Axel Lipp

A randomized trial of botulinum toxin A for treatment of drooling

The authors compared the efficacy of three different doses (18.75, 37.5, and 75 MU per parotid gland) of botulinum toxin A (BTX-A; Dysport, Ipsen Pharma, Germany) injections vs vehicle in patients with sialorrhea (n = 32) using a single-center, prospective, double-blind, placebo-controlled dose-finding study. The primary endpoint was achieved with 75 MU BTX-A without treatment-related adverse events, suggesting BTX-A is a safe and effective treatment for patients with sialorrhea.

Minocycline 1‐year therapy in multiple‐system‐atrophy: Effect on clinical symptoms and [11C] (R)‐PK11195 PET (MEMSA‐trial)

The aim of the study was to investigate the efficacy of the antibiotic minocycline as a drug treatment in patients with Multiple‐System‐Atrophy Parkinson‐type (MSA‐P). Sixty‐three patients were randomized to minocycline 200 mg/d (n = 32) or a matching placebo (n = 31). The primary outcome variable was the change in the value of the motor score of the Unified Multiple‐System‐Atrophy Rating‐Scale (UMSARSII) from baseline to 48 weeks. Secondary outcome variables included subscores and individual Parkinsonian symptoms as determined by the UMSARS and the Unified‐Parkinsons‐Disease Rating‐Scale (UPDRS). Health‐related quality of life (HrQoL) was assessed using the EQ‐5D and SF‐12. “Progression rate” was assumed to be reflected in the change in motor function over 48 weeks. At 24 weeks and 48 weeks of follow‐up, there was a significant deterioration in motor scores in both groups, but neither the change in UMSARSII nor in UPDRSIII differed significantly between treatment groups, i.e. “progression rate” was considered to be similar in both treatment arms. HrQoL did not differ among the two treatment arms. In a small subgroup of patients (n = 8; minocycline = 3, placebo = 5)[11C](R)‐PK11195‐PET was performed. The three patients in the minocycline group had an attenuated mean increase in microglial activation as compared to the placebo group (P = 0.07) and in two of them individually showed decreased [11C](R)‐PK11195 binding actually decreased. These preliminary PET‐data suggest that minocycline may interfere with microglial activation. The relevance of this observation requires further investigation. This prospective, 48 week, randomized, double‐blind, multinational study failed to show a clinical effect of minocycline on symptom severity as assessed by clinical motor function.

Baroreflex buffering and susceptibility to vasoactive drugs

Background—The overall effect of vasoactive drugs on blood pressure is determined by a combination of the direct effect on vascular tone and an indirect baroreflex-mediated effect, a baroreflex buffering of blood pressure. Differences in baroreflex function affect the responsiveness to vasoactive medications, particularly baroreflex buffering of blood pressure; however, the magnitude is not known. Methods and Results—We characterized baroreflex function and responses to vasoactive drugs in patients with idiopathic orthostatic intolerance, patients with essential hypertension, patients with monogenic hypertension and brachydactyly, patients with multiple system atrophy, and control subjects. We used phenylephrine sensitivity during ganglionic blockade as a measure of baroreflex buffering. Phenylephrine (25 &mgr;g) increased systolic blood pressure 6±1.6 mm Hg in control subjects, 6±1.1 mm Hg in orthostatic intolerance patients, 18±3.9 mm Hg in patients with essential hypertension, 31±3.4 mm Hg in patients with monogenic hypertension, and 25±3.4 mm Hg in patients with multiple system atrophy. Similar differences in sensitivities between groups were observed with nitroprusside. The sensitivity to vasoactive drugs was highly correlated with baroreflex buffering function and to a lesser degree with baroreflex control of heart rate. In control subjects, sensitivities to nitroprusside and phenylephrine infusions were correlated with baroreflex heart rate control and sympathetic nerve traffic. Conclusions—Our findings are consistent with an important effect of baroreflex blood pressure buffering on the sensitivity to vasoactive drugs. They suggest that even moderate changes in baroreflex function may have a substantial effect on the sensitivity to vasoactive medications.

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.

Phosphorylated α-synuclein in skin nerve fibres differentiates Parkinson’s disease from multiple system atrophy

Deposition of phosphorylated SNCA (also known as α-synuclein) in cutaneous nerve fibres has been shown pre- and post-mortem in Parkinsons disease. Thus far, no pre-mortem studies investigating the presence of phosphorylated SNCA in skin sympathetic nerve fibres of multiple system atrophy, another synucleinopathy, have been conducted. In this in vivo study, skin from the ventral forearm of 10 patients with multiple system atrophy and 10 with Parkinsons disease, together with six control subjects with essential tremor, were examined by immunohistochemistry. Phosphorylated SNCA deposits in skin sympathetic nerve fibres and dermal nerve fibre density were assessed. All patients with Parkinsons disease expressed phosphorylated SNCA in sympathetic skin nerve fibres, correlating with an age-independent denervation of autonomic skin elements. In contrast, no phosphorylated SNCA was found in autonomic skin nerve fibres of patients with multiple system atrophy and essential tremor control subjects. These findings support that phosphorylated SNCA deposition is causative for nerve fibre degeneration in Parkinsons disease. Moreover, pre-mortem investigation of phosphorylated SNCA in cutaneous nerve fibres may prove a relevant and easily conductible diagnostic procedure to differentiate Parkinsons disease from multiple system atrophy.

Osmosensitive mechanisms contribute to the water drinking-induced pressor response in humans

Background: Water drinking elicits a sympathetically mediated pressor response in multiple-system atrophy patients through an unknown mechanism. We reasoned that gastrointestinal distention, hyposomotic stimulation, or both contribute to the water-induced pressor response Methods: We compared the response to normal saline and water on blood pressure in 10 patients with probable multiple-system atrophy. Patients featured moderate to severe autonomic dysfunction. EKG and finger arterial blood pressure were recorded continuously, and 500 mL normal saline and distilled water were each given in a single-blinded fashion. Fluids were applied through a previously inserted nasogastric tube within a 5-minute period. Results: Blood pressure began to increase within 10 minutes after water administration and reached a maximum after 20 minutes. Blood pressure did not change after saline administration. The blood pressure change after 20 minutes was 8 ± 9/2 ± 5 mmHg with water and –1 ± 11/–1 ± 7 mmHg with normal saline administration (p = 0.02 between interventions). Heart rate did not change with either intervention. Conclusion: Ingestion of water elicits a greater pressor response than the ingestion of normal saline. Thus, gastric distention is probably not the crucial mechanisms for the water-induced pressor response. Instead, the response may be mediated through osmosensitive afferent structures in the gastrointestinal tract, portal vein, and liver.

Cerebral magnetic resonance elastography in supranuclear palsy and idiopathic Parkinson's disease

Detection and discrimination of neurodegenerative Parkinson syndromes are challenging clinical tasks and the use of standard T1- and T2-weighted cerebral magnetic resonance (MR) imaging is limited to exclude symptomatic Parkinsonism. We used a quantitative structural MR-based technique, MR-elastography (MRE), to assess viscoelastic properties of the brain, providing insights into altered tissue architecture in neurodegenerative diseases on a macroscopic level. We measured single-slice multifrequency MRE (MMRE) and three-dimensional MRE (3DMRE) in two neurodegenerative disorders with overlapping clinical presentation but different neuropathology — progressive supranuclear palsy (PSP: N = 16) and idiopathic Parkinsons disease (PD: N = 18) as well as in controls (N = 18). In PSP, both MMRE (Δμ = − 28.8%, Δα = − 4.9%) and 3DMRE (Δ|G*|: − 10.6%, Δφ: − 34.6%) were significantly reduced compared to controls, with a pronounced reduction within the lentiform nucleus (Δμ = − 34.6%, Δα = − 8.1%; Δ|G*|: − 7.8%, Δφ: − 44.8%). MRE in PD showed a comparable pattern, but overall reduction in brain elasticity was less severe reaching significance only in the lentiform nucleus (Δμ n.s., Δα = − 7.4%; Δ|G*|: − 6.9%, Δφ: n.s.). Beyond that, patients showed a close negative correlation between MRE constants and clinical severity. Our data indicate that brain viscoelasticity in PSP and PD is differently affected by the underlying neurodegeneration; whereas in PSP all MRE constants are reduced and changes in brain softness (reduced μ and |G*|) predominate those of viscosity (α and φ) in PD.

Sympathetic activation due to deep brain stimulation in the region of the STN

The autonomic nervous system is important in cardiovascular regulation. The peripheral autonomic nervous system is at least in part accessible to direct measurements. However, it is difficult to assess central autonomic nervous system function in humans and the role of CNS pathways in human autonomic regulation is poorly understood. In recent years, deep brain stimulation (DBS) of the basal ganglia has been used to alleviate motor symptoms in advanced Parkinson disease (PD) and other movement disorders. Although the impact of DBS on motor function is well described, little is known about DBS effects on nonmotor structures within the central components of the autonomic nervous system. Furthermore, DBS provides a unique opportunity to map autonomic pathways close to the stimulation site. We studied five patients (three men, two women, aged 61 ± 7 years; see table E-1 on the Neurology Web site at www.neurology.org) treated bilaterally with a subthalamic nucleus (STN) stimulator for an advanced Parkinson syndrome. The deep brain stimulator leads were equipped with four separated electrodes (1.5-mm wide, 0.5-mm space in between). We continuously measured heart rate (electrocardiogram), respiration (thoracic bioimpedance) and blood …

The role of autonomic testing in the differentiation of Parkinson's disease from multiple system atrophy

Differentiation of idiopathic Parkinsons disease (PD) from multiple system atrophy (MSA) can be difficult. Methods devised to help distinguish the two disorders include standardized autonomic testing and cardiac imaging with iodine-123 meta-iodobenzylguanidine myocardial scintigraphy. MSA patients had more severe adrenergic and overall autonomic dysfunction when compared to control and PD patients. Area of anhidrosis on thermoregulatory sweat test was greater in MSA (67.4±12.42, p<0.001) versus PD patients (area of anhidrosis, 1.7±2.96). Postganglionic cardiac sympathetic innervation (iodine-123 meta-iodobenzylguanidine) expressed as heart to mediastinal ratio was significantly lower in Parkinsons disease patients (1.4±0.40, p=0.025) compared to controls (2.0±0.29), but not in multiple system atrophy (2.0±0.76). These findings indicate that autonomic dysfunction is generalized and predominantly preganglionic in multiple system atrophy, and postganglionic in Parkinsons disease. In our hands the thermoregulatory sweat test provides the best distinction between MSA and PD. However further confirmatory studies using larger patient numbers are required. Currently a combination of clinical judgment and autonomic testing is recommended to help differentiate MSA and PD.

Monochromatic Ultra-Slow (~ 0.1 Hz) Oscillations in the human electroencephalogram and their relation to hemodynamics

Previous studies demonstrated the presence of Monochromatic Ultra-Slow Oscillations (MUSO) in human EEG. In the present study we explored the biological origin of MUSO by simultaneous recordings of EEG, Near-Infrared Spectroscopy (NIRS), arterial blood pressure, respiration and Laser Doppler flowmetry. We used a head-up tilt test in order to check whether MUSO might relate to Mayer waves in arterial blood pressure, known to be enhanced by the tilting procedure. MUSO were detected in 8 out of 10 subjects during rest and showed a striking monochromatic spectrum (0.07-0.14 Hz). The spatial topography of MUSO was complex, showing multiple foci variable across subjects. While the head-up tilt test increased the relative power of Mayer waves, it had no effect on MUSO. On the other hand, the relative spectral power of 0.1 Hz oscillations in EEG, NIRS and blood pressure signals were positively correlated across subjects in the tilted condition. Eight subjects showed a coherence between MUSO and NIRS/arterial blood pressure. Moreover, MUSO at different electrode sites demonstrated coherence not reducible to volume conduction, thus indicating that MUSO are unlikely to be generated by one source. We related our experimental findings to known biological phenomena being generated at about 0.1 Hz, i.e.: arterial blood pressure, cerebral and skin vasomotion, respiration and neuronal activity. While no definite conclusion can yet be drawn as to an exact physiological mechanism of MUSO, we suggest that these oscillations might be of a rather extraneuronal origin reflecting cerebral vasomotion.