New formulation of Botox: complete antibody-induced treatment failure in cervical dystonia.
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Antibody Formation↗
Biomedical subjects
D Dressler
Publications and source records attributed to D Dressler.
Clinical use of non-A botulinum toxins: botulinum toxin type B.
Botulinum neurotoxin type B (BT, BT-B) has been used as NeuroBloc/MyoBloc since 1999 for treatment of cervical dystonia, hyperhidrosis, spastic conditions, cerebral palsy, hemifacial spasm, bladder dysfunction, spasmodic dysphonia, sialorrhoea, anal fissures, piriformis syndrome, various pain conditions and cosmetic applications. Generally, its therapeutic effects are comparable to BT type A (BT-A). The adverse effect profiles of BT-B and BT-A, however, differ considerably. BT-B has been found to produce more regional as well as systemic anticholinergic adverse effects, such as dryness of mouth, accommodation difficulties, conjunctival irritation, reduced sweating, dysphagia, heartburn, constipation, bladder voiding difficulties and dryness of nasal mucosa. In BT-B the relationship between autonomic and motor effects known from BT-A is substantially shifted towards autonomic effects. BT-B, therefore, should be used carefully in patients with autonomic disorders and in patients with concomitant anticholinergic therapy. If NeuroBloc/MyoBloc is used to treat cervical dystonia patients with antibody-induced failure of BT-A therapy, 86% of those will develop complete secondary therapy failure after five applications. If NeuroBloc/MyoBloc used to treat cervical dystonia patients without prior exposure to BT, 44% of those will develop complete secondary therapy failure after nine applications. NeuroBloc/MyoBloc, therefore, is associated with substantial antigenicity problems originating from a particular low specific biological potency. Systemic anticholinergic adverse effects and high antigenicity limits the clinical use of NeuroBloc/MyoBloc considerably.
Animals↗
Clinical use of non-A botulinum toxins: botulinum toxin type C and botulinum toxin type F.
Botulinum neurotoxin (BoNT) serotype A is commonly used in the treatment of focal dystonia, but some patients are primarily or become secondarily resistant to it. Consequently, other serotypes have to be used when immuno-resistance is proven. In the literature, patients with focal dystonia have been treated with BoNT serotype F with clinical benefit but with short lasting effects. Recently, BoNT serotype C has been used with positive clinical outcome. An update on the clinical use of BoNT serotype F and BoNT serotype C is provided.
Adult↗
[Pharmacological aspects 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, BNT can block cholinergic neuromuscular innervation of intra- and extrafusal muscle fibres or cholinergic autonomic innervation of sweat, lacrimal, and salival glands and smooth muscles. Indirect CNS effects are numerous; direct ones have not been reported after intramuscular application. Botulinum toxin type A is distributed as Botox, Dysport, Xeomin, Hengli/CBTX-A, and Neuronox and BT type B as NeuroBloc/Myobloc. Differences in potency labelling of therapeutic BT preparations can be corrected by introduction of a conversion factor of 1:3 between Botox and Dysport, of 1:1 between Botox and Xeomin, and of 1:40 between Botox and NeuroBloc/Myobloc. Acute adverse effects of BT can be obligate, local or systemic. Adverse effect profiles of the different preparations are similar. However, BT type B frequently produces additional autonomic systemic adverse effects. Long-term application does not produce additional adverse effects. BNT can be partially or completely blocked by antibodies. Risk factors include the amount of BNT applied at each injection series, the interval between injection series, and the specific biological potency (SBP) of the BT preparation used. The SBP is 5 equivalent mouse units/ng BNT for NeuroBloc, 60 for Botox, 100 for Dysport, and 167 for Xeomin. Xeomin should therefore have a particularly low antigenicity. Clinical confirmation of this predicition, however, is lacking.
Botulinum Toxins↗
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.
Animals↗
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 BT's 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 Myobloc/NeuroBloc 5 MU-EV/ng neurotoxin. For Myobloc/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.
Animals↗
Botulinum toxin therapy of hemifacial spasm: comparing different therapeutic preparations.
Hemifacial spasm (HFS) is characterized by involuntary irregular clonic or tonic movements of the muscles innervated by cranial nerve VII on one side of the face, and is most often a result of vascular compression of the facial nerve at the root exit zone (Muscle and Nerve 1998;21:1740). Disability associated with this disorder ranges from social embarrassment to interference with vision resulting from involuntary eye closure. Treatment of HFS most often involves botulinum toxin injections, but may also include medications and surgery. We describe treatment with the three types of botulinum toxin currently commercially available--Botox, Dysport and Myobloc/NeuroBloc.
Anti-Dyskinesia Agents↗
Botulinum toxin therapy of writer's cramp.
The pathophysiology and management of writer's cramp is one of the most challenging amongst the various forms of focal dystonias. Frequently, the dystonic postures are confounded by compensatory muscle activity. Correct identification of target muscles for botulinum toxin (BT) injections determines the treatment success. The dosages of different preparations vary, with 1 unit of Botox roughly equalling 3.5 units of Dysport. Electromyographic guided injections yield better results and may also decrease the amount of toxin required. Weakness of target muscles interfering with other non-writing activities is a frequently encountered adverse effect. Studies have shown that BT is a safe long-term therapy option.
Anti-Dyskinesia Agents↗
Overactive bladder in Parkinson's disease: alteration of brainstem raphe detected by transcranial sonography.
Urinary dysfunction is very common in idiopathic Parkinson's disease (PD) and manifests primarily with symptoms of overactive bladder (OAB). Affection of central serotonergic systems has been suggested to play a role in OAB. The objective of this study was to evaluate whether in PD patients with OAB symptoms a specific alteration of the brainstem raphe (BR), which contains serotonergic neurons, can be detected with transcranial sonography (TCS). Of 116 PD patients enrolled, 19 had PD-related OAB symptoms (OAB+) unlike remaining 97 patients (OAB-). Patients were examined by a sonographer blinded to the clinical data. Reduced echogenicity of BR was found in 12 (63%) OAB+ patients but only in 18 (19%) of 93 assessable OAB- patients (Mann-Whitney U-test, P < 0.001). In OAB+ patients, lower raphe echogenicity score was associated with longer duration of OAB symptoms (anova, P = 0.033). Other TCS findings such as echogenicity of substantia nigra, thalami, lenticular and caudate nuclei, and widths of third and lateral ventricles did not differ between OAB+ and OAB- patients. TCS findings suggest a pathogenetic role of BR in OAB related to PD. Alterations may reflect disturbance of its central serotonergic system.
Adult↗
Diagnosis and management of acute movement disorders.
Most movement disorders, reflecting degenerative disorders, develop in a slowly progressive fashion. Some movement disorders, however, manifest with an acute onset. We wish to give an overview of the management and therapy of those acute-onset movement disorders.Drug-induced movement disorders are mainly caused by dopamine-receptor blockers (DRB) as used as antipsychotics (neuroleptics) and antiemetics. Acute dystonic reactions usually occur within the first four days of treatment. Typically, cranial pharyngeal and cervical muscles are affected. Anticholinergics produce a prompt relief. Akathisia is characterized by an often exceedingly bothersome feeling of restlessness and the inability to remain still. It is a common side effect of DRB and occurs within few days after their initiation. It subsides when DRB are ceased. Neuroleptic Malignant Syndrome is a rare, but life-threatening adverse reaction to DRB which may occur at any time during DRB application. It is characterised by hyperthermia, rigidity, reduced consciousness and autonomic failure. Therapeutically immediate DRB withdrawal is crucial. Additional dantrolene or bromocriptine application together with symptomatic treatment may be necessary. Paroxysmal dyskinesias are childhood onset disorders characterised by dystonic postures, chorea, athetosis and ballism occurring at irregular intervals. In Paroxysmal Kinesigenic Dyskinesia they are triggered by rapid movements, startle reactions or hyperventilation. They last up to 5 minutes, occur up to 100 times per day and are highly sensitive to anticonvulsants. In Paroxysmal Non-Kinesiogenic Dyskinesia they cannot be triggered, occur less frequently and last longer. Other paroxysmal dyskinesias include hypnogenic paroxysmal dyskinesias, paroxysmal exertional dyskinesia, infantile paroxysmal dystonias, Sandifer's syndrome and symptomatic paroxysmal dyskinesias. In Hereditary Episodic Ataxia Type 1 attacks of ataxia last for up to two minutes, may be accompanied by dysarthria and dystonia and usually respond to phenytoin. In Type 2 they can last for several hours, may be accompanied by vertigo, headache and malaise and usually respond to acetazolamide. Symptomatic episodic ataxias can occur in a number of metabolic disorders, but also in multiple sclerosis and Behcet's disease.
Adolescent↗
Sonographic detection of basal ganglia lesions in asymptomatic and symptomatic Wilson disease.
OBJECTIVE: To investigate whether transcranial brain parenchyma sonography (TCS) detects basal ganglia abnormalities in asymptomatic and symptomatic patients with Wilson disease (WD) and whether findings correlate with disease severity. METHODS: Twenty-one patients with WD with (n = 18) or without (n = 3) neurologic symptoms were investigated. Disease severity was assessed by three independent neurologists using a WD rating scale (WDRS) with the items dysarthria, akinesia, ataxia, tremor, and dystonia; the raters' median score was used for further analysis. Basal ganglia TCS was performed according to a standardized protocol. RESULTS: TCS revealed lenticular nucleus (LN) hyperechogenicity in all assessable neurologically symptomatic and in two of the three asymptomatic patients. Size of LN hyperechogenic area correlated with the WDRS score (Spearman correlation, rho = 0.604, p = 0.006), as did the size of thalamus hyperechogenic area (n = 7, rho = 0.891, p = 0.007), the width of third ventricle (n = 21, rho = 0.613, p = 0.003), and the width of lateral ventricles (n = 20, rho = 0.642, p < 0.001). Substantia nigra hyperechogenicity, detected in 10 patients, did not correlate with disease severity. There was no correlation between age at disease onset or disease duration and any TCS finding. Of the 19 patients with LN hyperechogenicity, only 12 showed abnormal LN on MRI. CONCLUSIONS: Transcranial brain parenchyma sonography (TCS) detects lenticular nucleus hyperechogenicity, likely to be caused by copper accumulation, in neurologically symptomatic and asymptomatic Wilson disease (WD). TCS findings correlate with disease severity. TCS appears a promising tool for disease monitoring in WD.
Adult↗
[Apomorphine in the treatment of Parkinson's Disease].
Apomorphine has long been used in many medical specialties. It is a highly potent D2-, D3- and D4-dopamine receptor agonist with a particularly high D1-dopamine receptor affinity. Due to its almost complete inactivation during liver passage it is usually applied subcutaneously. After rapid onset its effect is waning after about one hour. Apomorphine's action is not dependent on enteral dopamine resorption and on praesynaptic dopamine storage and dopamine secretion mechanisms. When applied subcutaneously its most common side effect is cutaneous nodules at the injection sites. Peripheral dopaminergic side effects, such as nausea and orthostatic hypotension, usually occur only during therapy initiation and respond well to domperidone. Hallucinations occur less frequently than with other dopamine receptor agonists. The apomorphine test determines the levodopasensitivity of a parkinsonian syndrome by application of an apomorphine bolus to distinguish between idiopathic Parkinson's disease and atypical parkinsonian syndromes. It indicates a levodopasensitivity in about 90% of the patients tested. False-negative results can occur in mild parkinsonian syndromes. A meta analysis indicates that intermittent subutaneous apomorphine applications (intermittent apomorphine therapy) with a self application device can reduce the daily duration of unpredictable off-phases by 48.8+/-8.7%. For this an average of 3.7+/-1.1 x 2.9+/-0.8 mg apomorphine has to be applied per day. Continuous subcutaneous apomorphine application with an extracorporal pump (continuous apomorhine therapy) during the wake phase reduces the duration of daily off-phases by 64.8+/-13.5% and the additional levodopa dose by 30.3+/-31.1%. 24-hour application reduces the daily duration of the off-phases by 63.5+/-19.1% and the additional levodopa dose by 65.5+/-21.9%. Levodopa-induced dyskinesias are also substantially reduced. A gradual conversion to an apomorphine monotherapy is possible. Even after prolonged treatment times no significant loss of efficacy occurs. With this profile apomorphine is a highly successful treatment option for off-phases and levodopa-induced dyskinesias in advanced cases of idiopathic Parkinson's disease which should be used before more invasive approaches are considered.
Antiparkinson Agents↗
[Botulism caused by consumption of smoked salmon].
Fresh fish products are exquisitely prone to be the source for food botulism because of primary contamination with Clostridium botulinum spores, lack of heat inactivation of C. botulinum spores, frequently used air-tight packaging, lack of preservatives, lack of heat inactivation of already produced botulinum toxin and because of substantial low temperature resistance of C. botulinum type E typically found in fish botulism. We can reporting a 25-year-old patient with food botulism presenting with an anticholinergic syndrome with mydriasis, accommodation difficulties, dryness of mouth, reduced sweating, constipation and reduced heart rate variance and only discrete involvement of striate muscles with ptosis, diplopia and generalised fatigue, all of which developed 12 h after the consumption of airtight sealed smoked salmon. The salmon was consumed 3 days after the 'use by' date had expired.
Adult↗
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.
Aged↗
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.
Aged↗
[Antibody-induced failure of botulinum toxin therapy].
Botulinum toxin (BT) has been used with great success in a large number of medical specialities. In some patients, however, formation of antibodies against BT (BTAB), with therapy failure (ABTF) occurs. Risk factors for ABTF are the amount of BT given at each injection series and the duration of the intervals between injection series. Treatment time and cumulative BT dose as well as patient age and gender are not independent risk factors. BTAB titres drop spontaneously after cessation of BT therapy, but latencies are too long to be compatible with a clinically effective therapy. Once these titres have dropped, BT therapy can be restarted using improved parameters and improved BT preparations with lower antigenicity. Increasing the BT dosage can be successful for overcoming ABTF when BTAB titres are low and target muscle responses are only moderately reduced. The use of alternative BT type A preparations fails to overcome ABTF. Alternative BT types such as types B and F are initially successful in ABTF but stimulate the formation of antibodies against the alternative BT types after few applications. When type B is used, substantial systemic anticholinergic side effects can occur. Prevention of BTAB formation is of paramount importance. Risk factors for BTAB formation have to be taken into account when planning BT therapy. The most interesting perspective, however, seems to be the development of new BT preparations with improved specific potency and reduced antigenicity.
Antibodies↗
[Use of botulinum toxin the the treatment of muscle pain].
The analgesic effects of botulinum toxin (BTX) have been discussed controversially due to substantial placebo effects and flaws in the study designs used. Additionally, pathophysiological concepts of pain and the specific analgesic mechanisms of BTX remain largely unclear. Apart from pain reduction through the well-documented effects of BTX at the neuromuscular endplate, additional analgesic mechanisms, including other synaptic and local effects, have been suggested. Currently, BTX can be recommended for pain treatment in dystonia and spasticity. In myofascial pain syndromes, pain relief by BTX injections has been reported, but definite proof according to evidence-based medicinal criteria is still lacking. In fibromyalgia, there seems to be no analgesic effect. The role of BTX in pain therapy is likely to increase in the future.
Botulinum Toxins, Type A↗
[Initial experiences with clinical use of botulinum toxin type B].
Recently, botulinum toxin type B (BT-B) was introduced for treatment of cervical dystonia (CD). We wish to report on experience with BT-B derived from registration studies and from our own preliminary clinical experience. Botulinum toxin type B can be used successfully in CD patients with antibody-induced failure of botulinum toxin type A therapy (antibody patients). In our own 15 antibody patients, 11835 +/- 2,039 mouse units of BT-B (NeuroBloc) reduced the Toronto Western spasmodic torticollis rating scale (TWSTRS) score from 20.5 +/- 3.6 to 13.1 +/- 5.4. BT-B can also be used successfully in CD patients not previously exposed to BT-A or BT-B (de novo patients). In our own nine de novo patients, 10436 +/- 3,320 mouse units of BT-B reduced the TWSTRS score from 18.4 +/- 5.4 to 9.2 +/- 4.8. Altogether, dryness of the mouth occurred in 21 CD patients (severe 10, moderate 7, mild 4), accommodation difficulties in seven, conjunctival irritation in five, reduced sweating in four, swallowing difficulties in three, heartburn in three, constipation in three, bladder voiding difficulties in two, and dryness of nasal mucosa, head instability, and thrush in one each. BT-B produces substantially more systemic autonomic side effects than BT-A. It can be considered the therapy of choice in antibody patients. For de novo patients and for BT-A-treated CD patients, BT-B cannot be recommended currently.
Adult↗