Dirk Dressler

Brain parenchyma sonography discriminates Parkinson's disease and atypical parkinsonian syndromes.

Objective: To study the use of brain parenchyma sonography (BPS) in discriminating between patients with idiopathic PD (IPD) and atypical parkinsonian syndromes (APS). Methods: Twenty-five patients with APS, 9 with progressive supranuclear palsy (PSP) and 16 with multiple-system atrophy (MSA), and 25 age-matched patients with IPD were prospectively studied with BPS according to a standardized protocol. Results: Twenty-four of the 25 (96%) IPD patients exhibited hyperechogenicity of the substantia nigra (SN) but only 2 of 23 (9%) APS patients (Mann–Whitney U test, p < 0.001). In those two APS patients, SN hyperechogenicity was moderate only, whereas the remaining 21 APS patients had normal SN echogenicity. The specificity of SN hyperechogenicity in detection of clinically diagnosed IPD patients was 96%, and the sensitivity was 91%. If SN hyperechogenicity was marked, APS could be excluded because of a positive predictive value of 100% for IPD. Nucleus lentiformis hyperechogenicity was found in 17 of 22 (77%) APS patients but in only 5 of 22 (23%) IPD patients (Mann–Whitney U test, p < 0.001). Nucleus caudatus and thalamus echogenicity and widths of the third ventricle and of the frontal horns of the lateral ventricles did not discriminate between IPD and APS. Two patients with PSP could not be assessed because of an insufficient bone window. Conclusions: BPS is a novel and noninvasive method to differentiate highly specifically between IPD and APS. Therefore, BPS might become a standard investigation in parkinsonian disorders.

Substantia nigra echogenicity is normal in non-extrapyramidal cerebral disorders but increased in Parkinson's disease

Summary. Transcranial sonography (TCS) revealed substantia nigra (SN) hyperechogenicity in idiopathic Parkinsons disease (IPD). To further evaluate specificity of this finding, we examined 30 IPD patients and 30 age-matched subjects with non-extrapyramidal cerebral disorders (NED). All IPD patients showed a SN hyperechogenicity, in 17 it was bilateral and in 13 unilateral. 7 NED patients had a SN hyperechogenicity, in all it was unilateral, confirming previous results in healthy subjects. Bilateral SN hyperechogenicity indicates IPD and normal SN echogenicity indicates NED. In 30% of patients TCS does not distinguish between IPD and NED. Data further support the assumption that bilateral SN hyperechogenicity is specific for IPD.

Autonomic side effects of botulinum toxin type B treatment of cervical dystonia and hyperhidrosis

Recently, botulinum toxin type B (BT-B) has become available to treat muscle hyperactivity in cervical dystonia (CD). When we started the clinical use of BT-B, we noticed a side effect profile not seen with botulinum toxin type A (BT-A) before. Altogether 30 consecutive patients were included in this open controlled study. 24 patients were treated for CD with 11,310 ± 2,616 mouse units (MU) of BT-B (NeuroBloc®) and 6 for focal hyperhidrosis (HH) with 4,000–10,000 MU. In 5 of them, BT-A (Botox®) was used additionally for comparison of effectiveness. In CD, side effects consisted of dryness of mouth (total 21, duration 4.4 ± 2.0 weeks, 10 severe, 7 moderate, 4 mild), accommodation difficulties (7), conjunctival irritation (5), reduced sweating (4), swallowing difficulties (3), heartburn (3), constipation (3), bladder voiding difficulties (2), head instability (1), dryness of nasal mucosa (1) and thrush (1). In HH, side effects consisted of accommodation difficulties (4), dryness of mouth (2) and conjunctival irritation (1). Autonomic side effects occur far more often after BT-B than after BT-A. Their localization suggests systemic BT-B spread. BT-B should be applied carefully in patients with pre-existent autonomic dysfunction, additional anticholinergic treatment and in conditions where anticholinergics are contraindicated.

Botulinum toxin: mechanisms of action

Botulinum toxin (BT) has been perceived as a lethal threat for many centuries. In the early 1980s, this perception completely changed when BTs therapeutic potential suddenly became apparent. We wish to give an overview over BTs mechanisms of action relevant for understanding its therapeutic use. BTs molecular mode of action includes extracellular binding to glycoprotein structures on cholinergic nerve terminals and intracellular blockade of the acetylcholine secretion. BT affects the spinal stretch reflex by blockade of intrafusal muscle fibres with consecutive reduction of Ia/II afferent signals and muscle tone without affecting muscle strength (reflex inhibition). This mechanism allows for antidystonic effects not only caused by target muscle paresis. BT also blocks efferent autonomic fibres to smooth muscles and to exocrine glands. Direct central nervous system effects are not observed, since BT does not cross the blood-brain barrier and since it is inactivated during its retrograde axonal transport. Indirect central nervous system effects include reflex inhibition, normalisation of reciprocal inhibition, intracortical inhibition and somatosensory evoked potentials. Reduction of formalin-induced pain suggests direct analgesic BT effects possibly mediated by blockade of substance P, glutamate and calcitonin gene-related peptide.

Brain parenchyma sonography detects preclinical parkinsonism

Substantia nigra (SN) hyperechogenicity on brain parenchyma sonography (BPS) is highly characteristic for idiopathic PD. We studied 7 symptomatic and 7 asymptomatic parkin mutation carriers (PMC) from a large kindred with adult‐onset parkinsonism. BPS revealed larger SN echogenic sizes in PMC with parkin mutations on both alleles (homozygous, compound‐heterozygous), compared to PMC with only one mutated allele (Mann–Whitney U test, P = 0.007). In symptomatic PMC, larger SN echogenic size was correlated with younger age at onset of the disease (Spearman rank correlation, Rho = −0.937, P = 0.002) but not with age, disease duration, or disease severity. BPS demonstrated SN hyperechogenicity, in concordance with abnormal nigrostriatal 18F‐dopa positron emission tomography (PET), in all symptomatic and 3 asymptomatic PMC. In 2 asymptomatic PMC, PET and BPS were normal. However, in another 2 asymptomatic PET‐normal PMC, SN hyperechogenicity could be detected. Data suggest SN hyperechogenicity as an early marker to detect preclinical parkinsonism.

Pharmacology of botulinum toxin: differences between type A preparations

Different types of botulinum neurotoxin (BoNT) block different proteins of the soluble N‐ethylmaleimide sensitive factor attachment protein receptor (SNARE) protein complex within cholinergic nerve terminals, producing blockade of cholinergic neuromuscular and autonomic synapses. Animal studies indicate the longest duration of action for BoNT type A (BoNTA) followed by types B, F, and E. Diffusion to adjacent and remote muscles may be related to protein composition, dilutions, volume, target muscle selection, and injection technique. A review of head‐to‐head, randomized, controlled trials of BoNTA preparations (Botox® and Dysport®) suggests that Dysport® tends to have higher efficacy, longer duration, and higher frequency of adverse effects. Conversion factors between the preparations varied, however, and remain controversial. In clinical settings, a Botox®:Dysport® conversion ratio of 1:3 may be appropriate. Animal studies suggest a conversion ratio of 1:2.5–3. When therapeutic effects between these preparations are attempting to be equalized, Dysport® seems to produce more adverse effects. In mice, Botox® appears to have a better safety margin than Dysport® and BoNTB. In rats, diffusion margins are similar for Botox® and Dysport®. Jitter derived from stimulation single‐fiber EMG of injected and remote muscles show no differences between Botox® and Dysport®. Atrophy of extrafusal muscle fibers of injected and remote muscles do not differ between the BoNTA preparations.

Botulinum Toxin: Mechanisms of Action

Botulinum toxin (BT) has been perceived as a lethal threat for many centuries. In the early 1980s, this perception completely changed when BT’s therapeutic potential suddenly became apparent. We wish to give an overview over BT’s mechanisms of action relevant for understanding its therapeutic use. BT’s molecular mode of action includes extracellular binding to glycoprotein structures on cholinergic nerve terminals and intracellular blockade of the acetylcholine secretion. BT affects the spinal stretch reflex by blockade of intrafusal muscle fibres with consecutive reduction of Ia/II afferent signals and muscle tone without affecting muscle strength (reflex inhibition). This mechanism allows for antidystonic effects not only caused by target muscle paresis. BT also blocks efferent autonomic fibres to smooth muscles and to exocrine glands. Direct central nervous system effects are not observed, since BT does not cross the blood-brain barrier and since it is inactivated during its retrograde axonal transport. Indirect central nervous system effects include reflex inhibition, normalisation of reciprocal inhibition, intracortical inhibition and somatosensory evoked potentials. Reduction of formalin-induced pain suggests direct analgesic BT effects possibly mediated by blockade of substance P, glutamate and calcitonin gene-related peptide.

Immunological aspects of Botox®, Dysport® and Myobloc™/NeuroBloc®

In some patients treated with botulinum toxin (BT), antibodies are produced in association with certain treatment parameters, patient characteristics and immunological properties of the BT preparation used. Therapeutic BT preparations are comprised of botulinum neurotoxin, non‐toxic proteins and excipients. Antibodies formed against botulinum neurotoxin can block BTs biological activity. The antigenicity of a BT preparation depends on the amount of botulinum neurotoxin presented to the immune system. This amount is determined by the specific biological activity, the relationship between the biological activity and the amount of botulinum neurotoxin contained in the preparation. For Botox® the specific biological activity is 60 MU‐EV/ng neurotoxin, for Dysport® 100 MU‐EV/ng neurotoxin and for MyoblocTM/NeuroBloc® 5 MU‐EV/ng neurotoxin. For MyoblocTM/NeuroBloc® this translates into an antibody‐induced therapy failure rate of 44% in patients treated for cervical dystonia, whereas for BT type A preparations this figure is approximately 5%. No obvious differences in antigenicity of BT type A preparations have been detected thus far. For the current formulation of Botox®, the rate of antibody‐induced therapy failure is reportedly less than 1%. To determine the antigenicity of different BT preparations in more detail, prospective studies on large series of unbiased patients with sensitive and specific BT antibody tests are necessary.

Pharmacology of therapeutic botulinum toxin preparations

Therapeutic preparations of botulinum toxin (BT) consist of botulinum neurotoxin (BNT), complexing proteins and excipients. Depending on the target tissue BT can block the cholinergic neuromuscular or the cholinergic autonomic innervation of exocrine glands and smooth muscles. Additional effects can be demonstrated on the muscle spindle organ. Indirect effects on the central nervous system are numerous, direct ones have not been recorded after intramuscular injections. BT type A is being distributed as Botox®, Dysport® and Xeomin®, BT type B as NeuroBloc®/Myobloc®. Adverse effects can be obligate, local or systemic. The adverse effect profiles of the available BT preparations are similar. BT type B, however, has additional systemic autonomic adverse effects. Long-term treatment does not produce additive adverse effects. BNT can be partially or completely blocked by antibodies. The major risk factors for antibody-induced therapy failure are the amount of BNT applied at each injection series, the interval between injection series and the specific biological activity (SBA) of the BT preparation used. The SBA is 5 for NeuroBloc®, 60 for Botox®, 100 for Dysport® and 167MU-E/ng BNT for Xeomin® (MU-E: equivalence mouse units). Therapeutic BT preparations are a group of highly potent drugs with an intriguing mechanism of action. With the advent of new competitors comparative studies amongst different therapeutic BT preparations will become more and more interesting.

Sonographic discrimination of corticobasal degeneration vs progressive supranuclear palsy

Objective: To study the use of brain parenchyma sonography (BPS) in discriminating between patients with corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Methods: Thirteen patients with PSP and eight with CBD were studied with BPS according to a standardized protocol. Results: Seven (88%) of the eight CBD patients showed marked hyperechogenicity of the substantia nigra (SN) but none of eleven PSP patients (Mann-Whitney U test, p < 0.001). This finding indicated CBD with a positive predictive value of 100%. Marked dilatation of the third ventricle (width > 10 mm) was found in 10 (83%) of 12 PSP patients, but in none of the CBD patients (p < 0.005). BPS measurements of ventricle widths closely matched MRI measurements (Pearson correlation, r = 0.90, p < 0.001). The presence of at least one of the BPS findings 1) marked SN hyperechogenicity and 2) third-ventricle width < 10 mm indicated CBD with a sensitivity of 100%, a specificity of 83%, and a positive predictive value of 80%. Other BPS findings such as echogenicity of lentiform and caudate nuclei and widths of the frontal horns did not discriminate between CBD and PSP. One PSP patient could not be assessed because of insufficient acoustic temporal bone windows. Conclusions: Substantia nigra hyperechogenicity, reported earlier as characteristic brain parenchyma sonography finding in idiopathic Parkinson disease, is also typical for corticobasal degeneration.