Eduardo E. Benarroch

Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome

Roy Freeman • Wouter Wieling • Felicia B. Axelrod • David G. Benditt • Eduardo Benarroch • Italo Biaggioni • William P. Cheshire • Thomas Chelimsky • Pietro Cortelli • Christopher H. Gibbons • David S. Goldstein • Roger Hainsworth • Max J. Hilz • Giris Jacob • Horacio Kaufmann • Jens Jordan • Lewis A. Lipsitz • Benjamin D. Levine • Phillip A. Low • Christopher Mathias • Satish R. Raj • David Robertson • Paola Sandroni • Irwin Schatz • Ron Schondorff • Julian M. Stewart • J. Gert van Dijk

The Central Autonomic Network: Functional Organization, Dysfunction, and Perspective

The central autonomic network (CAN) is an integral component of an internal regulation system through which the brain controls visceromotor, neuroendocrine, pain, and behavioral responses essential for survival. It includes the insular cortex, amygdala, hypothalamus, periaqueductal gray matter, parabrachial complex, nucleus of the tractus solitarius, and ventrolateral medulla. Inputs to the CAN are multiple, including viscerosensory inputs relayed on the nucleus of the tractus solitarius and humoral inputs relayed through the circumventricular organs. The CAN controls preganglionic sympathetic and parasympathetic, neuroendocrine, respiratory, and sphincter motoneurons. The CAN is characterized by reciprocal interconnections, parallel organization, state-dependent activity, and neurochemical complexity. The insular cortex and amygdala mediate high-order autonomic control, and their involvement in seizures or stroke may produce severe cardiac arrhythmias and other autonomic manifestations. The paraventricular and other hypothalamic nuclei contain mixed neuronal populations that control specific subsets of preganglionic sympathetic and parasympathetic neurons. Hypothalamic autonomic disorders commonly produce hypothermia or hyperthermia. Hyperthermia and autonomic hyperactivity occur in patients with head trauma, hydrocephalus, neuroleptic malignant syndrome, and fatal familial insomnia. In the medulla, the nucleus of the tractus solitarius and ventrolateral medulla contain a network of respiratory, cardiovagal, and vasomotor neurons. Medullary autonomic disorders may cause orthostatic hypotension, paroxysmal hypertension, and sleep apnea. Neurologic catastrophes, such as subarachnoid hemorrhage, may produce cardiac arrhythmias, myocardial injury, hypertension, and pulmonary edema. Multiple system atrophy affects preganglionic autonomic, respiratory, and neuroendocrine outputs. The CAN may be critically involved in panic disorders, essential hypertension, obesity, and other medical conditions.

CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity.

We have defined a new paraneoplastic immunoglobulin G (IgG) autoantibody specific for CRMP‐5, a previously unknown 62‐kd neuronal cytoplasmic protein of the collapsin response‐mediator family. CRMP‐5 is in adult central and peripheral neurons, including synapses, and in small‐cell lung carcinomas. Since 1993, our Clinical Neuroimmunology Laboratory has detected CRMP‐5‐IgG in 121 patients among approximately 68,000 whose sera were submitted for standardized immunofluorescence screening because a subacute neurological presentation was suspected to be paraneoplastic. This makes CRMP‐5 autoantibody as frequent as PCA‐1 (anti‐Yo) autoantibody, second only to ANNA‐1 (anti‐Hu). Clinical information, obtained for 116 patients, revealed multifocal neurological signs. Most remarkable were the high frequencies of chorea (11%) and cranial neuropathy (17%, including 10% loss of olfaction/taste, 7% optic neuropathy). Other common signs were peripheral neuropathy (47%), autonomic neuropathy (31%), cerebellar ataxia (26%), subacute dementia (25%), and neuromuscular junction disorders (12%). Spinal fluid was inflammatory in 86%, and CRMP‐5‐IgG in 37% equaled or significantly exceeded serum titers. Lung carcinoma (mostly limited small‐cell) was found in 77% of patients; thymoma was in 6%. Half of those remaining had miscellaneous neoplasms; all but two were smokers. Serum IgG in all cases bound to recombinant CRMP‐5 (predominantly N‐terminal epitopes), but not to human CRMP‐2 or CRMP‐3. Ann Neurol 2001:49:146–154

Neuron-astrocyte interactions: partnership for normal function and disease in the central nervous system.

Interactions between neurons and astrocytes are critical for signaling, energy metabolism, extracellular ion homeostasis, volume regulation, and neuroprotection in the central nervous system. Astrocytes face the synapses, send end-foot processes that enwrap the brain capillaries, and form an extensive network interconnected by gap junctions. Astrocytes express several membrane proteins and enzymes that are critical for uptake of glutamate at the synapses, ammonia detoxification, buffering of extracellular K+, and volume regulation. They also participate in detection, propagation, and modulation of excitatory synaptic signals, provide metabolic support to the active neurons, and contribute to functional hyperemia in the active brain tissue. Disturbances of these neuron-astrocyte interactions are likely to play an important role in neurologic disorders including cerebral ischemia, neurodegeneration, migraine, cerebral edema, and hepatic encephalopathy.

Amphiphysin autoimmunity: paraneoplastic accompaniments

Amphiphysin‐IgG was identified in 71 patients among 120,000 evaluated serologically for paraneoplastic autoantibodies. Clinical information was available for 63 patients. Cancer was detected in 50 (mostly limited), proven histologically in 46, and was imaged intrathoracically in 4 patients (lung, small–cell [27] and non–small cell [1]), breast [16] and melanoma [2]). Neurological accompaniments included (decreasing frequency): neuropathy, encephalopathy, myelopathy, stiff‐man phenomena, and cerebellar syndrome. In a case examined neuropathologically, parenchymal T‐lymphocyte infiltration (predominantly CD8+) was prominent in lower brainstem, spinal cord, and dorsal root ganglion. Coexisting paraneoplastic autoantibodies, identified in 74% of patients, predicted a common neoplasm and indicated other neuronal autoantigen targets that plausibly explained several neurological manifestations; for example, P/Q‐type Ca2+‐channel antibody with Lambert–Eaton syndrome (n = 5), anti‐neuronal nuclear antibody type 1 with sensory neuronopathy (n = 7), K+‐channel antibody with limbic encephalitis (n = 1) or neuromyotonia (n = 1), and collapsin response‐mediator protein‐5‐IgG with optic neuritis (n = 3). Patients with isolated amphiphysin‐IgG (n = 19) were more likely to be women (with breast cancer, p < 0.05) and to have myelopathy or stiff‐man phenomena (p < 0.01). Overall, a minority of women (39%) and men (12%) had stiff‐man phenomena. Only 10% of women (some with lung carcinoma) and 4% of men fulfilled diagnostic criteria for stiff‐man syndrome. Ann Neurol 2005;58:96–107

Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome.

Roy Freeman • Wouter Wieling • Felicia B. Axelrod • David G. Benditt • Eduardo Benarroch • Italo Biaggioni • William P. Cheshire • Thomas Chelimsky • Pietro Cortelli • Christopher H. Gibbons • David S. Goldstein • Roger Hainsworth • Max J. Hilz • Giris Jacob • Horacio Kaufmann • Jens Jordan • Lewis A. Lipsitz • Benjamin D. Levine • Phillip A. Low • Christopher Mathias • Satish R. Raj • David Robertson • Paola Sandroni • Irwin Schatz • Ron Schondorff • Julian M. Stewart • J. Gert van Dijk

Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder.

OBJECTIVE To determine the pathologic substrates in patients with rapid eye movement (REM) sleep behavior disorder (RBD) with or without a coexisting neurologic disorder. METHODS The clinical and neuropathologic findings were analyzed on all autopsied cases from one of the collaborating sites in North America and Europe, were evaluated from January 1990 to March 2012, and were diagnosed with polysomnogram (PSG)-proven or probable RBD with or without a coexisting neurologic disorder. The clinical and neuropathologic diagnoses were based on published criteria. RESULTS 172 cases were identified, of whom 143 (83%) were men. The mean±SD age of onset in years for the core features were as follows - RBD, 62±14 (range, 20-93), cognitive impairment (n=147); 69±10 (range, 22-90), parkinsonism (n=151); 68±9 (range, 20-92), and autonomic dysfunction (n=42); 62±12 (range, 23-81). Death age was 75±9 years (range, 24-96). Eighty-two (48%) had RBD confirmed by PSG, 64 (37%) had a classic history of recurrent dream enactment behavior, and 26 (15%) screened positive for RBD by questionnaire. RBD preceded the onset of cognitive impairment, parkinsonism, or autonomic dysfunction in 87 (51%) patients by 10±12 (range, 1-61) years. The primary clinical diagnoses among those with a coexisting neurologic disorder were dementia with Lewy bodies (n=97), Parkinsons disease with or without mild cognitive impairment or dementia (n=32), multiple system atrophy (MSA) (n=19), Alzheimers disease (AD)(n=9) and other various disorders including secondary narcolepsy (n=2) and neurodegeneration with brain iron accumulation-type 1 (NBAI-1) (n=1). The neuropathologic diagnoses were Lewy body disease (LBD)(n=77, including 1 case with a duplication in the gene encoding α-synuclein), combined LBD and AD (n=59), MSA (n=19), AD (n=6), progressive supranulear palsy (PSP) (n=2), other mixed neurodegenerative pathologies (n=6), NBIA-1/LBD/tauopathy (n=1), and hypothalamic structural lesions (n=2). Among the neurodegenerative disorders associated with RBD (n=170), 160 (94%) were synucleinopathies. The RBD-synucleinopathy association was particularly high when RBD preceded the onset of other neurodegenerative syndrome features. CONCLUSIONS In this large series of PSG-confirmed and probable RBD cases that underwent autopsy, the strong association of RBD with the synucleinopathies was further substantiated and a wider spectrum of disorders which can underlie RBD now are more apparent.

Autonomic dysfunction in dementia with Lewy bodies

Objective: To assess autonomic function in patients with dementia with Lewy bodies (DLB). Methods: The authors compared data from 20 DLB patients evaluated from 1995 to 2000 to 20 age-matched multiple system atrophy (MSA) and Parkinson disease (PD) patients evaluated from 1999 to 2002. Analysis of variance, Fisher exact test, and Student t-test were applied to compare disease characteristics, autonomic symptoms, and function tests on the Composite Autonomic Scoring Scale (CASS) and Thermoregulatory Sweat Test (TST). Results: In DLB, mean age at onset of autonomic symptoms was 70.3 ± 8.9 years. Orthostatic symptoms were common and orthostatic hypotension occurred in 10/20 DLB, 17/20 MSA, and 1/20 PD patients (p = 0.023, 0.003). CASS-sudomotor for DLB, MSA, and PD were 1.6 ± 1.2, 2.5 ± 0.7, and 0.9 ± 0.8 (p < 0.00001). CASS-cardiovagal were 1.4 ± 0.9, 2.1 ± 0.8, and 0.7 ± 0.6 (p < 0.00001). CASS-adrenergic function were 2.4 ± 1.2, 3.5 ± 0.9, and 0.5 ± 0.6 (p < 0.00001). Total CASS were 5.2 ± 2.0, 8.1 ± 1.3, and 2.2 ± 1.2 (p < 0.00001). The most common pattern of TST in DLB was distal anhidrosis. Mean duration of follow-up was 3.0 ± 1.8 years. Six patients needed medication to maintain blood pressure and five had good response. Conclusions: Autonomic dysfunction is frequent in dementia with Lewy bodies and the severity is intermediate between that of multiple system atrophy and Parkinson disease.

The ictal bradycardia syndrome : Localization and lateralization

Summary:  Purpose: Previous studies have established the importance of the insular cortex and temporal lobe in cardiovascular autonomic modulation. Some investigators, based on the results of cortical stimulation response, functional imaging, EEG recordings of seizures, and lesional studies, have suggested that cardiac sympathetic and parasympathetic function may be lateralized, with sympathetic representation lateralized to the right insula, and parasympathetic, to the left. These studies have suggested that ictal bradycardia is most commonly a manifestation of activation of the left temporal and insular cortex. However, the evidence for this is inconsistent. We sought to assess critically the predictable value of ictal bradycardia for seizure localization and lateralization.

The locus ceruleus norepinephrine system: Functional organization and potential clinical significance

The locus ceruleus (LC) contains norepinephrine (NE)-synthesizing neurons that send diffuse projections throughout the CNS. The LC-NE system has a major role in arousal, attention, and stress response. In the brain, NE may also contribute to long-term synaptic plasticity, pain modulation, motor control, energy homeostasis, and control of local blood blow. The LC is severely affected in neurodegenerative disorders such as Alzheimer disease (AD) and Parkinson disease (PD). Dysregulation of LC-NE system has been implicated in sleep and arousal disorders, attention deficit hyperactivity disorder, and posttraumatic stress disorder and constitutes a target for pharmacologic treatment of these conditions. The neurobiology of the LC–noradrenergic system has been the subject of several excellent reviews.1–9 The LC is a cluster of NE-containing neurons located in the upper dorsolateral pontine tegmentum (figure 1). These neurons have extensively branched axons that project throughout the neuraxis and provide the sole source of NE to the neocortex, hippocampus, cerebellum, and most of the thalamus.1,2 Despite its widespread distribution, noradrenergic innervation shows regional specificity. For example, brain areas involved in spatial attention (such as the prefrontal and parietal cortices) receive particularly dense LC-NE inputs. In general, individual LC neurons send axon collaterals to multiple targets that process the same sensory information. Norepinephrine is released both at typical synapses and at nonsynaptic release sites; extrasynaptic NE mediates paracrine effects on neurons, glial cells, and microvessels.1–4,8 Figure 1 Anatomic organization of the locus ceruleus–norepinephrine system The norepinephrine (NE) neurons of the locus ceruleus (LC) are located in the upper dorsolateral pontine tegmentum and can be identified by their immunoreactivity for tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis. These neurons have extensively branched axons that project throughout the neuraxis and provide the sole source of NE to the neocortex, hippocampus, cerebellum, and most of the thalamus. Modified, …