Botulinum neurotoxin serotype D – A potential treatment alternative for BoNT/A and B non-responding patients

ObjectivesBotulinum neurotoxin serotypes A and B (BoNT/A & B) are highly effective medicines to treat hyperactive cholinergic neurons. Due to neutralizing antibody formation, some patients may become non-responders. In these cases, the serotypes BoNT/C-G might become treatment alternatives. BoNT/D is genetically least related to BoNT/A & B and thereby circumventing neutralisation in A/B non-responders. We produced BoNT/D and compared its pharmacology with BoNT/A ex vivo in mice tissue and in vivo in human volunteers.MethodsBoNT/D was expressed recombinantly in E. coli, isolated by chromatography and its ex vivo potency was determined at mouse phrenic nerve hemidiaphragm preparations. Different doses of BoNT/D or incobotulinumtoxinA were injected into the extensor digitorum brevis (EDB) muscles (n = 30) of human volunteers. Their compound muscle action potentials were measured 11 times by electroneurography within 220 days.ResultsDespite a 3.7-fold lower ex vivo potency in mice, a 110-fold higher dosage of BoNT/D achieved the same clinical effect as incobotulinumtoxinA while showing a 50% shortened duration of action.ConclusionsBoNT/D blocks dose-dependently acetylcholine release in human motoneurons upon intramuscular administration, but its potency and duration of action is inferior to approved BoNT/A based drugs.SignificanceBoNT/D constitutes a potential treatment alternative for BoNT/A & B non-responders.     

Ninhydrin sweat test: a simple method for detecting antibodies neutralizing botulinum toxin type A.

Approximately 5% of patients with cervical dystonia receiving repeated botulinum neurotoxin A (BoNT/A) injections develop secondary loss of treatment benefit. Currently available tests to directly detect neutralizing BoNT/A antibodies (BoNT/A-AB) are either expensive or time consuming. To establish a simple, clinically useful test for antibody detection, we adapted the ninhydrin sweat test (NST). Eighteen dystonic patients with secondary nonresponse and clinically suspected BoNT/A-AB formation were tested for BoNT/A-AB in the mouse diaphragm test (MDT). In addition, the size of the anhidrotic area was determined by the NST 21 days after an intradermal dose of 10 U Dysport into the hypothenar region of the left palm. In nine patients, positive BoNT-AB titers were found in the MDT. There was a significant correlation between the BoNT/A-AB titers and the anhidrotic area (Spearman's rho = -0.9, P < 0.0001). Both tests provided comparably good results with respect to qualitative antibody detection. In the clinical situation of secondary nonresponse to BoNT/A therapy, the economical NST may be a helpful tool to detect neutralizing BoNT/A-AB.     

Neutralizing botulinum toxin type a antibodies: clinical observations in patients with cervical dystonia

Neutralization of antibodies poses a problem for a substantial number of cervical dystonia (CD) patients treated with botulinum toxin type A (BoNT/A). Presence of these antibodies may lead to a secondary nonresponse to BoNT/A treatment. In this study, we compared 6 antibody-positive (Ab+) with 12 antibody- negative (Ab-) CD patients treated with BoNT/A (Dysport) and matched for du- ration of treatment, number of BoNT/A injections, and severity of clinical symptoms. The two groups differed in cumulative BoNT/A dose (Ab+, 5984 mouse units [MU ], SD = 3151 MU; Ab-, 3143 MU, SD =1294 MU; P <.05), in addition, ab+ patients were significantly younger (ab+ mean age = 41.3 y, sd =5.9 y; ab - mean age = 56.8 y, sd = 15.3 y; p <.05), in or- der to avoid formation of neutralizing antibodies, doses of bont/a should be kept as low as possible, the risk of antibody formation seems to be higher in younger patients.     

The rescue effect of plasma exchange for neuromyelitis optica

Neuromyelitis optica (NMO) is an uncommon idiopathic demyelinating disease of the central nervous system and is sometimes unresponsive to steroid treatment as compared to multiple sclerosis (MS). There are only a few reports of plasma exchange (PE) as an effective rescue treatment when high-dose steroid therapy fails in exacerbations of NMO. Thus, we aimed to evaluate the efficacy of PE for acute attacks of NMO that failed to respond to high-dose steroid therapy. A retrospective review and clinical follow-up were conducted in two hospitals from January 2001 to January 2008. We recruited patients with NMO who had failed to respond to high-dose steroid treatment, and who then received PE during an acute relapse. We evaluated a global functional assessment of the change in the neurological condition, and the Expanded Disability Status Scale (EDSS) score. All nine patients were middle-aged women (mean age: 48.7 years old), five of whom tested positive for anti-aquaporin (AQP)-4 antibodies in the study. The patients were severely disabled at the initiation of PE (median EDSS score, 8.7; range, 8.5-9.0). Improvement occurred early in the course of PE. At the 2-month post-PE follow-up, eight of nine patients had improved to their pre-attack condition. This study highlights the potential role of PE as a rescue therapy in the management of steroid-unresponsive acute attacks of NMO, especially in patients with auto-antibodies against AQP-4.     

Long-term treatment of cervical dystonia with botulinum toxin A: efficacy, safety, and antibody frequency

Data from 616 patients suffering from idiopathic cervical dystonia were analyzed to determine the efficacy and safety of treatment with botulinum neurotoxin type A (BoNT/A). Since the specific purpose of this study was to determine the long-term effects of this treatment, the analysis focused specifically on the patients (n = 303) having received six or more injections. Statistical analysis of a standardized documentation showed sustained significant benefit as measured by a disease severity score independent of the type of cervical dystonia. Furthermore, pronounced individual differences were found in response to this treatment although initial clinical scores and doses of BoNT/A were similar. There was no indication of previously unknown adverse events, the only risk being the development of serum antibodies against the toxin. As in previous studies on short-term effects of BoNT/A treatment, the most frequent adverse event was dysphagia, which occurred on average 9.7 days after injection and lasted on average 3.5 weeks. While secondary nonresponse was seen in approx. 5% of patients, antibody tests revealed neutralizing serum antibodies in only 2%. On the basis of the present data, therapy of cervical dystonia with BoNT/A seems to be safe and yields good stable results even after 5 years of treatment. Received: 26 June 1997 Received in revised form: 17 July 1998 Accepted: 4 August 1998     

Further studies using higher doses of botulinum toxin type F for torticollis resistant to botulinum toxin type A

OBJECTIVE—A previous study of botulinum toxin typeF (BTX-F) treatment for torticollis had shown a dose of 520 MU to beeffective, but for a much shorter duration than is usual with botulinumtoxin type A (BTX-A). The objective was to assess the effect of ahigher dose of BTX-F.
METHODS—Four of the previously treated patients,plus an additional patient, were treated with a higher dose of 780 MUBTX-F. All were secondary non-responders to BTX-A due to neutralisingantibodies. A test injection of 40 MU BTX-F was also given into theextensor digitorum brevis muscle (EDB), to examine the time course ofthe biological effect of the toxin electrophysiologically. Patients were followed up at two, four, eight, and 12weeks.
RESULTS—All patients reported subjectiveimprovement lasting from seven to 11 (mean 8.6) weeks accompanied by asignificant reduction in mean clinical severity scores at two weeks.Four patients had pain which was substantially reduced. Theelectrophysiological studies confirmed biological sensitivity to thetoxin in all patients, showing a significant change beginning at twoweeks and returning to baseline at 12 weeks. The time course of thiseffect paralleled roughly that of the clinical response. The fourpatients who had previously received 520 MU BTX-F reported that theresponse was better and longer in duration with 780 MU. Dysphagia wasmore common than reported with the lower dose.
CONCLUSION—Better results are possible with higherdoses of BTX-F but the duration of benefit is still shorter than withBTX-A, seemingly due to a shorter duration of neuromuscular junction blockade.

     

Sudomotor testing predicts the presence of neutralizing botulinum A toxin antibodies

The increasing number of patients being treated with botulinum toxin A complex (BoNT/A) has led to a higher incidence of neutralizing anti-BoNT/A antibodies (ABAs). Because BoNT/A is known to inhibit sweating, here we report sudometry as a possibility for predicting the presence of ABA. Sixteen patients suffering from spasmodic torticollis were selected: in 2 patients, BoNT/A treatment continued to be effective, in 9 patients, the treatment effect was impaired, and in 5 patients, secondary treatment failure developed. BoNT/A (100 mouse units, Dysport; Ipsen Pharma, Berkshire, United Kingdom) was injected subcutaneously into the lateral calves. Sweating was visualized with iodine starch staining. In addition, quantitative sudomotor axon reflex testing was performed at the injection site. Individual ABA titers were determined with a mouse bioassay. Results of sudometry significantly correlated with the BoNT/A treatment success. The quantitative sudomotor axon reflex testing was 0.58 +/- 0.63 fraction of the normal mean in patients with treatment failure, 0.18 +/- 0.13 fraction of the normal mean in those who responded partially, and 0 in responders (p < 0.01). Accordingly, the areas of the anhidrotic skin after subcutaneous injections were 4.5 +/- 10.3 cm(2), 32.7 +/- 16.5 cm(2), and 62 cm(2) (p < 0.01). Discrimination analysis indicated that the presence of ABA (6 ABA-positive and 10 ABA-negative) could be predicted correctly in all patients from the results of sudometry. Therefore, sudometry is a useful tool for identifying patients with neutralizing ABAs and might be helpful for identifying reasons for BoNT/A treatment failure.     

Liquorpheresis (CSF-filtration): An effective treatment in acute and chronic severe autoimmune polyradiculoneuritis (Guillain-Barré syndrome)

Summary In recent years, plasmapheresis has become a well established treatment of acute and chronic polyradiculoneuritis (Guillain-Barré syndrome, GBS). Nervertheless, there are still non-responders and there are particular risks associated with this treatment. Despite all efforts, the duration of severe forms of Guillain-Barré syndrome is still considerable. Inflammation and demyelination start intrathecally. We therefore used liquorpheresis (cerebrospinal fluid filtration) as a new effective therapeutic approach. Our first patient, severely disabled with acute GBS, artificially ventilated, had undergone plasma exchange without effect. Plasma immunoadsorption led only to transient improvement. After several liquorphereses, the patient recovered completely. In three additional patients with acute and two with chronic GBS an improvement of clinical signs in close temporal relation to liquorpheresis was observed. Twice, liquorpheresis was combined with immunoadsorption of cerebrospinal fluid. Liquorpheresis was well tolerated in all cases. This procedure may be effective by eliminating humoral or cell-bound factors responsible for the onset or/and maintenance of inflammation. Further controlled studies are necessary and are in progress.Parts of this paper were presented at the symposium of the German Neurological Society, Bad Nauheim, 29.09.1989     

Intravenous immunoglobulin treatment in lower motor neuron disease associated with highly raised anti-GM1 antibodies

The effect of intravenous immunoglobulin (IVIg) treatmentwas studied in five patients with lower motor neuron disease associated with highly raised anti-GM1 antibodies but without evidence of conduction block on neurophysiological examination. The patients received IVIg treatment (0.4 g/kg for five consecutive days) in an openstudy. Only one patient responded to IVIg treatment, which wasconfirmed in a double blind, placebo controlled study (two placebotreatments and two IVIg treatments in a randomised order). However,after six months of maintenance IVIg treatment (0.4 g/kg weekly) muscleweakness gradually deteriorated below pretreatment levels despitecontinued treatment. It is concluded that the presence of raisedanti-GM1 antibodies does not identify a subgroup of patients with lowermotor neuron disease who respond to IVIg treatment and although somepatients with lower motor neuron disease may initially respond, IVIgtreatment does not seem to be sufficient as long term treatment.

     

Very early reduction in efficacy of botulinum toxin therapy for cervical dystonia in patients with subsequent secondary treatment failure: a retrospective analysis

The objective of this study was to estimate the probability of development of partial secondary treatment failure (PSTF) in patients with cervical dystonia (CD) who had been treated over up to 9 years with repetitive intramuscular injections of botulinum neurotoxin type A (BoNT/A). The temporal course of treatment response in patients in whom PSTF was detected retrospectively was compared to patients with a normal clinical response. For this purpose, charts of all CD patients treated in our outpatient clinic between 1988 and 2001 were retrospectively analyzed. Extracted data included time of all injections, dose per visit, disease severity measured by TSUI scores, and time of determination of neutralizing antibodies. Final data analysis using a special formal definition of PSTF was based on charts of 568 patients having exclusively been treated with abobotulinumtoxinA. PSTF onset was observed in our CD cohort during the entire treatment period analyzed, with no clustering at any time point. Probability to develop PSTF was 14.5 % in 9 years. Thus, mean PSTF incidence was 1.6 % per year. The mean TSUI score of patients with retrospectively defined PSTF (n = 33) became already significantly worse after the second injection when compared with the group without PSTF (n = 535). Our data indicate that clinical response in patients developing PSTF later on differs from that of patients without PSTF already very early in the course of botulinum neurotoxin type A treatment, and that PSTF remains undetected at this early stage. Reduced response may therefore be present in a number of CD patients who think they still respond normally to continuous BoNT/A treatment.     

Psychiatric morbidity in epilepsy: a case controlled study of adults receiving disability benefits

OBJECTIVE—To compare the prevalence of non-organic psychiatric disorders among disabled patients of normal intelligence with epilepsy with the prevalence of similar psychiatric disorders among age and sex matched disabled patients with other somatic diseases.
METHODS—A case-control study was carried out in Iceland among people receiving disability benefits using information available at the State Social Security Institute. There were 344 patients with epilepsy in Iceland 16 to 66 years of age (inclusive) receiving disability benefits in 1995. By excluding mentally retarded patients, autistic patients, and patients with organic psychoses, 241 index cases with epilepsy qualified for the study. For each case two age and sex matched controls were selected from all patients receiving disability benefits who had cardiovascular diseases, respiratory diseases, or arthropathies. The same exclusion criteria were applied to the controls as the index cases. In both patient groups psychiatric diagnoses were classified into one of the four following categories: (1) psychotic illness; (2) neurotic illness or personality disorders; (3) alcohol or drug dependence or misuse; and (4) other mental disorders.
RESULTS—Psychiatric diagnosis was present among 35% ( 85/241) of the cases compared with 30% (143/482) of the controls (p=0.15). There was a difference in the distribution of the two groups into different psychiatric categories (p=0.02). This was mainly due to an excess of men in the index group with psychosis, particularly schizophrenia or paranoid states.
CONCLUSION—The results suggest that there is not a difference in the prevalence of non-organic psychiatric disorders among disabled patients of normal intelligence with epilepsy compared with patients with other disabling somatic diseases. However, the data indicate that when psychopathology is present disabled patients with epilepsy are more likely to have psychotic illness than the other disabled patients.

     

Cognitive function and pallidotomy

The risk factors for treatment related clinical fluctuations,relapses occurring after initial therapeutic induced stabilisation orimprovement, were evaluated in a group of 172 patients with Guillain-Barré syndrome. Clinical, laboratory, and electrodiagnostic features of all 16 patients with Guillain-Barré syndrome with treatment related fluctuations, of whom 13 were retreated, were compared with those who did not have fluctuations. No significant differences were found between patients with Guillain-Barré syndrome treated with plasma exchange and patients treated with intravenous immune globulins either alone or in combination with high dose methylprednisolone. None of the patients with Guillain-Barré syndrome with preceding gastrointestinal illness, initial predominant distal weakness, acute motor neuropathy, or anti-GM1 antibodies showed treatment related fluctuations. On the other hand patients with fluctuations showed a trend to have the fluctuations after a protracted disease course. It is therefore suggested that treatment related clinical fluctuations are due to a more prolonged immune attack. Thereis no indication that the fluctuations are related to treatment modality. The results of this study may help the neurologist to identify patients with Guillain-Barré syndrome who are at risk fortreatment related fluctuations.

     

Botulinum toxin type B in antibody-induced botulinum toxin type A therapy failure

Recently, it was reported that botulinum toxin type B complex (BoNT/B) (NeuroBloc®, Elan Pharmaceuticals) can produce an adequate therapeutic response in patients with antibody induced failure of botulinum toxin type A complex (BoNT/A) therapy. We wanted to study whether this effect is transient or sustained. For this, 10 consecutive patients (6 males, 4 females, age 54.6 ± 14.3 years, duration of illness 15.8 ± 7.0 years) with complete BoNT/A therapy failure and BoNT/A antibody titres in excess of 10mU/ml in the mouse diaphragm assay (MDA) received BoNT/B in an initial dose of 12370 ± 1804MU. After the first BoNT/B application the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) improved from 20.1 ± 3.0 to 11.9 ± 3.4. In all patients systemic anticholinergic side effects occurred. Three patients had stable continuous responses to two, three and five subsequent BoNT/B applications. Six patients showed complete secondary therapy failure to the second or third subsequent BoNT/B applications. Side effects did no longer occur. In four of them the BoNT/B doses were doubled without producing any therapeutic benefit or any side effects. In five of them MDA testing was performed and revealed BoNT/B antibody titres in excess of 1mU/ml. One patient lost half of her initial BoNT/B responsiveness indicating partial secondary BoNT/B therapy failure. This partial therapy failure was seen on two consecutive application series and has not proceeded to complete therapy failure so far. BoNT/B seems to be only temporarily effective in the majority of patients with BoNT/A antibody induced therapy failure. Whether the formation of BoNT/B antibody points to a high antigenic potency of BoNT/B, to an increased immunoreactivity in BoNT/A antibody carriers or whether it is due to the large amount of protein applied in BoNT/B therapy needs to be studied.     

Successful treatment of IgM paraproteinaemic neuropathy with fludarabine

OBJECTIVES—To evaluate the response of four patients with IgM paraproteinaemic neuropathy to a novel therapy—pulsed intravenous fludarabine.
BACKGROUND—The peripheral neuropathy associated with IgM paraproteinaemia usually runs a chronic, slowly progressive course which may eventually cause severe disability. Treatment with conventional immunosuppressive regimens has been unsatisfactory. Fludarabine is a novel purine analogue which has recently been shown to be effective in low grade lymphoid malignancies.
METHODS—Four patients were treated with IgM paraproteinaemic neuropathy with intravenous pulses of fludarabine. Two of the four patients had antibodies to MAG and characteristic widely spaced myelin on nerve biopsy and a third had characteristic widely spaced myelin only. The fourth had an endoneurial lymphocytic infiltrate on nerve biopsy and a diagnosis of Waldenström''s macroglobulinaemia.
RESULTS—In all cases subjective and objective clinical improvement occurred associated with a significant fall in the IgM paraprotein concentration in three cases. Neurophysiological parameters improved in the three patients examined. The treatment was well tolerated. All patients developed mild, reversible lymphopenia and 50% mild generalised myelosuppression, but there were no febrile episodes.
CONCLUSION—Fludarabine should be considered as a possible treatment for patients with IgM MGUS paraproteinaemic neuropathy.

     

Cervical dystonia: clinical and therapeutic features in 85 patients

We studied patients with cervical dystonia (CD) to determine clinical features and response to botulinum toxin A (BoNT/A). Patients were submitted to clinical, laboratory and neuroimaging evaluation. BoNT/A was injected locally in 81 patients using electromyographic guidance. Four patients who had had previous treatment were considered to be in remission. The average ages at onset of focal dystonia and segmental dystonia were greater than for generalized dystonia (p<0.0003). The severity of the abnormal head-neck movements were more severe among the patients with generalized dystonia (p<0.001). Pain in the cervical area was noted in 59 patients. It was not possible to determine the etiology of the disease in 62.3% of patients. Tardive dystonia was the most common secondary etiology. A major improvement in the motor symptoms of CD and pain was observed in patients following treatment with BoNT/A. The tardive dystonia subgroup did not respond to the treatment. Dysphagia was observed in 2.35% of the patients.     

Health related quality of life is improved by botulinum neurotoxin type A in long term treated patients with focal dystonia

OBJECTIVES: The advent of botulinum neurotoxin type A (BoNT/A) gave rise to substantial progress in the treatment of focal dystonias. In the light of the high costs of the toxin and the necessity to establish valid outcome indices for this treatment apart from sheer reduction of dystonic muscle tone and posture, the impact of focal dystonia and its treatment with BoNT/A on patients' health related quality of life (HRQL) was determined. METHODS: Fifty patients with cranial and cervical dystonia treated long term with BoNT/A were enrolled in a prospective, open labelled cohort study. The HRQL was assessed using the EuroQol (EQ-5D) and the short form 36 health survey questionnaire (SF-36) at baseline before BoNT/A injections and at two follow up visits after 6 and 12 weeks covering one BoNT/A treatment period with maximum effect size at the first follow up. RESULTS: Compared with a general population sample, a considerable negative impact of focal dystonia on HRQL was found in patients under investigation. In both disease types, BoNT/A treatment led to a significant improvement in several HRQL dimensions, in particular providing moderate to marked effect sizes in the fields of mental health and pain. The impairment of HRQL due to pain as well as the BoNT/A induced improvement within this SF-36 subscore were significantly higher in patients with cervical dystonia. Under BoNT/A therapy, no correlation was found between changes of clinical outcome scores and HRQL measures. CONCLUSIONS: The data confirm that BoNT/A is able to induce a significant, but temporary amelioration of several aspects of HRQL in both types of focal dystonia. This may substantially contribute to the patients' subjective benefit from the therapy. Moreover, the data provide further arguments to accept high costs of the BoNT/A treatment in these severely handicapped patients, as a consequence of its considerable benefit on quality of life.     

Subcutaneous apomorphine in late stage Parkinson's disease: a long term follow up

OBJECTIVES—Despite the recent introduction of newperoral drugs as well as neurosurgical methods for Parkinson'sdisease, treatment of late stage parkinsonian patients remainsdifficult and many patients become severely handicapped because offluctuations in their motor status. Injections and infusions ofapomorphine has been suggested as an alternative in the treatment ofthese patients, but the number of studies describing the effects ofsuch a treatment over longer time periods is still limited. Theobjective was to investigate the therapeutic response and range of sideeffects during long term treatment with apomorphine in advancedParkinson's disease.
METHODS—Forty nine patients (30 men, 19 women; agerange 42-80 years) with Parkinson's disease were treated for 3 to 66 months with intermittent subcutaneous injections or continuousinfusions of apomorphine.
RESULTS—Most of the patients experienced a longterm symptomatic improvement. The time spent in "off" wassignificantly reduced from 50 to 29.5% with injections and from 50 to25% with infusions of apomorphine. The quality of the remaining"off" periods was improved with infusion treatment, but wasrelatively unaffected by apomorphine injections. The overall frequencyand intensity of dyskinesias did not change. The therapeutic effects ofapomorphine were stable over time. The most common side effect waslocal inflammation at the subcutaneous infusion site,whereas the most severe were psychiatric side effects occurring in 44%of the infusion and 12% of the injection treated patients.
CONCLUSION—Subcutaneous apomorphine is a highlyeffective treatment which can substantially improve the symptomatologyin patients with advanced stage Parkinson's disease over a prolongedperiod of time.

     

Development of facial palsy during immunoadsorption plasmapheresis in Miller Fisher syndrome: a clinical report of two cases

Immunoadsorption plasmapheresis (IAP) using a tryptophan linkedgel column has been shown to effectively remove serum IgG anti-GQ1bantibody which may contribute to the pathogenesis of Miller Fishersyndrome. Two patients are reported on with Miller Fisher syndrome, whodeveloped bilateral facial palsy during IAP using a tryptophan column,while ophthalmoplegia, ataxia, and, areflexia were improving. In thesepatients, the titre of anti-GQ1b antibodies was reduced. The IAP usinga tryptophan column has a beneficial effect on Miller Fisher syndromebut may not inhibit the development of facial palsy. The mechanism ofsuch a dissociated effect of IAP on Miller Fisher syndrome is discussed.

     

Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-responsive cervical dystonia.

OBJECTIVE: To determine the safety and efficacy of botulinum toxin type B (BoNT/B) in patients with cervical dystonia (CD). BACKGROUND: BoNT/B is a form of chemodenervation therapy for the treatment of patients with CD. METHODS: The authors performed a 16-week, randomized, multicenter, double-blind, placebo-controlled trial of BoNT/B in patients with CD who continue to respond to botulinum toxin type A. Placebo, or 5,000 U or 10,000 U of BoNT/B was administered in two to four muscles involved clinically in CD. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at week 4 was the primary efficacy measure. Clinical assessments and adverse events were recorded for treatment day 1 and at weeks 2, 4, 8, 12, and 16. RESULTS: A total of 109 patients were enrolled randomly across all three treatment groups. The mean improvement in the TWSTRS-Total scores in each group at week 4 was 4.3 (placebo), 9.3 (5,000 U), and 11.7 (10,000 U). For the prospectively defined primary contrast (10,000 U versus placebo), highly significant differences were noted for the primary (TWSTRS-Total, baseline to week 4, p = 0.0004) and supportive secondary (Patient Global Assessment, baseline to week 4, p = 0.0001) outcome measures. Improvement in pain, disability, and severity of CD occurred for patients who were treated with BoNT/B when compared with placebo-treated patients. Overall, improvements associated with BoNT/B treatment were greatest for patients who received the 10,000-U dose. The duration of treatment effect for BoNT/B was 12 to 16 weeks for both doses. CONCLUSION: Botulinum toxin type B (NeuroBloc) is safe and efficacious at 5,000 U and 10,000 U for the management of patients with cervical dystonia.     

Autoimmune neuropathies: diagnosis, treatment, and recent topics

Here, we have reviewed the clinical patterns, diagnostic paradigms, etiopathogenesis, and therapeutic strategies of autoimmune neuropathies such as Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), and IgM paraproteinemic neuropathy. Antiganglioside antibodies are frequently present in the serum samples obtained during the acutephase of GBS and Miller Fisher syndrome (MFS), a subtype of GBS. Recently, we found that some patients with GBS and MFS have serum antibodies against antigenic epitopes formed by 2 different gangliosides (ganglioside complex). The antibodies against GD1a/GD1b and/or GD1b/GT1b complexes are associated with severe disability and a requirement for mechanical ventilation. Anti-GM1/GalNAc-GD1a antibodies are found to be associated with pure motor GBS with frequent conduction blocks. In GBS, corticosteroids given alone do not significantly hasten the recovery or affect the long-term treatment outcome. Intravenous immunoglobulin therapy (IVIg) or plasma exchange (PE) is equally effective. Combined treatment with corticosteroids and IVIg may be a promising therapy for GBS. On the basis of the EFNS/PNS guidelines, we describe the treatment of chronic autoimmune neuropathies such as CIDP, MMN, and IgM paraproteinemic neuropathy. In treating CIDP, corticosteroids, IVIg, and plasma exchange are equally effective. In MMN, IVIg is the first-choice therapy; corticosteroids and PE are ineffective or even detrimental. IgM paraproteinemic neuropathies are known to be intractable, and these patients often have anti-myelin-associated glycoprotein antibodies and may respond to immunosuppressive and immunomodulatory therapies. However, the potential therapeutic benefits should be balanced against their possible side effects and usual slow disease progression.