Faculty Bibliography

Orthostatic hypotension is defined as a blood pressure fall of > 20 mm Hg systolic and/or 10 mm Hg diastolic within 3 minutes of an upright position. The Movement Disorders Society commissioned a task force to assess existing clinical rating scales addressing symptoms of orthostatic hypotension in Parkinson's disease. Seven neurologists and a clinimetrician assessed each scale's previous use and critiqued its clinimetric properties. A scale was "recommended" if it had been applied to populations of patients with Parkinson's disease, with data on its use in studies beyond the group that developed the scale, and was found to be clinimetrically valid. A scale was considered "suggested" if it had been applied to Parkinson's disease, but only 1 of the other criteria was applied. A scale was "listed" if it met only 1 criterion. Symptoms of orthostatic hypotension are generally assessed in scales on wider autonomic or nonmotor symptoms. Some scales designed to detect orthostatic hypotension-related symptoms provide information on their severity: the AUTonomic SCale for Outcomes in PArkinson's Disease and the COMPosite Autonomic Symptom Scale met criteria for recommended with some limitations; the Novel Non-Motor Symptoms Scale and the Orthostatic Grading Scale were classified as suggested. The Self-completed Non-Motor Symptoms Questionnaire for Parkinson's Disease was classified as suggested as a tool for screening orthostatic symptoms. However, these and the listed scales need further validation and application before they can be recommended for clinical use in patients with Parkinson's disease.

Whereas aging affects cognitive and psychomotor processes negatively, the impact of aging on emotional processing is less clear. Using an "old-new" binary decision task, we ascertained the modulation of response latencies after presentation of neutral and emotional pictures in "young" (M = 27.1 years) and "young-old" adults with a mean age below 60 (M = 57.7 years). Stimuli varied on valence (pleasant, neutral, and unpleasant) and arousal (high and low) dimensions. Young-old adults had significantly longer reaction times. However, young and young-old adults showed the exact same pattern of response time modulation by emotional stimuli: Response latencies were longer for high-arousal than for low-arousal pictures and longer for negative than for positive or neutral stimuli. This result suggests that the specific effects of implicitly processed emotional valence and arousal information on behavioral response time are preserved in young-old adults despite significant age-related psychomotor decline.

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.

The Riley-Day syndrome is the most common of the hereditary sensory and autonomic neuropathies (Type III). Among the well-recognized clinical features are reduced pain and temperature sensation, absent deep tendon reflexes and a progressively ataxic gait. To explain the latter we tested the hypothesis that muscle spindles, or their afferents, are absent in hereditary sensory and autonomic neuropathy III by attempting to record from muscle spindle afferents from a nerve supplying the leg in 10 patients. For comparison we also recorded muscle spindles from 15 healthy subjects and from two patients with hereditary sensory and autonomic neuropathy IV, who have profound sensory disturbances but no ataxia. Tungsten microelectrodes were inserted percutaneously into fascicles of the common peroneal nerve at the fibular head. Intraneural stimulation within muscle fascicles evoked twitches at normal stimulus currents (10-30 microA), and deep pain (which often referred) at high intensities (1 mA). Microneurographic recordings from muscle fascicles revealed a complete absence of spontaneously active muscle spindles in patients with hereditary sensory and autonomic neuropathy III; moreover, responses to passive muscle stretch could not be observed. Conversely, muscle spindles appeared normal in patients with hereditary sensory and autonomic neuropathy IV, with mean firing rates of spontaneously active endings being similar to those recorded from healthy controls. Intraneural stimulation within cutaneous fascicles evoked paraesthesiae in the fascicular innervation territory at normal stimulus intensities, but cutaneous pain was never reported during high-intensity stimulation in any of the patients. Microneurographic recordings from cutaneous fascicles revealed the presence of normal large-diameter cutaneous mechanoreceptors in hereditary sensory and autonomic neuropathy III. Our results suggest that the complete absence of functional muscle spindles in these patients explains their loss of deep tendon reflexes. Moreover, we suggest that their ataxic gait is sensory in origin, due to the loss of functional muscle spindles and hence a compromised sensorimotor control of locomotion

Autoimmune autonomic ganglionopathy (AAG) and myasthenia gravis (MG) are both autoimmune channelopathies mediated by antibodies directed against nicotinic acetylcholine receptors. While both diseases target acetylcholine receptors, skeletal muscle and ganglionic receptor subtypes have key immunologic and genetic distinctions, and reports of patients with both AAG and MG are rare. We report a patient with antibody-confirmed AAG and elevated levels of ACh binding antibodies that did not meet clinical or electrodiagnostic criteria for MG. We presume that his skeletal muscle nAChR seropositivity was a false positive, perhaps due to the cross reactivity of the patient's ganglionic nAChR antibodies with skeletal nAChR subtypes

Familial dysautonomia (FD) is an autosomal recessive disorder characterized by autonomic and sensory neuropathy. Owing to pervasive dysfunction, the disease has protean clinical manifestations, affecting the ocular, gastrointestinal, pulmonary, orthopedic, vasomotor, and neurologic systems. The gastrointestinal perturbations, including dysphagia, gastroesophageal dysmotility, gastroesophageal reflux, and vomiting crises, are among the earliest signs. Here, we present the first 3 instances of gastric ulcers in patients with FD and discuss their common presenting features and the special management that was required

OBJECTIVE: Panayiotopoulos syndrome is a benign idiopathic childhood epilepsy characterized by altered autonomic activity at seizure onset. METHODS: Three siblings with Panayiotopoulos syndrome underwent 24-hour EEG recording and head-up tilt testing with continuous blood pressure and RR interval monitoring. Plasma catecholamines and vasopressin were measured while supine, upright, and during a typical seizure. RESULTS: Patient 1, a 12-year-old girl, had a history of involuntary lacrimation, abdominal pain, and recurrent episodes of loss of muscle tone and unresponsiveness followed by somnolence. Her EEG revealed bilateral frontotemporal spikes. Patient 2, a 10-year-old boy, had episodic headaches with pinpoint pupils, skin flushing of the face, trunk, and extremities, purple discoloration of hands and feet, diaphoresis, nausea, and vomiting. Tilt testing triggered a typical seizure after 9minutes; there was a small increase in blood pressure (+5/4mm Hg, systolic/diastolic) and pronounced increases in heart rate (+59bpm) and norepinephrine (+242pg/mL), epinephrine (+175pg/mL), and vasopressin (+22.1pg/mL) plasma concentrations. Serum glucose was elevated (206mg/dL). His EEG revealed right temporal and parietal spikes. Patient 3, an 8-year-old boy, had a history of restless legs at night, enuresis, night terrors, visual hallucinations, cyclic abdominal pain, and nausea. His EEG showed bitemporal spikes. CONCLUSION: Hypertension, tachycardia, and the release of vasopressin suggest activation of the central autonomic network during seizures in familial Panayiotopoulos syndrome. These autonomic and neuroendocrine features may be useful in the diagnosis and may have therapeutic implications

Familial dysautonomia (FD) is caused by an intronic splice mutation in the IKBKAP gene that leads to partial skipping of exon 20 and tissue-specific reduction in I-kappa-B kinase complex-associated protein/elongation protein 1 (IKAP/ELP-1) expression. Kinetin (6-furfurylaminopurine) has been shown to improve splicing and increase WT IKBKAP mRNA and IKAP protein expression in FD cell lines and carriers. To determine whether oral kinetin treatment could alter mRNA splicing in FD subjects and was tolerable, we administered kinetin to eight FD individuals homozygous for the splice mutation. Subjects received 23.5 mg/Kg/d for 28 d. An increase in WT IKBKAP mRNA expression in leukocytes was noted after 8 d in six of eight individuals; after 28 d, the mean increase compared with baseline was significant (p = 0.002). We have demonstrated that kinetin is tolerable in this medically fragile population. Not only did kinetin produce the desired effect on splicing in FD patients but also that effect seems to improve with time despite lack of dose change. This is the first report of a drug that produces in vivo mRNA splicing changes in individuals with FD and supports future long-term trials to determine whether kinetin will prove therapeutic in FD patients. ABBREVIATIONS::

Background: Patients with familial dysautonomia (FD) fail to increase respiratory drive in response to low oxygen and high CO₂ levels. Many hypoventilate and have frequent apneic events during sleep, a time associated with an increased incidence of sudden death. To assess the need for non-invasive ventilation, patients with FD routinely undergo sleep studies with end-tidal CO₂ monitoring. Because most have severe lung disease, it is not known, however, whether end-tidal CO₂ levels accurately reflect arterial blood CO₂ levels. Methods: We studied 88 patients with FD (mean age 25 +/- 1, 45; females:43 males). We measured the partial pressure of CO₂ in blood obtained from the radial artery at the wrist (ABL80 FLEX, Radiometer, Denmark). End-tidal CO₂ was continuously sampled from a nasal canula (infrared analysis 5200 Ohmeda, USA). The average CO₂ value obtained over 10 full tidal breaths was used. All measurements were obtained during relaxed spontaneous breathing in the supine position. The relationship between end-tidal and arterial CO₂ measurements was examined using Pearson correlations. Results: All patients had a history of at least one aspiration pneumonia. The average partial pressure of oxygen in arterial blood was 87 +/- 2 mmHg. Thirty-one patients (36%) had arterial oxygen levels B80 mmHg. The average partial pressure of CO₂ was 43 +/- 0.4 mmHg (range 34-57 mmHg). Thirty-four patients (39%) had hypercapnia with CO₂ in arterial blood >=45 mmHg. Measurements of end-tidal CO₂ correlated tightly with CO₂ measured in arterial blood (y = 0.88x + 2.23, R² = 0.50, p<0.001). Conclusions: Our results show that in patients with FD, despite severe lung disease, the partial pressure of CO₂ measured in expired air (i.e. end tidal CO₂) accurately reflects the partial pressure ofCO₂ in arterial blood. Monitoring end tidal CO₂ is critically important to determine the potential role of apnea/hypoventilation in sudden death during sleep