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Research Highlights from the Literature

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2003; Volume 13(5) from Clinical Autonomic Research                                           
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"Venous Pooling" Due to Interstitial Edema in a Subset of Patients with POTS
    I has been recognized clinically that patients with POTS have exaggerated "venous pooling" on standing. However, few studies have systematically studied whether this occurs in all patients, its mechanism, or its potential importance in the pathophysiology of this disorder. Stewart has previously reported that adolescents with POTS can be subset based on their normal or inappropriately increased leg blood flow while upright. Now he reports that patients who have high leg blood flow and impaired vasoconstriction also have increased microvascular filtration in lower limbs, as suggested previously by Brown and Hainsworth (Clin Auton Res 1999;9:69-73). In contrast, patients with normal orthostatic leg blood flow seem to have normal microvascular filtration. 
    This work provides a mechanism for the "venous pooling" observed clinically, and adds to the evidence that orthostatic intolerance is a heterogeneous disease. Stewart's subset of patients with inappropriately high orthostatic leg blood flow may correspond to the neuropathic (lower limb denervation) form of the disease. 
    Stewart JM (2003) Microvascular filtration is increased in postural tachycardia syndrome. Circulation 107:2816-2822.

Markers of Oxidative Stress in Parkinson Disease and Related Disorders
    Oxidative stress has been suspected as contributing to neurodegenerative disorders, including Parkinson’s disease and related conditions. Fessel et al measured products of lipid oxidation in post-mortem substantial nigra samples of controls (n=5), patients with Parkinson’s disease (PD, 7), multiple system atrophy (MSA, 4), dementia of Lewy body disease (DLB, 4) and Alzheimer’s disease (AD, 5). They measured F2-isoprostanes and isofurans. Both are products of lipid peroxidation, but formation of isofurans is favored under conditions of increased oxygen tension. Isofurans were increased only in PD and DLB, but not in MSA or AD. F2-isoprostanes were slightly higher in PD and DLB, but differences were not significant. The authors conclude that high oxygen tension oxidative stress contributes to Parkinson’s disease and Lewy body disease, but not to multiple system atrophy. These findings, if confirmed in a larger number of specimens, would suggest different underlying mechanisms of dopaminergic neurogeneration between these conditions.
    Fessel JP, Hulette C, Powell S, et al (2003) Isofurans, but not F2-isoprostanes, are increased in the substantia nigra of patients with Parkinson's disease and with dementia with Lewy body disease. J Neurochem 85:645-650.

Plasma Normetanephrine in the Biochemical Diagnosis of Pheochromocytoma
    Diagnosis of pheochromocytoma remains a challenge. Eisenhofer et al examined the biochemical characteristics of 208 patient with pathologically-confirmed pheochromocytoma and 648 in whom pheochromocytoma was excluded.  Plasma norepinephrine > 2,400, normetanephrine > 400 and metanephrine > 235 pg/ml where highly suggestive of pheochromocytoma. Plasma catechols were between normal and these high values in a substantial number of patients with (true positives) and without (false positives) pheochromocytoma. False positives can be resolved with the clonidine suppression test.  Suppression of normetanephrine was found to be more reliable than that of norepinephrine. False positive elevations of plasma catechols were frequently caused by tricyclic antidepressants (but not by selective serotonin reuptake inhibitors) and the alpha blocker phenoxybenzamine (frequently used to treat pheochromocytoma). Some patients with pheochromocytoma had normal plasma normetanephrine. The incidence of this problem may be enriched in this series because of the inclusion of asymptomatic patients that were screened because of familiar pheochromocytoma.
    Eisenhofer G, Goldstein DS, Walther MM, et al (2003) Biochemical diagnosis of pheochromocytoma: How to distinguish true- from false-positive test results. Journal of Clinical Endocrinology and Metabolism 88:2656-2666.

Is the Pressor Effect of Water a Spinal Reflex?
    Plain, room-temperature, tap water can increase systolic blood pressure by an average of 40 mm Hg in autonomic failure patients. Sympathetic mechanisms appear to be involved because this effect is prevented by autonomic blockade with trimethaphan. Tank et al now report that water also increases blood pressure in tetraplegic patients with complete spinal cord injury. Mean systolic blood pressure increased from 123 to 138 mm Hg after 35-40 min. This was associated with reflex bradycardia and increased total peripheral resistance. Thus, the pressor effect of water is seen even if the direct connection between CNS centers and efferent sympathetic nerve fibers is interrupted. It is unlikely that oral water increases blood pressure by increasing volume, because previous studies have shown that the same volume infused intravenously has no pressor effect, sympathetic activation has been documented in normals, and vasoconstriction was observed in this study. These results suggest that a spinal reflex is involved in the genesis of the pressor effect of water. We still don’t know the afferent signal that triggers this reflex. Also, spinal reflexes are sudden in onset, whereas the pressor effect of water ingestion is gradual. It is not know if this difference is explained by gradual recruitment of afferent fibers activated by water ingestion, or if unknown intermediate steps exist between water ingestion and afferent fiber activation, or between efferent activation and the pressor effect.
    Tank J, Schroeder C, Stoffels M, et al (2003) Pressor Effect of Water Drinking in Tetraplegic Patients May Be a Spinal Reflex. Hypertension 41:1234-1239.

Autonomic Failure in Parkinson’s Disease. A Syndrome We Need to Learn More About
    Autonomic failure can be seen in patients with otherwise a classical presentation of Parkinson’s disease ("Parkinson’s plus"). Sharabi et al evaluated 12 such patients. Mean orthostatic drop in systolic blood pressure was 40 mmHg, suggesting that in some patients orthostatic hypotension was rather modest by autonomic failure standards. Blood pressure response to Valsalva maneuver was abnormal in all. As previously reported by this group of investigators, all patients had decreased fluorodopamine cardiac uptake, indicating loss of postganglionic sympathetic fibers. In this regard, autonomic failure in Parkinson’s disease resembles that seen in pure autonomic failure, which is also characterized by loss of post-ganglionic sympathetic fibers, rather than that seen in multiple system atrophy. Patients with Parkinson’s plus had a blunted increase in plasma norepinephrine on standing Unfortunately, only relative changes but not actual plasma norepinephrine levels were reported. Of interest, sweat production to iontophoretic administration of acetylcholine was present in the forearm, indicating preserved sympathetic cholinergic fibers in the forearm despite cardiac sympathetic denervation. Cholinergic parasympathetic function was not reported. More detailed characterization of the autonomic failure of Parkinson’s disease is needed, but these results suggest differential involvement of autonomic pathways.
    Autosomal recessive early-onset parkinsonism can result from various mutations in the PARK2 (parkin, chromosome 6), PARK6 or PARK7 (chromosome 1) genes. Khan et al reported the clinical characteristics of 24 Parkinson’s patients with PARK2 mutations, including 11 isolated cases, and 13 patients from five unrelated families. Clinical characteristics were similar to those previously reported for familial parkinsonism, but three new phenotypes were observed: cervical dystonia, pure exercise-induced dystonia, and autonomic dysfunction with peripheral neuropathy. Detailed autonomic function was not systematically evaluated but "autonomic symptoms" were reported in 60% of patients, including urgency (45%), impotence (38% of males) and orthostatic faintness (13%). One case was evaluated in more detail and found to have abnormal sympathetic and parasympathetic function, and asymptomatic axonal peripheral neuropathy revealed by nerve conduction studies. More detailed evaluation is required to determine if autonomic failure is indeed part of the clinical presentation of genetic forms of Parkinson disorders, and to understand its pathophysiology.
    Sharabi Y, Li ST, Dendi R, et al (2003) Neurotransmitter specificity of sympathetic denervation in Parkinson's disease. Neurology 60:1036-1039.
    Khan NL, Graham E, Critchley P, et al (2003) Parkin disease: a phenotypic study of a large case series. Brain 126:1279-1292.

Ganglionic Blockade and Blood Pressure Variability in Hypertensive Disorders
    The contribution of the sympathetic nervous system to hypertension has long been suspected but difficult to assess. Diedrich et al combined acute sympathetic withdrawal with ganglionic blockade with measurements of cardiovascular variability, to study patients with multiple system atrophy (MSA, characterized by sympathetically-driven supine hypertension), pure autonomic failure (PAF, characterized by sympathetically-independent supine hypertension), normal controls and patients with essential hypertension (HTN). Ganglionic blockade with trimethaphan abolished high and low frequency heart rate fluctuations and low frequency blood pressure variability (LFSBP). "Intrinsic blood pressure" (after autonomic blockade) remained high in PAF but dropped to normal in MSA. Baseline LFSBP was higher in MSA and HTN, and very low in PAF. Of interest, patient groups that had high LFSBP also had a higher LF/HFRRI ratio (a controversial index of "sympathovagal balance") suggesting that this index is indeed influenced by sympathetic function. Patients with HTN had a wider range of "intrinsic blood pressure" and LFSBP levels. The decrease in LFSBP induced by ganglionic blockade correlated with the reduction in blood pressure, with a steeper slope in MSA and HTN compared to controls. Thus, ganglionic blockade, alone or coupled to LFSBP, discriminated between human models of sympathetic-dependent (MSA) and independent (PAF) hypertension. This approach may aid in assessing the contribution of the sympathetic nervous system in essential hypertension, in which sympathetic dependence is variably expressed.
    Diedrich A, Jordan J, Tank J, et al (2003) The sympathetic nervous system in hypertension: Assessment by blood pressure variability and ganglionic blockade. J Hypertens 21:1677-1686.