Wolfgang H. Jost

Vulnerability of the nigrostriatal system as detected by transcranial ultrasound

Objective: To assess the incidence of a hyperechogenic substantia nigra (SN) by transcranial sonography (TCS) in healthy people and to evaluate whether an enlarged hyperechogenic SN area is associated with functional impairment of the nigrostriatal system. Background and Methods: Until now, preclinical impairment of the nigrostriatal system could be identified only by functional neuroimaging techniques such as PET in selected groups of patients. TCS is a new, noninvasive ultrasound technique that has demonstrated an increased echogenicity of the SN in patients with PD, whereas in most healthy individuals, the SN is either barely detectable or undetectable by TCS. Results: Of 330 healthy volunteers, 8.6% exhibited an increased echogenicity of the SN. From these, 10 clinically healthy individuals with distinct unilateral or bilateral hyperechogenic signals in the SN region (SN area above 0.25 cm2) underwent comprehensive motor testing, neuropsychological assessment, MRI, and [18F]-dopa PET examination. With regard to motor functions, these individuals did not differ from 10 age- and sex-matched controls with a low echogenic SN and an area of echogenic signals below 0.2 cm2. Enlargement of hyperechogenic areas in the 10 healthy individuals was associated with a marked decrease in the accumulation of [18F]-dopa in the caudate nucleus and putamen. Conclusions: Substantia nigra hyperechogenicity appears to indicate a functional impairment of the nigrostriatal system. Transcranial sonography may be a suitable method of identifying persons at risk of nigrostriatal alterations, making possible the introduction of early neuroprotective therapy.

Efficacy and safety of a new Botulinum Toxin Type A free of complexing proteins in the treatment of blepharospasm

Summary.NT 201 is a new development of Botulinum Toxin Type A free of complexing proteins. In this double-blind Phase III trial, we compared the efficacy and safety of NT 201 and BOTOX® in patients suffering from blepharospasm. Of 304 enrolled patients, 300 patients received study medication (intent-to-treat population), and 256 patients completed the study as planned (per-protocol population). At baseline, patients received a single injection of NT 201 or BOTOX® (≤35 units per eye). No significant differences were found between NT 201 and BOTOX® for all efficacy and safety variables three weeks after injection. Both the NT 201 and the BOTOX® group showed a decrease in the Jankovic Rating Scale (JRS) sum score signifying an improvement in the symptoms of blepharospasm during this time period. These data show that NT 201* is an effective and safe treatment for patients suffering from blepharospasm.

Nonmotor fluctuations in Parkinson disease: severity and correlation with motor complications.

Objective: To evaluate frequency, severity, and correlation of nonmotor symptoms (NMS) with motor complications in fluctuating Parkinson disease (PD). Methods: The Multicenter NonMotor Fluctuations in PD cross-sectional study used clinical examination of 10 NMS (dysphagia, anxiety, depression, fatigue, excessive sweating, inner restlessness, pain, concentration/attention, dizziness, bladder urgency) quantified using a visual analogue scale (VAS) in motor-defined on (NMSOn) and off state (NMSOff) combined with motor assessments and self-ratings at home in 100 patients with advanced PD. Results: All NMS except dysphagia, excessive sweating, and bladder urgency fluctuated in conjunction to motor fluctuations with more frequent and severe symptoms in off compared to on state. The proportions of patients experiencing autonomic/sensory NMS in both motor states were similar to those with these NMS exclusively in off state (ratios 0.4–1.3), while for mental/psychic NMS the proportions with exclusive manifestation in off state were higher (ratios 1.8–3.1). Demographic and clinical characteristics correlated neither with NMS frequency patterns and severities nor with ΔNMSOn/Off severities (defined as the differences of VAS scores between on and off). Severities of NMSon, NMSOff, and ΔNMSOn/Off did not correlate with motor function. Presence of anxiety, depression, fatigue, and pain had negative impact on health-related quality of life (HRQOL) measured by Parkinsons Disease Questionnaire–8 scoring independent of their occurrence with respect to motor state. Fluctuations of these NMS but not of fatigue deteriorated HRQOL. Conclusion: Patterns of NMS fluctuations are heterogeneous and complex, but psychic NMS fluctuate more frequently and severely. Demographic parameters and motor function do not correlate with NMS or nonmotor fluctuation severities in fluctuating PD.

Gastrointestinal dysfunction in Parkinson's Disease

Gastrointestinal (GI) motility is very frequently disturbed in Parkinsons disease (PD), manifesting chiefly as dysphagia, impaired gastric emptying and constipation. All these symptoms - constipation in particular - may precede the clinical diagnosis of PD for years. In the future, these symptoms might serve as useful early indicators in the premotor stage. Disturbed gastric emptying is an important factor in unpredictable fluctuations. The most likely causes are degenerations of the dorsal vagal nucleus and the intramural plexus of the whole intestine. These degenerations are likely to develop prior to the degeneration of dopaminergic neurons of the substantia nigra. Diagnosis includes history, clinical examination, barium meal, breath test, scintiscan of stomach, and colonic transit time. Therapeutic efforts are limited when it comes to disturbed motility of the upper GI-tract. Hypersalivation can be reduced by anticholinergics or botulinum toxin injections; motility of the upper gastrointestinal tract is only moderately impacted on by domperidone. In constipation, the conservative therapeutic option is administration of macrogol (polyethylene glycol), which leads to marked improvement.

Striatal FP-CIT uptake differs in the subtypes of early Parkinson's disease.

Summary.In idiopathic Parkinson’s disease (PD), a tremor-dominant type (TDT), an akinetic-rigid type (ART), and a mixed type (MT) are distinguished. We compared cerebral [I-123]FP-CIT SPECT in the PD subtypes (67 patients Hoehn and Yahr stage 1:26 with ART, 19 with MT, 22 with TDT). We measured the ratios putamen/occipital lobe binding and caudate nucleus/occipital lobe binding. Parkinsonian motor symptoms were quantified by UPDRS motor scale. In both putamen and caudate nucleus contralateral to the clinically affected body side TDT patients showed a significantly higher FP-CIT uptake than ART or MT patients (ANOVA; p<0.01). Contralateral putamen and caudate nucleus FP-CIT uptake correlated significantly with severity of rigidity (p<0.01) and hypokinesia (p<0.01) but not with severity of resting or postural tremor (p>0.05). The missing correlation between striatal FP-CIT uptake and tremor suggests, that further systems besides the nigrostriatal dopaminergic system may contribute to generation of parkinsonian tremor.

FP-CIT and MIBG scintigraphy in early Parkinson's disease

Methods provided by nuclear medicine may be helpful in diagnosis of Parkinsons disease (PD). For that purpose, the sensitivity of iodine‐123 metaiodobenzylguanidine ([123I]MIBG) scintigraphy and [123I]FP‐CIT single photon emission computed tomography (SPECT) was studied in patients with PD onset (Hoehn and Yahr Stage 1). Cerebral [123I]FP‐CIT and cardiac [123I]MIBG scintigraphy were carried out in 18 patients with idiopathic Parkinsons disease, according to Hoehn and Yahr Stage 1. For quantification purposes, we calculated the striatum/posterior lobe binding of FP‐CIT and the heart‐to‐mediastinum (H/M) count ratio regarding MIBG scintigraphy. In 15 of 18 patients, we observed markedly reduced or asymmetric striatal FP‐CIT tracer accumulation. FP‐CIT binding of the affected striatum was significantly lower as compared with that of the unaffected side. Striatal FP‐CIT binding correlated significantly with the motor part of the Unified Parkinsons disease rating scale (UPDRS) but not with age, disease duration, or gender. MIBG scintigraphy delivered significant pathological results in 13 of 18 patients. There was no significant correlation between the H/M ratio relating to MIBG scintigraphy and the motor part of UPDRS, age, disease duration, or gender; however, binding of striatal FP‐CIT correlated significantly with cardiac MIBG accumulation. According to the clinical criteria, it might be difficult to prove the diagnosis of PD in patients with slight symptoms and in these cases, FP‐CIT SPECT and MIBG scintigraphy may contribute to the early diagnosis of PD. In addition, the functional loss of nigrostriatal and cardiac sympathetic neurons seems to be coupled closely.

Myocardial sympathetic degeneration correlates with clinical phenotype of Parkinson's disease

In idiopathic Parkinsons disease (PD), different clinical subtypes are distinguished due to predominant motor symptoms: a tremor‐dominant type (TDT), an akinetic rigid type (ART), and a mixed type (MT). We compared myocardial sympathetic innervation, measured by MIBG scintigraphy, in different subtypes of PD at early and advanced stages of PD. We applied MIBG scintigraphy in 102 patients with PD. About 57 patients were at Hoehn and Yahr (H&Y) stage 1, 22 at H&Y stage 2, and 23 at H&Y stages 3 and 4. For quantification of myocardial MIBG uptake, the heart‐to‐mediastinum (H/M) count‐ratio was calculated. At all H&Y stages, myocardial MIBG uptake was significantly higher in TDT patients than in ART or MT patients (P < 0.05; ANOVA). Furthermore, at each H&Y stage, myocardial MIBG uptake correlated significantly with severity of hypokinesia (P < 0.05; Spearmans correlation) and rigidity (P < 0.05), but not with severity of resting or postural tremor. The significant correlation between myocardial sympathetic degeneration and severity of hypokinesia and rigidity suggests that myocardial sympathetic degeneration and hypokinetic‐rigid symptoms develop in a closely coupled manner in early as well as advanced PD. No such correlation can be found between myocardial sympathetic degeneration and parkinsonian tremor.

Is levodopa toxic

Abstract.The objective of this workshop was to review and discuss the debate on neurotoxicity of levodopa in the treatment of Parkinson’s disease (PD) with consideration of preclinical and clinical findings. We concluded that in particular preclinical outcomes of in vitro models of neurodegeneration describe neurotoxic effects of levodopa, whereas trials in animal models provided controversial results. To date, clinical trials in PD patients showed no convincing proof of direct neurotoxic effects of levodopa on progression of neurodegeneration with various applied functional imaging techniques particularly with specific radiotracers for nigral dopaminergic neurotransmission. However, the controversy on neurotoxicity of levodopa only partially considered indirect mechanisms, i. e. levodopa-associated homocysteine elevation. But there is accumulating evidence that this long-term side effect of chronic levodopa administration dose dependently individually contributes to progression of neurodegeneration due to increased release of neurotoxins, induction of oxidative stress and mitochondrial dysfunction according to results of in vitro and animal trials and to at least peripheral neuronal degeneration and increased risk for onset of atherosclerosis-related disorders according to clinical trials in PD patients. From this point of view we demand that future research on the efficacy and putative neurotoxicity of antiparkinsonian compounds should also consider putative toxic longterm effects of drug administration and should look for putative peripheral biomarkers and individual, environmental or nutritative risk factors in order to establish a preventive therapy, i. e. folic acid administration in the case of levodopa-associated homocysteine elevation.

Botulinum toxin treatment of secretory disorders.

Botulinum neurotoxin serotype A (BoNT/A) has revolutionised the treatment of a variety of autonomic hypersecretory disorders. Several open and controlled studies indicate that BoNT/A is a safe and effective treatment for focal hyperhidrosis of the axillae and palms, for gustatory sweating, and for some other rare conditions associated with focal hyperhidrosis. There is class I evidence for the efficacy of botulinum toxin in axillary hyperhidrosis and class II evidence for palmar hyperhidrosis and gustatory sweating. BoNT/A has the potential to replace current invasive and surgical techniques and should at least be considered as a viable alternative. The results of pilot studies to treat sialorrhea are encouraging. However, the optimal dose, best mode of application, side effects, and duration of BoNT/A action in this condition remain uncertain. We need further formal clinical trials to evaluate risks and benefits of BoNT/A for palliative treatment in of sialorrhea in Parkinsons disease and in bulbar amyotrophic lateral sclerosis. Based on the few reports published, BoNT/A injections into the lacrimal gland for hyperlacrimation may be an elegant method to treat this sometimes disabling condition. Again, larger studies are needed to evaluate the risks and long‐term benefits of this treatment option.

Repeat Botulin Toxin Injections in Anal Fissure (In Patients with Relapse and After Insufficient Effect of First Treatment)

Botulin toxin (BoTx) injections are analternative treatment for uncomplicated anal fissures.Until recently, surgical management has been advocatedfor therapeutic failure of BoTx and recurrent fissures. In 20 patients with recurring anal fissure weexamined the remission rate following a second course ofbotulin treatment. The dose was identical to the firsttreatment (5 units Botox®). In group 2, 30 patients with therapeutic failure were treated with ahigher dose of botulin toxin (10 units). In our patientswith recurring fissure, 19 of 20 were pain-free withina week (95%). After three months, 14 patients (70%) had healed fissures. In group 2, 22 of 30patients (73%) became pain-free within the first weekfollowing the second course of treatment. Two patients(7%) suffered from transient mild incontinence. Nineteen patients (63%) showed healed fissuresthree months following the second BoTx treatment. BoTxremains an effective treatment in recurring anal fissureas well as in patients with therapeutic failure of prior BoTx injections.