Wolfgang Singer

Acetylcholinesterase inhibition: a novel approach in the treatment of neurogenic orthostatic hypotension

Background: Pharmacological treatment of orthostatic hypotension is often limited because of troublesome supine hypertension. Objective: To investigate a novel approach to treatment using acetylcholinesterase inhibition, based on the theory that enhanced sympathetic ganglion transmission increases systemic resistance in proportion to orthostatic needs. Design: Prospective open label single dose trial. Material: 15 patients with neurogenic orthostatic hypotension caused by: multiple system atrophy (n = 7), Parkinson’s disease (n = 3), diabetic neuropathy (n = 1), amyloid neuropathy (n = 1), and idiopathic autonomic neuropathy (n = 3). Methods: Heart rate, blood pressure, peripheral resistance index (PRI), cardiac index, stroke index, and end diastolic index were monitored continuously during supine rest and head up tilt before and one hour after an oral dose of 60 mg pyridostigmine. Results: There was only a modest non-significant increase in supine blood pressure and PRI. In contrast, acetylcholinesterase inhibition significantly increased orthostatic blood pressure and PRI and reduced the fall in blood pressure during head up tilt. Orthostatic heart rate was reduced after the treatment. The improvement in orthostatic blood pressure was associated with a significant improvement in orthostatic symptoms. Conclusions: Acetylcholinesterase inhibition appears effective in the treatment of neurogenic orthostatic hypotension. Orthostatic symptoms and orthostatic blood pressure are improved, with only modest effects in the supine position. This novel approach may form an alternative or supplemental tool in the treatment of orthostatic hypotension, specially for patients with a high supine blood pressure.

Autopsy confirmed multiple system atrophy cases: Mayo experience and role of autonomic function tests

Background Multiple system atrophy (MSA) is a sporadic progressive neurodegenerative disorder characterised by autonomic failure, manifested as orthostatic hypotension or urogenital dysfunction, with combinations of parkinsonism that is poorly responsive to levodopa, cerebellar ataxia and corticospinal dysfunction. Published autopsy confirmed cases have provided reasonable neurological characterisation but have lacked adequate autonomic function testing. Objectives To retrospectively evaluate if the autonomic characterisation of MSA is accurate in autopsy confirmed MSA and if consensus criteria are validated by autopsy confirmation. Methods 29 autopsy confirmed cases of MSA evaluated at the Mayo Clinic who had undergone formalised autonomic testing, including adrenergic, sudomotor and cardiovagal functions and Thermoregulatory Sweat Test (TST), from which the Composite Autonomic Severity Score (CASS) was derived, were included in the study. Results Patient characteristics: 17 men, 12 women; age of onset 57±8.1 years; disease duration to death 6.5±3.3 years; first symptom autonomic in 18, parkinsonism in seven and cerebellar in two. Clinical phenotype at first visit was MSA-P (predominant parkinsonism) in 18, MSA-C (predominant cerebellar involvement) in eight, pure autonomic failure in two and Parkinsons disease in one. Clinical diagnosis at last visit was MSA for 28 cases. Autonomic failure was severe: CASS was 7.2±2.3 (maximum 10). TST% was 65.6±33.9% and exceeded 30% in 82% of patients. The most common pattern was global anhidrosis. Norepinephrine was normal supine (203.6±112.7) but orthostatic increment of 33.5±23.2% was reduced. Four clinical features (rapid progression, early postural instability, poor levodopa responsiveness and symmetric involvement) were common. Conclusion The pattern of severe and progressive generalised autonomic failure with severe adrenergic and sudomotor failure combined with the clinical phenotype is highly predictive of MSA.

Light propagation through microlenses: a new simulation method

A new numrical method is described for analysis of the imaging properties of microlenses. This wave-propagation method is compared with the classical beam-propagation method from which it is derived. The applicability of the two methods is given and demonstrated by examples. The beampropagation method is fast but is applicable only for small apertures; the new wave-propagation method requires no paraxial approximation but requires more computational effort.

Acetylcholinesterase inhibition in patients with orthostatic intolerance

Summary: The efficacy of current therapeutic measures in orthostatic intolerance (OI) varies among patients and is oftentimes unsatisfactory. New approaches to alleviate symptoms of OI are therefore clearly needed. Recent reports have demonstrated that acetylcholinesterase inhibition is effective in the treatment of orthostatic hypotension with the presumed mechanism of enhancing sympathetic ganglionic transmission. Based on the hypothesis that acetylcholinesterase inhibition, by improving the safety factor of cholinergic transmission, will result in enhanced vascular adrenergic tone and a vagal shift in cardiac sympathovagal balance, we evaluated the role of acetylcholinesterase inhibition in the treatment of patients with OI. We monitored heart rate (HR), blood pressure, and indexes for cardiac output, end-diastolic volume, and systemic resistance continuously in 18 patients with OI during supine rest and during 5 minutes of 70° head-up tilt before and 1 hour after oral administration of 60 mg pyridostigmine. Plasma catecholamines and baroreflex sensitivity were determined for the supine and upright position before and after medication. Patients scored orthostatic symptoms for both tilt studies. The excessive HR response to orthostatic stress was significantly blunted after pyridostigmine administration. HR was significantly lower in the supine and more so in the upright position. Baroreflex sensitivity in the upright position was significantly higher after pyridostigmine. Norepinephrine was increased in both supine and upright position. These changes were associated with significant improvement of orthostatic symptoms. We conclude that pyridostigmine improves orthostatic tolerance in patients with OI. Our findings support the suggested mechanisms of enhanced sympathetic ganglionic neurotransmission and a vagal shift in cardiac sympathovagal balance. Acetylcholinesterase inhibition could be a new useful concept in the treatment of OI.

Comparison of the filtered backpropagation and the filtered backprojection algorithms for quantitative tomography

We compare the filtered backpropagation algorithm with the filtered backprojection algorithm for reconstructing the complex refractive-index distribution of semitransparent, cylindrical objects. Before reconstruction, the recorded scattered light is propagated back to the reconstruction area by inverse diffraction. Our comparison is based on computer-simulated data, and experimental optical data obtained from fibers with step-index, graded-index, and uniform-index distributions. The results show that both the filtered backpropagation algorithm and the filtered backprojection algorithm can produce accurate reconstructions of the complex refractive-index distribution as long as the weak-scattering approximation is valid. The good agreement between the results obtained from these two reconstruction algorithms indicates that the errors introduced by the assumption of straight-line propagation inside the object are negligible compared with those introduced by the weak-scattering approximation.

Abnormal vasoreaction to arousal stimuli--an early sign of diabetic sympathetic neuropathy demonstrated by laser Doppler flowmetry.

Summary Early diagnosis of diabetic autonomic neuropathy contributes to the prevention of serious complications and improves the prognosis of patients with diabetes. Common tests of peripheral autonomic function are the quantitative sudomotor axon reflex test or the sympathetic skin response (SSR). Quantitative sudomotor axon reflex test is quantifiable but technically demanding. Sympathetic skin response cannot be quantified easily. To study whether measurement of skin vasomotion is suited to assess early sympathetic peripheral neuropathy, we monitored skin blood flow at the index finger pulp using laser Doppler flowmetry before and after electrical stimulation. We assured that the stimulus was sufficient to elicit an efferent sympathetic response by monitoring palmar SSR ipsilateral to the flow measurement. In 21 diabetic patients with at least stage one polyneuropathy and 21 age-matched controls, SSR was recorded from one palm and sole following electrical stimulation at the contralateral wrist. Sympathetic skin response was present at the palms in all patients and controls and absent at the sole of two patients only. Eight patients (38.9%) had abnormal SSR, with absent plantar responses in two patients, prolonged plantar latencies in six patients, and prolonged volar SSR latencies in two patients. Skin blood flow responses were more often abnormal (46.1%) than SSR (P < 0.05), responses were delayed in two patients and absent in another 8 patients. Skin blood flow retest reliability was high with a repeatability coefficient of 10.64% in controls and 12.34 % in patients. Skin blood flow monitoring after sympathetic stimulation provides a reproducible parameter of sympathetic vasomotor control and complements the diagnostic value of SSR testing.

Transition of the scalar field at a refracting surface in the generalized Kirchhoff diffraction theory

We propose a new method for the analysis of light propagation through thick phase elements of homogeneous refractive index. The Laue equation is shown to be a generalization of Snell’s law of refraction, yielding correct amplitude and phase changes at a single refracting surface. The application to blazed phase gratings is outlined.

Gradient-index microlenses: numerical investigation of different spherical index profiles with the wave propagation method

Ion-exchange microlenses are available with different gradient-index profiles. We investigate the dependence of the imaging properties on the steepness of the index profiles. Therefore we model the index distribution by the Fermi function as radial distribution with spherical symmetry. The results are compared to index profiles according to the Doremus model.

A report of the autonomic symptom profile in patients with fibromyalgia.

Autonomic dysregulation is thought to contribute to the pathophysiology and symptoms in patients with fibromyalgia (FM). The majority of studies in FM that have reported autonomic dysregulation have relied on heart rate variability measurement and report increased sympathetic and decreased parasympathetic tone, chronotropic incompetence, and impaired autonomic cardiovascular regulation with blunted sympathetic reactivity to acute stress. 1Y3 These results may have clinical implications as increased sympathetic tone contributes to symptoms such as muscle tension and pain, fatigue, heightened stress response, and unrefreshing sleep, all common patient-reported symptoms in FM. 1,3Y6 The Autonomic Symptom Profile (ASP) is a validated selfreport questionnaire that comprehensively assesses autonomic symptoms across 11 subscales and yields a Composite Autonomic Symptoms Scale (COMPASS) score. 7 The ASP is unique in comparison to other commonly utilized self-report measures in that it assesses both symptoms and functional status. For example, the secretomotor subscale of the ASP assesses secretomotor symptoms such as sweating with vigorous exercise, ability to tolerate heat, and mucosal secretory dysfunction including dry eyes and dry mouth. 8 Similarly, the pupillomotor subscale of the ASP assesses pupillomotor symptoms such as light sensitivity, visual blurring, and dysfunction pupillomotor including trouble focusing eyes and difficulty seeing at night. 8 The ASP also includes a sleep subscale that evaluates presence of sleep disorders such as narcolepsy, obstructive sleep apnea, and abnormal sleeping patterns in addition to assessment of sleep quality. This is relevant as sleep and autonomic function are interdependent by virtue of their common controls, regulatory neurochemicals, and functions, but also because unrefreshing sleep is a predominant complaint in patients with FM. 9,10 There is one previous report utilizing the ASP in patients with FM. In this study, the Spanish version of the ASP was administered to 20 patients with FM, and results were compared with those of 30 patients with rheumatoid arthritis and 30 control subjects. 11 Patients with FM had the highest COMPASS scores in comparison with patients with rheumatoid arthritis and control subjects. In addition, total COMPASS scores correlated with FIQ total scores, suggesting a potential association between FM severity and autonomic dysfunction. 11 Our objective was to assess autonomic symptoms utilizing the ASP and their correlation with the Fibromyalgia Impact QuestionnaireYRevised (FIQ-R) in a large sample of patients with FM. METHODS Participants

Refractive-index measurement of gradient-index microlenses by diffraction tomography

Diffraction tomography is applied to reconstruction of the gradient-index distribution of planar gradient-index microlenses, fabricated by thermal ion exchange. Measurements of the single-phase projections are performed by phase-shifting interferometry For reconstruction, the Rytov approximation for smooth inhomogeneities is applied. Results are compared with measurement results from other methods and simulation results.