observed. The magnitude of the SBP fall (r=-0.07, P=NS) and the lowest upright SBP (r=0.08, P=NS) did not correlate with any reported symptom. These results suggest a poor relationship between the magnitude of the orthostatic BP fall, the upright orthostatic BP, and symptoms. Many patients are asymptomatic despite substantial SBP falls and low orthostatic blood pressures. These findings have implications for clinical care of patients with OH and clinical trials to treat patients with OH.

Orthostatic Hypotension: JACC State-of-the-Art Review.

Neurogenic orthostatic hypotension is a highly prevalent and disabling feature of autonomic failure due to both peripheral and central neurodegenerative diseases. Community-based epidemiological studies have demonstrated a high morbidity and mortality associated with neurogenic orthostatic hypotension. It is due to impairment of baroreflex-mediated vasoconstriction of the skeletal muscle and splanchnic circulation and is caused by damage or dysfunction at central and/or peripheral sites in the baroreflex efferent pathway. Nonpharmacological and pharmacological interventions may be implemented to ameliorate the symptoms of orthostatic intolerance and improve quality of life. Many patients will be adequately treated by education, counseling, removal of hypotensive medications, and other nonpharmacological interventions, whereas more severely afflicted patients require pharmacological interventions. The first stage of pharmacological treatment involves repletion of central blood volume. If unsuccessful, this should be followed by treatment with sympathomimetic agents.

Blood pressure oscillations in baroreflex failure.

A 67-year-old man presented with labile hypertension and orthostatic hypotension after radical neck dissection and radiotherapy for squamus cell carcinoma. Baroreflex failure is clearly evident on autonomic testing.

Pathophysiology and Treatment of Orthostatic Hypotension in Parkinsonian Disorders.

OPINION STATEMENT: Orthostatic hypotension (OH) is defined as a sustained pathological reduction in blood pressure within 3 min after orthostatic stress such as tilt-table testing or active standing. Non-neurogenic OH is caused by either decreased cardiac output or impaired vasoconstriction without a primary autonomic disorder whereas neurogenic OH results from inadequate release of norepinephrine in the vasomotor sympathetic system. Once non-neurogenic causes of OH such as medications and cardiac problems are ruled out, neurogenic OH can be considered. Neurogenic OH can accompany parkinsonian diseases in different stages and is associated with increased risk of morbidity and mortality. The pathophysiology of neurogenic OH in parkinsonian diseases includes sympathetic neurocirculatory failure and impaired cardiovagal activity. The inadequate release of peripheral norepinephrine upon orthostatic stress is a final pathologic pathway for neurogenic OH and is important for many therapeutic interventions. With mild or early autonomic failure, OH that occurs beyond 3 min of standing (defined as delayed OH) can result in orthostatic intolerance. Supine hypertension and postprandial hypotension are frequent comorbidities and may exacerbate orthostatic hypotension. The non-pharmacologic therapies should be tried initially, followed by pharmacologic treatments. Common medications used in the treatment of OH include fludrocortisone, midodrine, pyridostigmine, and droxidopa. Only midodrine and droxidopa have received FDA approval for the treatment of orthostatic hypotension.

Ischemic neuropathy associated with livedoid vasculitis.

BACKGROUND: Livedoid vasculitis is a chronic dermatological problem with an unclear etiology. Clinical findings are petechiae with painful ulcers in both lower extremities, which heal to become hyperpigmented and porcelain-white satellite lesions. There are only a few reported cases of livedoid vasculitis presenting in combination with peripheral neuropathy. CASE REPORT: We report the first case of a Korean patient presenting with mononeuritis multiplex combined with livedoid vasculitis, which was confirmed by electrophysiological and pathological studies. CONCLUSIONS: Our report supports the possible vaso-occlusive etiology of livedoid vasculitis in multifocal ischemic neuropathy.

Circulating endothelial progenitor cells as a new marker of endothelial dysfunction or repair in acute stroke.

BACKGROUND AND PURPOSE: Understanding on distinct subsets of endothelial progenitor cells may provide insights of endothelial dysfunction or repair in the acute ischemic event. Recent in vitro data have reported the colony-forming unit (CFU) and outgrowth cell population as a subset of endothelial progenitor cells. In this study, we undertook to validate the significance of CFU number and outgrowth cell yield in acute stroke. METHODS: Mononuclear cells were isolated from the peripheral blood of 75 patients with acute stroke, 45 patients with chronic stroke, and 40 age-matched healthy volunteers. CFU numbers were counted after culturing them for 7 days, and outgrowth cell appearance was measured during the 2 months of culture. Endothelial progenitor cell function was also evaluated by matrigel plate assays. Independent parameters predicting CFU number and outgrowth cell yield were assessed using logistic regression analysis. RESULTS: The CFU numbers and tube formation abilities in matrigel assays were significantly reduced in patients with acute stroke compared with patients with chronic stroke or healthy control subjects. Moreover, patients with large artery atherosclerosis had much lower CFU numbers and functional activities than ones with cardioembolism. Outgrowth cells were isolated from 10% of healthy control subjects and 22% of patients with chronic stroke during the cultures, but from 71% of patients with stroke. Multivariate analysis identified glycosylated hemoglobin and National Institutes of Health Stroke Scale on admission as significant independent predictors of a low CFU number and a high isolation frequency of outgrowth cells, respectively. CONCLUSIONS: CFU number may thus represent an accumulated endothelial progenitor cell dysfunctional status, whereas outgrowth cell appearance may reflect the resilience of the systemic circulation to acute ischemic stress.

Identification of neuronal outgrowth cells from peripheral blood of stroke patients.

OBJECTIVE: Recent studies have identified a subset of outgrowth cell population with endothelial phenotype in long-term cultures of peripheral blood mononuclear cells. The concept that peripheral blood-derived cells participate in neuronal regeneration remains highly controversial, and no specific cell type has been identified. In this study, we undertook to characterize outgrowth cells in the peripheral blood culture from stroke patients. METHODS: Mononuclear cells were isolated from the peripheral blood of 30 acute stroke patients, 20 risk factor-only subjects, and 20 healthy volunteers. The isolation frequency of outgrowth cells was measured during the 2 months of culture. The outgrowth cells were characterized by in vitro cultures and in vivo model of transplantation into the ischemic rat brain. RESULTS: Outgrowth cells could be more efficiently isolated from stroke patients (80%) than risk factor-only (30%) and healthy groups (10%). Outgrowth cells were more detected in the patients with greater National Institute of Health Stroke Scale scores (p = 0.023). They exhibited heterogenous populations with different morphologies, for example, cobblestone, palisading, or branching features. Two different types of outgrowth cells were identified: endothelial; neuronal, according to their morphological characteristics; and protein or gene expression profiles. The transplanted neuronal outgrowth cells survived in the ischemic rat brains over 6 months after transplantation. Targeted migration of the transplanted cells was seen in the ischemic brains with phenotypes of neuronal phenotypes. INTERPRETATION: The feasibility of extracting and culturing neuronal outgrowth cells in large numbers suggests that such autologous cells will be useful for applications ranging from basic research to cell-based therapy.

Systemic transplantation of human adipose stem cells attenuated cerebral inflammation and degeneration in a hemorrhagic stroke model.

Adipose-derived stem cells (ASCs) are readily accessible multipotent mesenchymal stem cells and are known to secrete multiple growth factors, and thereby to have cytoprotective effects in various injury models. In the present study, the authors investigated the neuroprotective effect of ASCs in an intracerebral hemorrhage (ICH) model. ICH was induced via the stereotaxic infusion of collagenase, and human ASCs (three million cells per animal) isolated from human fresh fat tissue, were intravenously administered at 24 h post-ICH induction. Acute brain inflammation markers, namely, cell numbers positively stained for terminal transferase dUTP nick end labeling (TUNEL), myeloperoxidase (MPO), or OX-42, and brain water content were checked at 3 days post-ICH. In addition, the authors quantified brain degeneration by measuring hemispheric atrophy and perihematomal glial thickness at 6 weeks post-ICH, and determined modified limb placing behavioral scores weekly over 5 weeks post-ICH. The results showed that brain water content, TUNEL+, and MPO+ cell numbers were significantly reduced in the ASC-transplanted rats. ASC transplantation attenuated neurological deficits from 4 to 5 weeks post-ICH, and reduced both the brain atrophy and the glial proliferation at 6 weeks. Transplanted ASCs were found to densely populate perihematomal areas at 6 weeks, and to express endothelial markers (von Willebrand factor and endothelial barrier antigen), but not neuronal or glial markers. In summary, ASCs transplantation in the ICH model reduced both acute cerebral inflammation and chronic brain degeneration, and promoted long-term functional recovery.

Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage.

Angiotensin II exerts its central nervous system effects primarily via its receptors AT1 and AT2, and it participates in the pathogenesis of ischemia via AT1. The selective AT1 receptor blocker (ARB) is used in the hypertension treatment, and it exerts a variety of pleiotropic effects, including antioxidative, antiapoptotic, and anti-inflammatory effects. In this study, we investigated the therapeutic effect of the ARB telmisartan in experimental intracerebral hemorrhage (ICH) in normotensive rats. ICH was induced via the collagenase infusion or autologous blood injection. Either telmisartan at 30 mg/kg/dose or phosphate-buffered saline was orally administered 2 h after ICH induction. We evaluated hemorrhage volume, brain water content, and functional recovery, and we performed the histological analysis for terminal deoxynucleotidyl transferase dUTP nick-end labeling, leukocyte infiltration, and microglia activation. A variety of intracellular signals, in terms of oxidative stress, apoptotic molecules, and inflammatory mediators, were also measured. Telmisartan reduced hemorrhage volume, brain edema, and inflammatory or apoptotic cells in the perihematomal area. Telmisartan was noted to induce the expression of endothelial nitric-oxide synthase and peroxisome proliferator-activated receptor gamma and decrease oxidative stress, apoptotic signal, tumor necrosis factor-alpha, and cyclooxygenase-2 expression. The telmisartan-treated rats exhibited less pronounced neurological deficits and recovered better. Thus, telmisartan seems to offer neural protection, including antiapoptosis, anti-inflammatory, and antioxidant benefits in the intracerebral hemorrhage rat model.

Valproic acid-mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation.

The modification of histone N-terminal tails by acetylation or deacetylation can alter the interaction between histones and DNA, and thus regulate gene expression. Recent experiments have demonstrated that valproic acid (VPA), a well-known anti-epileptic drug, can directly inhibit histone deacetylase (HDAC) activity and cause the hyperacetylation of histones. Moreover, VPA has been shown to mediate neuronal protection by activating signal transduction pathways and by inhibiting proapoptotic factors. In this study, we attempted to determine whether VPA alleviates cerebral inflammation and perihematomal cell death after intracerebral hemorrhage (ICH). Adult male rats received intraperitoneal injections of 300 mg/kg VPA or PBS twice a day after ICH induction. VPA treatment inhibited hematoma expansion, perihematomal cell death, caspase activities, and inflammatory cell infiltration. In addition, VPA treatment had the following expressional effects; it activated the translations of acetylated histone H3, pERK, pAKT, pCREB, and HSP70; up-regulated bcl-2 and bcl-xl but down-regulated bax; and down-regulated the mRNAs of Fas-L, IL-6, MMP-9, MIP-1, MCP-1, and tPA. VPA-treated rats also showed better functional recovery from 1 day to 4 weeks after ICH. Here we show that VPA induces neuroprotection in a murine ICH model and that its neuroprotective effects are mediated by transcriptional activation following HDAC inhibition.

Proteasomal inhibition in intracerebral hemorrhage: neuroprotective and anti-inflammatory effects of bortezomib.

Inflammation is an important pathophysiologic mechanism of injury induced by intracerebral hemorrhage (ICH). The ubiquitin-proteasome system (UPS) regulates the inflammatory responses via the up-regulation of several pro-inflammatory molecules. In this study, we determined that a potent proteasome inhibitor, bortezomib, exerted therapeutic effects in experimental model of ICH. Either bortezomib (0.05, 0.2, 0.5, 1mg/kg) or vehicle was intravenously administered 2h after ICH induction. The high doses of bortezomib caused high mortality rates. Bortezomib at 0.2 mg/kg reduced the early hematoma growth and alleviated hematoma volume and brain edema at 3 days after ICH, compared with the ICH-vehicle group. The numbers of myeloperoxidase(+) neutrophils, Ox42(+) microglia, and TUNEL(+) cells in the perihematomal regions were decreased by bortezomib. Bortezomib induced significant decrements of mRNA expression of TNF-alpha and IL-6. The production of iNOS and COX2 was also reduced significantly by bortezomib. We concluded that the early treatment with bortezomib induced a reduction in the early hematoma growth and mitigated the development of brain edema, coupled with a marked inhibitory effect on inflammation in ICH.

Pharmacological induction of heat shock protein exerts neuroprotective effects in experimental intracerebral hemorrhage.

Heat shock proteins (HSPs) are reported to reduce inflammation and apoptosis in a variety of brain insults. Geranylgeranylacetone (GGA), developed as an antiulcer in Japan, has been known to induce HSP70 and to exert cytoprotective effects. In this study, we investigated whether GGA, as a specific HSP inducer, exerts therapeutic effects in experimentally induced intracerebral hemorrhage (ICH). ICH was induced with male Sprague-Dawley rats via the collagenase infusion. GGA (800 mg/kg) was administered via oral tube according to various schedules of treatment. The treatment with GGA, beginning before the induction of ICH and continuing until day 3, showed the reduction of brain water content and the increased level of HSP70 protein, as compared to the treatment with vehicle, although GGA started after the induction of ICH or administered as a single dose before ICH failed to up-regulate HSP70 and to reduce brain edema. The rats treated with GGA exhibited better functional recovery than those treated with vehicle. In the pre- and post- treatment group, inflammatory cells and cell death in the perihematomal regions were found to have been decreased. The treatment of GGA inhibited the mRNA expression of MMP-9, uPA, IL-6 and MIP-1, with concomitant increment of eNOS and phosphorylated STAT3 and Akt after ICH. We demonstrated that GGA induced a reduction in the brain edema along with marked inhibitory effects on inflammation and cell death after ICH.

Pharmacological Induction of Ischemic Tolerance by Glutamate Transporter-1 (EAAT2) Upregulation.

BACKGROUND AND PURPOSE: Astrocytic glutamate transporter protein, GLT-1 (EAAT2), recovers extracellular glutamate and ensures that neurons are protected from excess stimulation. Recently, beta-lactam antibiotics, like ceftriaxone (CTX), were reported to induce the upregulation of GLT-1. Here, we investigated ischemic tolerance induction by CTX in an experimental model of focal cerebral ischemia. METHODS: CTX (200 mg/kg per day, IP) was administered for 5 consecutive days before transient focal ischemia, which was induced by intraluminal thread occlusion of the middle cerebral artery for 90 minutes or permanently. RESULTS: Repeated CTX injections enhanced GLT-1 mRNA and protein expressions after 3 and 5 days of treatment, respectively. CTX-pretreated animals showed a reduction in infarct volume by 58% (reperfusion) and 39% (permanent), compared with the vehicle-pretreated animals at 24 hours postischemia (P<0.01). Lower doses of CTX (20 mg/kg per day and 100 mg/kg per day) reduced infarct volumes to a lesser degree. The injection of GLT-1 inhibitor (dihydrokainate) at 30 minutes before ischemia ameliorated the effect of CTX pretreatment. However, CTX administration at 30 minutes after ischemia produced no significant reduction in infarct volume. CTX reduced the levels of proinflammatory cytokines (tumor necrosis factor-alpha, FasL), matrix metalloproteinase (MMP)-9, and activated caspase-9 (P<0.01). In addition, CTX-pretreated animals showed better functional recovery at day 1 to week 5 after ischemia (P<0.05). CONCLUSIONS: This study presents evidence that CTX induces ischemic tolerance in focal cerebral ischemia and that this is mediated by GLT-1 upregulation.