Faculty Bibliography

The glutamate neurotransmitter system has the potential to transform our knowledge of the pathophysiology of schizophrenia and help us identify potential treatment targets. In this section of the supplement, the dopamine system is first reviewed as it relates to schizophrenia and its treatment with the currently available antipsychotics, followed by a discussion of glutamate receptors and how they, too, can impact on positive, negative, and cognitive symptoms. Symptoms of schizophrenia can be theoretically explained by a hyper-dopaminergic state existing in the mesolimbic pathway and a hypodopaminergic state in the mesocortical pathways; the former results in positive symptoms and the latter leads to negative, cognitive, and affective symptoms. Current FDA-approved pharmacologic options for the treatment of schizophrenia involve dopamine blockade at the dopamine D2 receptor. Although commercially available antipsychotic agents have at least some degree of antagonism at the dopamine D2 receptor, there are some investigational agents that produce an antipsychotic effect in the absence of direct dopamine D2 receptor antagonism. The glutamate-dopamine model of schizophrenia offers new therapeutic targets, including NMDA agonists, glycine transport inhibitors, and metabotropic glutamate receptor agonists.

Leukoencephalopathy and autonomic dysfunction have been described in individuals with very low serum B(12) levels (<200 pg/ml), in addition to psychiatric changes, neuropathy, dementia and subacute combined degeneration. Elevated homocysteine and methylmalonic acid levels are considered more sensitive and specific for evaluating truly functional B(12) deficiency. A previously healthy 62-year-old woman developed depression and cognitive deficits with autonomic dysfunction that progressed over the course of 5 years. The patient had progressive, severe leukoencephalopathy on multiple MRI scans over 5 years. Serum B(12) levels ranged from 267 to 447 pg/ml. Homocysteine and methylmalonic acid levels were normal. Testing for antibody to intrinsic factor was positive, consistent with pernicious anaemia. After treatment with intramuscular B(12) injections (1000 mug daily for 1 week, weekly for 6 weeks, then monthly), she made a remarkable clinical recovery but remained amnesic for major events of the last 5 years. Repeat MRI showed partial resolution of white matter changes. Serum B(12), homocysteine and methylmalonic acid levels are unreliable predictors of B(12)-responsive neurologic disorders, and should be thoroughly investigated and presumptively treated in patients with unexplained leukoencephalopathy because even long-standing deficits may be reversible

BACKGROUND: Familial dysautonomia (FD) is due to a genetic deficiency of the protein IKAP, which affects development of peripheral neurons. Patients with FD display complex abnormalities of the baroreflex of unknown cause. METHODS: To test the hypothesis that the autonomic phenotype of FD is due to selective impairment of afferent baroreceptor input, we examined the autonomic and neuroendocrine responses triggered by stimuli that either engage (postural changes) or bypass (cognitive/emotional) afferent baroreflex pathways in 50 patients with FD and compared them to those of normal subjects and to those of patients with pure autonomic failure (PAF), a disorder with selective impairment of efferent autonomic neurons. RESULTS: During upright tilt, in patients with FD and in patients with PAF blood pressure fell markedly but the heart rate increased in PAF and decreased in FD. Plasma norepinephrine levels failed to increase in both groups. Vasopressin levels increased appropriately in patients with PAF but failed to increase in patients with FD. Head-down tilt increased blood pressure in both groups but increased heart rate only in patients with FD. Mental stress evoked a marked increase in blood pressure and heart rate in patients with FD but little change in those with PAF. CONCLUSION: The failure to modulate sympathetic activity and to release vasopressin by baroreflex-mediated stimuli together with marked sympathetic activation during cognitive tasks indicate selective failure of baroreceptor afference. These findings indicate that IKAP is critical for the development of afferent baroreflex pathways and has therapeutic implications in the management of these patients

BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) is an increasingly recognized complication of familial dysautonomia (FD), a neurodevelopmental disorder with protean systemic manifestations that are the result of sensory and autonomic dysfunction. Progressive renal dysfunction occurs due to chronic volume depletion and cardiovascular lability with supine hypertension and orthostatic hypotension. By age 25, nearly one-half of all patients with FD will have reached stage 3 CKD. Furthermore, dialysis for ESRD in FD patients is associated with multiple complications and poor outcomes. Design, settings, participants, & measurements: We report two patients with FD who developed ESRD at ages 27 and 16, respectively, and underwent renal transplantation. Transplant was performed after 3 months on intermittent hemodialysis (HD) in the first case and after 1 month on twice-weekly continuous veno-venous hemodialysis (CVVHD) in the second case. RESULTS: Both patients tolerated surgery well and have maintained good graft function at 20 and 24 months posttransplantation, respectively. Symptomatic and functional improvements have included lower supine BP and increased sensitivity to antihypertensive agents. CONCLUSIONS: As general supportive care improves the lifespan of FD patients, issues related to the management of ESRD will become more important. Renal transplantation provides a viable alternative to dialysis for FD patients with ESRD

We report the case of a woman with Munchausen syndrome who surreptitiously injected epinephrine causing recurrent ventricular tachyarrhythmias accompanied by dramatically high plasma levels of epinephrine and normal norepinephrine levels

OBJECTIVE: To test the hypothesis that panic disorder (PD) patients have a heightened or deregulated autonomic nervous system at rest and during autonomic challenge compared with healthy controls (HC); and to test a second hypothesis that severity of illness differentiates patients'; sympathovagal balance both at rest and during orthostatic challenge. METHODS: Spectral analysis of heart rate (HR) and blood pressure was performed on 30 PD and 10 HC participants during an orthostatic challenge (head-up tilt). RESULTS: PD patients presented higher HR (p < .001), lower heart rate variability (HRV) (p < .015), higher mean diastolic blood pressure (p < .006), higher low-frequency component of HR (p < .001), and a higher ratio of low-frequency to high-frequency component of HR (LF/HF) (p < .022) than HC at baseline. During tilt, PD patients responded with higher HR (p < .039), lower HRV (p < .043), increased mean diastolic blood pressure (p < .028), and a mild increase in LF/HF, whereas controls responded with a five-fold increase in LF/HF (p < .022). Patients with higher illness severity ratings (Clinical Global Impression Scale) showed higher HR (p < .002), lower HRV (p < .026), and a lower total power of systolic blood pressure (p < .02) compared with less ill patients. CONCLUSION: These findings demonstrate a consistently higher or deregulated autonomic arousal in PD patients at rest and during orthostatic challenge compared with HC. These data also reveal a possible association between the level of anxiety illness severity and sympathovagal balance, which may imply greater cardiac risk

Renal failure is a common problem in patients with familial dysautonomia (FD). By age 25, 20% of patients with FD have end stage renal disease. To determine the role of arterial hypertension in the development and progression of kidney disease, we compared glomerular filtration rate (Cockcroft-Gault equation) over time in 50 patients with FD according to their level of arterial hypertension throughout childhood (until age 15). In addition, to assess the possible impact of increased blood pressure variability on renal function we examined the relationship between the standard deviation of ambulatory blood pressure over 24-h, an indicator of blood pressure volatility, and glomerular filtration rate. Patients with average systolic blood pressure[180 mmHg during childhood (stage III and IV hypertension American Heart Association) had a faster decline in glomerular filtration rate over time than patients with lower blood pressures (Kaplan-Meyer survival curve). There was an inverse relationship between the standard deviation of ambulatory blood pressure over 24-h and glomerular filtration rate, i.e., patients with higher standard deviation had lower glomerular filtration rates (y = - 3.3044x + 167.54, R² = 0.1949, p<0.01). Our results indicate that arterial hypertension during childhood and the magnitude of blood pressure volatility are risk factors for the development of renal failure in patients with familial dysautonomia. Prospective studies are warranted to determine whether controlling hypertension and blood pressure variability can delay the onset or slow the progression of renal failure in these patients

Background: Neurogenic orthostatic hypotension (NOH) is a disabling feature of autonomic failure. NOH causes a variety of symptoms such as dizziness, vision disturbance, fatigue, generalized weakness and impairment or loss of consciousness. Symptomatic NOH results from impaired norepinephrine release from sympathetic nerve terminals leading to low blood pressure (BP) upon standing and tissue hypoperfusion. Droxidopa is a synthetic amino acid that can augment norepinephrine levels and improve standing BP thereby reducing the signs and symptoms of NOH. We are conducting a study to evaluate the clinical benefit, safety and tolerability of droxidopa to treat symptomatic NOH. Methods: This clinical trial is being conducted at 85 centers in Austria, Canada, Czech Republic, France, Germany, Italy, Romania, Ukraine, and USA. The study enrolled 142 patients between January 2008 and May 2010. It is projected that the complete sample size of 150 will be enrolled by the end of June 2010. Patients were confirmed to have symptomatic NOH of non-diabetic origin during a 2-week baseline evaluation period. At the time of writing, 39% of patients were diagnosed with Parkinson's disease, 15% with multiple system atrophy, 33% with pure autonomic failure and 13% with other autonomic neuropathies. The population is equally distributed between females (51%) and males (49%) and is predominantly Caucasian (98%) with a mean age of 54 years. Patients enter an open-label, forced titration to determine an optimal treatment dose of droxidopa ranging from 100 mg T.I.D. to 600 mg T.I.D in 100 mg T.I.D. increments. No apparent trend has emerged to date with respect to dose as an approximately equal number of patients have been determined to be optimally treated at all dose levels. Following titration, patients are washed out of drug for 1 week. Subsequently, patients are randomized in a blinded fashion to either resume droxidopa treatment at their previously determined optimal dose or receive placebo (1:1). Study outcome measures are assessed 1 week later. Results/Conclusion: The clinical effectiveness of droxidopa will be discussed in terms of its impact on each of the 10 components of the Orthostatic Hypotension Questionnaire (OHQ), clinical global impressions of disease severity and hemodynamics. The primary efficacy variable for the trial is the OHQ composite score, which measures the global impact of NOH in a patient's life. Data currently available from the open-label titration on the first 120 patients indicates a highly significant average improvement in standing systolic blood pressure of 23 mmHg measured during clinical testing. Finally, the safety of droxidopa based on the occurrence of treatment-emergent adverse events, ECG, and laboratory findings across the study will be presented