OBJECTIVE:To analyze the risk factors, presentation, etiologies, and outcomes of adult cancer patients with intracranial hemorrhage (IH).METHODS:We analyzed 208 patients retrospectively with the diagnosis of IH from the Memorial Sloan-Kettering neurology database from January 2000 through December 2007. Charts were examined for clinical and radiographic data. Survival was calculated using the Kaplan-Meier method. Survival between groups was compared via the log-rank test. Logistic regression models were used to assess for prognostic indicators of 30- and 90-day mortality.RESULTS:There were 181 intracerebral and 46 subarachnoid hemorrhages. Sixty-eight percent of patients had solid tumors, 16% had primary brain tumors, and 16% had hematopoietic tumors. Hemiparesis and headache were the most common symptoms. Intratumoral hemorrhage (61%) and coagulopathy (46%) accounted for the majority of hemorrhages, whereas hypertension (5%) was rare. Median survival was 3 months (95% confidence interval [CI] 2-4), and 30-day mortality was 31%. However, nearly one-half of patients were completely or partially independent at the time of discharge. Patients with primary brain tumors had the longest median survival (5.9 months, 95% CI 2.9-11.8, p = 0.05). Independent predictors of 30-day mortality were not having a primary brain tumor, impaired consciousness, multiple foci of hemorrhage, hydrocephalus, no ventriculostomy, and treatment of increased intracranial pressure.CONCLUSIONS:Intracranial hemorrhage in patients with cancer is often due to unique mechanisms. Prognosis is poor, but comparable to intracranial hemorrhage in the general population. Aggressive care is recommended despite high mortality, because many patients have good functional outcomes.

The common familial dysautonomia (FD) mutation causes a splicing defect that leads to production of both wild-type (WT) and mutant (MU) IKBKAP mRNA. Because drugs may alter splicing, seven drugs, fludrocortisone, midodrine, diazepam, albuterol, clonidine, caffeine, and dopamine were screened. Since only fludrocortisone negatively altered gene expression, we assessed fludrocortisone's efficacy in treating postural hypotension, and its effect on survival and secondary long-term FD problems. For 341 FD patients we obtained demographic data and clinical information from the last Center evaluation (most current or prior to death) including mean blood pressures (supine, 1 min erect and 5 min erect) and history regarding syncope and presyncope symptoms. For 175 fludrocortisone-treated patients, data from the evaluation prior to start of fludrocortisone and from the last Center evaluation were compared. The fludrocortisone-treated patient cohort was compared to the nontreated patient cohort with respect to overall survival and event-free survival for crisis frequency, worsening gait, frequent fractures, spine curvature, renal insufficiency, and pacemaker insertion. Overall survivals of patients on fludrocortisone alone, on fludrocortisone and midodrine, and on neither drug were compared. Cumulative survival was significantly higher in fludrocortisone-treated patients than in non-treated patients during the first decade. In subsequent decades, the addition of midodrine improved cumulative survival. Fludrocortisone significantly increased mean blood pressures and decreased dizziness and leg cramping, but not headaches or syncope. Fludrocortisone was associated with more long-term problems, which may reflect more symptomatic status associated with longer survival. Our data suggest that fludrocortisone has clinical efficacy despite negative in vitro observations on gene expression.

Familial dysautonomia (FD) patients frequently experience debilitating orthostatic hypotension. Since physical countermaneuvers can increase blood pressure (BP) in other groups of patients with orthostatic hypotension, we evaluated the effectiveness of countermaneuvers in FD patients.In 17 FD patients (26.4 +/- 12.4 years, eight female), we monitored heart rate (HR), blood pressure (BP), cardiac output (CO), total peripheral resistance (TPR) and calf volume while supine, during standing and during application of four countermaneuvers: bending forward, squatting, leg crossing, and abdominal compression using an inflatable belt. Countermaneuvers were initiated after standing up,when systolic BP had fallen by 40mmHg or diastolic BP by 30mmHg or presyncope had occurred.During active standing, blood pressure and TPR decreased, calf volume increased but CO remained stable.Mean BP increased significantly during bending forward (by 20.0 (17 - 28.5) mmHg; P = 0.005) (median (25(th) - 75(th) quartile)), squatting (by 50.8 (33.5 - 56) mmHg; P = 0.002), and abdominal compression (by 5.8 (-1 - 34.7) mmHg; P = 0.04) - but not during leg-crossing. Squatting and abdominal compression also induced a significant increase in CO (by 18.1 (-1.3 - 47.9) % during squatting (P = 0.02) and by 7.6 (0.4 - 19.6) % during abdominal compression (P=0.014)). HR did not change significantly during the countermaneuvers. TPR increased significantly only during squatting (by 37.2 (11.8 - 48.2) %; P = 0.01). However, orthopedic problems or ataxia prevented several patients from performing some of the countermaneuvers. Additionally, many patients required assistance with the maneuvers.Squatting, bending forward and abdominal compression can improve orthostatic BP in FD patients, which is achieved mainly by an increased cardiac output. Squatting has the greatest effect on orthostatic blood pressure in FD patients. Suitability and effectiveness of a specific countermaneuver depends on the orthopedic or neurological complications of each FD patient and must be individually tested before a therapeutic recommendation can be given.

Einleitung: Bei Familiärer Dysautonomie (FD) sind postprandiale hypertensive Krisen häufig. Der zentrale α2-Agonist Clonidin mildert diese Krisen. Fragestellung: Bei FD-Patienten sollte die Clonidin-Wirkung auf die kardiovaskuläre Modulation und Baroreflexempfindlichkeit (BRE) nach Nahrungsaufnahme (NA) geprüft werden.

Background: Pathological brain iron deposition has been implicated as a source of neurotoxic reactive oxygen species in Alzheimer disease (AD). Recent reports suggest that heterozygosity for the two common hfe mutations responsible for hereditary hemochromatosis (HH) may be a risk factor for AD, possibly by accelerating brain iron accumulation. Methods: To test this hypothesis, we genotyped 213 sporadic AD, 106 MCI, and 63 normal elderly control (NEC) individuals for the H63D and C282Y hfe mutations by polymerase chain reaction (PCR)/restriction fragment length polymorphism (RFLP) analysis. We determined the relationship of these mutations to the demographic, clinical, and neuropsychological features of AD and MCI, and evaluated whether an interaction existed between hfe and apolipoprotein E (apoE) status in these patients. Results: We observed no significant impact of H63D or C282Y heterozygosity on age at AD symptoms onset or diagnosis, age at onset of cognitive symptoms (AD and MCI combined), rates of MCI-to-AD conversion or specific neuropsychological deficits. No interactions between hfe zygosity and apoE status were discerned. Patients homozygous for H63D exhibited trends towards accelerated MCI-to-AD conversion rates and a subset of younger individuals (aged 55–75) exhibited earlier onset of cognitive symptoms relative to wild-type hfe and H63D heterozygotes. Conclusions: Contrary to earlier reports, the results of the present study do not implicate the common hfe mutations as genetic modifiers of sporadic AD and MCI. Trends towards accelerated cognitive dysfunction in H63D homozygotes warrant further study.

Background Patients with familial dysautonomia (FD) frequently experience hypertensive crises after gastrostomy feeding. The central alpha(2)-agonist clonidine attenuates feeding-induced crises. The aim of this study was to assess the effect of clonidine on cardiovascular autonomic modulation and particularly baroreflex sensitivity in familial dysautonomia after gastrostomy feeding.Material and methods In nine patients, we monitored the RR-interval and systolic blood pressure at supine rest before ( baseline 1) and after gastrostomy feeding (GF1). One day later, recordings were repeated after clonidine intake (baseline 2, GF2). We determined spectral powers of RR-interval and systolic blood pressure in the low-(LF) and high-frequency range (HF). Sympathovagal balance was determined from the LF/HF ratio of RR-interval. Baroreflex sensitivity was assessed from the alpha-index of systolic blood pressure and RR-interval.Results Gastrostomy feeding decreased RR-interval, while systolic blood pressure remained stable. Clonidine induced higher RR-intervals before and after gastrostomy feeding but decreased systolic blood pressure at baseline only. Gastrostomy feeding decreased HF-power of RR-interval significantly without clonidine, but only slightly after premedication. Clonidine increased the HF-power of RR-interval slightly at baseline and significantly after gastrostomy feeding. Gastrostomy feeding increased the LF/HF ratio without clonidine only. Clonidine decreased the LF/HF ratio at baseline and after gastrostomy feeding. Gastrostomy feeding did not change baroreflex sensitivity, but baroreflex sensitivity was higher at visit 2 than visit 1.Conclusions In familial dysautonomia, clonidine augments baroreflex sensitivity and parasympathetic modulation. The resulting cardiovascular stabilization might attenuate feeding-induced crises.

Bei Patienten mit familiärer Dysautonomie kann Nahrungsaufnahme zu autonomer Dysregulation mit hypertensiven Krisen führen. Die Pathophysiologie der Krisen ist bislang nicht bekannt. In dieser Studie sollten die kardiovaskulär-autonome Modulation und die Baroreflexempfindlichkeit bei Patienten mit familiärer Dysautonomie vor und nach Bolusernährung untersucht werden. Bei neun Kindern mit familiärer Dysautonomie (11,6±3,1 Jahre, 4 Mädchen) zeichneten wir RR-Intervall, systolischen Blutdruck (Colin Pilot®) und Atemfrequenz in Ruhe vor und 20 Minuten nach Bolusernährung über Gastrostomie-Sonde mit 7,4ml/kg Isomil®, einem sojaproteinhaltigen, laktosefreiem Gemisch aus Kornsirup, Sukrose und essenziellen Fettsäuren, auf. Mit autoregressiver Analyse von 90s Signalsegmenten berechneten wir die spektralen Leistungen der RR-Intervalle – und systolische Blutdruck-Oszillationen im sympathisch vermittelten LF-Bereich (0,04–0,15Hz) und im – für RR-Intervall parasympathisch vermittelten – HF-Bereich (0,15–0,5Hz). Als Maß der Baroreflexempfindlichkeit berechneten wir den alpha-Index als Wurzel aus dem Quotienten der LF-RR-Intervall- und LF-systolischen Blutdruck-Leistungen sofern die Signal-Kohärenz >0,5 war. Bolusernährung führte zur Abnahme von RR-Intervallen (623,3±85,2 ms vs. 707,7±68,8 ms, p<0,05) und der HF-Leistung der RR-Intervalle (35,8±31,3 ms2 vs. 225,5±131,6 ms2, p<0,05). Unverändert blieben dagegen Atemfrequenz, systolischer Blutdruck, die LF-Leistungen von systolischem Blutdruck und RR-Intervalle sowie die Baroreflexempfindlichkeit. Bolusernährung verursacht Blutpooling im Splanchnikus-Gefäßgebiet. Der Blutdruck blieb bei den Patienten mit familiärer Dysautonomie nach Bolusgabe dennoch stabil, vermutlich infolge des kompensatorischen Herzfrequenz-Anstieges. Dagegen stieg die sympathische LF-Modulation von RR-Intervall und systolischem Blutdruck nach Bolusernährung nicht an, vermutlich aufgrund der bei familiärer Dysautonomie eingeschränkten sympathischen Innervation. Der Abfall der parasympathischen HF-Modulation von RR-Intervallen nach Bolusgabe weist darauf hin, dass die Herzfrequenz infolge Vagus-Zügelung anstieg. Die fehlende Änderung der Baroreflexempfindlichkeit belegt eine eingeschränkte Fähigkeit der Patienten mit familiärer Dysautonomie, einen exzessiven Anstieg von Herzfrequenz oder Blutdruck nach Sondenernährung über den Baroreflex zu zügeln.

Bei familiärer Dysautonomie ist die hochgradige orthostatische Hypotonie medikamentös ungenügend therapierbar. Körperliche Gegenmanöver können den Blutdruck bei Patienten mit orthostatischer Hypotonie stabilisieren. Diese Studie sollte die Wirksamkeit von Gegenmanövern bei Patienten mit familiärer Dysautonomie prüfen. Bei 17 Patienten mit familiärer Dysautonomie (26,4±12,4 Jahre, acht Frauen) registrierten wir Herzrate, systolischen, diastolischen und mittleren Blutdruck (BPsys, BPdia, BPmean) im Liegen, im Stehen und während folgender Gegenmanöver: Oberkörper-Vorbeugen, Hockerstellung, Beine-Überkreuzen mit Beinmuskel-Anspannung, 20mmHg abdominelle Kompression mittels aufblasbarem Bauchgürtel. Die Manöver begannen, sobald BPsys >40mmHg oder BPdia >30mmHg abfiel oder präsynkopale Symptome auftraten. Wir verglichen die niedrigsten und höchsten Blutdruck-Werte vor und während der Manöver. Im Liegen betrug BPsys 148,9 ±7,1mmHg, BPdia 91,1±5,1mmHg, BPmean 114,3±6,6mmHg. Beim Stehen fielen BPsys um 60,5±6,7mmHg, BPdia um 42,7 ±5,0mmHg, BPmean um 49,7±6,2mmHg. Wegen Ataxie, orthopädischer oder Atem-Beschwerden war bei 3 Patienten das Vorbeugen, 7 Patienten die Hockerstellung, 4 Patienten das Beine-Überkreuzen, 3 Patienten die abdominelle Kompression nicht möglich. Weitere 10 Patienten benötigten Hilfe beim Vorbeugen, 4 Patienten beim Beine-Überkreuzen. Die Herzrate blieb im Liegen, Stehen und während der Manöver unverändert. Der Blutdruck stieg signifikant (p<0,05) während Vorbeugen (BPsys um 24,2±3,7mmHg, BPdia um 15,0±2,1mmHg, BPmean um 19,9±3,0mmHg), Hockerstellung (BPsys um 43,4±8,1mmHg, BPdia um 34,8±6,7mmHg, BPmean um 43,5±7,8mmHg), Beine-Überkreuzen (BPsys um 13,5 ±4,4mmHg, BPdia um 6,7±3,4mmHg, BPmean nicht signifikant um 6,9±5,6mmHg), abdomineller Kompression (BPsys um 24,3 ±7,6mmHg, BPmean um 20,1±8,1mmHg, BPdia stieg nicht signifikant um 11,2±6,4mmHg). Bei einzelnen Patienten können physikalische Gegenmanöver die orthostatische Hypotonie verbessern. Meist benötigen Patienten mit familiärer Dysautonomie bei den Manövern Unterstützung. Die Eignung der Manöver variiert individuell und hängt von zusätzlichen Komplikationen der familiären Dysautonomie ab. Somit haben Gegenmanöver bei Patienten mit familiärer Dysautonomie eingeschränkten therapeutischen Wert.

Cardiovascular abnormalities are prominent in the genetic disorder, familial dysautonomia (FD). To determine if autonomic dysfunction involves cardiac, as well as peripheral vascular integrity, noninvasive tests were performed in 10 FD patients and 8 healthy control subjects while supine and at 90 degrees tilt. Simultaneous blood pressure (BP) and heart rate (HR) and QTc were obtained, while performing signal-averaged electrocardiography (SAECG) and heart rate variability (HRV). FD subjects were tested on 2 separate days, before and 1 h after oral fludrocortisone or midodrine; controls were tested once without medication. With tilt, all FD subjects decreased mean BP > or = 24 mm Hg by 5 min. On SAECG, 70% of supine FD subjects had a prolonged tQRS; only 2 FD subjects shortened tQRS with tilt. The QTc interval was prolonged (> 440 ms) in 2 supine FD subjects; with tilt, the QTc prolonged in a third. Frequency domain analysis of HRV revealed that mid (MF) and high frequency band areas were significantly decreased when supine, but not when upright. On time domain analysis, the pNN50 was significantly decreased in FD subjects (8.9 +/- 1.7 vs. 17.7 +/- 3.6%, p < 0.01). Fludrocortisone lowered supine BP and HR and increased supine MF area. Midodrine raised supine and erect BP, lowered erect HR, and shortened erect QTc. Although all FD subjects have abnormal orthostatic BP and HR responses, cardiac tone, as assessed by electrocardiographic and HRV responses, varies. Prolongation of the tQRS appears to be a sensitive but not specific indicator of autonomic dysfunction. QTc prolongation may indicate more extensive sympathetic dysfunction. HRV data suggest some FD patients have abnormalities in parasympathetic, as well as sympathetic, cardiac tone.

This report extends previous investigations of endogenous catecholamine levels in patients with orthostatic hypotension due to familial dysautonomia (FD), to define better the neurochemical phenotype and elucidate possible pathophysiological mechanisms. Ten FD patients (age 26.1 +/- 2.6 (SEM) years) and eight control subjects (age 29.5 +/- 3.7 years) were studied. Heart rate, blood pressure and venous blood samples were obtained while supine and after 5 min in the upright position. Plasma levels of dihydroxyphenylalanine (DOPA), noradrenaline (NA), adrenaline (A), dopamine (DA), dihydroxyphenylglycol (DHPG) and dihydroxyphenylacetic acid (DOPAC) were measured. When supine, the FD group had greater NA and DOPA levels, and lower DHPG levels. Plasma NA did not increase with erect posture in FD patients. Individual FD mean blood pressures were correlated positively with plasma NA levels when supine and with plasma DA and DOPAC when upright. In FD, DOPA:DHPG ratios were above the range found in normal subjects or that reported in patients with acquired forms of dysautonomia regardless of posture, whereas DOPAC:DHPG ratios remained normal. Thus FD patients have a characteristic neurochemical pattern which probably reflects either decreased vesicular storage of catecholamines or limited oxidative deamination despite normal or increased tyrosine hydroxylation.

We describe two Hispanic adolescents with Allgrove syndrome (alacrima, achalasia, and sensorimotor polyneuropathy) in whom we documented cholinergic dysfunction by cardiovascular autonomic tests. Both patients had orthostatic hypotension and decreased heart rate variability.