Long-term efficacy and respective potencies of botulinum toxin A and B: a randomized, double-blind study.

BACKGROUND: Mouse units (mU) are used for quantification of the biological activity of botulinum A and B toxin preparations. However, in human tissue, mU values between preparations are not equivalent and lack of clarity concerning efficacy and safety remains with regard to their respective potencies, duration of drug effect and diffusion qualities. OBJECTIVES: To compare short-term and long-term effects of Botox(®) (BOT; Allergan Inc., Irvine, CA, U.S.A.) and Neurobloc(®)/Myobloc(®) (NBC; Solstice Neurosciences Inc., Malvern, PA, U.S.A.) in different doses and dilutions in a human skin model. METHODS: In this prospective randomized double-blind study, 18 healthy volunteers (eight women and 10 men; mean ± SD age 28·4 ± 5·7 years) were injected intradermally with pure saline, BOT and NBC at 10 points in the abdomen in random order, using the BOT/NBC conversion ratio 1 : 75 and different dilution schemes. For an objective outcome, the ninhydrin sweat test was used to compare the anhidrotic areas (action halos). Ten measurements were taken during a time period of 54 weeks. RESULTS: Both preparations showed a peak effect at week 3, with significantly larger anhidrotic areas for NBC. Thereafter, however, the rate of decline was lower in BOT and after week 24, mean BOT areas were larger. The effect of dilution was higher in NBC and the mean dose equivalence conversion ratio (BOT/NBC) was 1 : 29 (area under the curve). Gender effects were seen in both products, with smaller action halos in women. CONCLUSIONS: These results have important implications in clinical routine, especially for autonomic indications.

Safety study of high-frequency transcranial magnetic stimulation in patients with chronic stroke.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is a potential therapeutic tool to rehabilitate chronic stroke patients. In this study, the safety of high-frequency rTMS in stroke was investigated (Phase I). METHODS: The safety of 20 and 25 Hz rTMS over the motor cortex (MC) of the affected hemisphere, with intensities of 110-130% of the motor threshold (MT), was evaluated using surface electromyography (EMG) of hand and arm muscles. RESULTS: Brief EMG bursts, possibly representing peripheral manifestations of after discharges, and spread of excitation to proximal muscles are considered to be associated with a high risk of seizure occurrence. These events were recorded after the rTMS trains. Neither increased MC excitability nor improved pinch force dynamometry was found after rTMS. CONCLUSIONS: Stimulation parameters for rTMS, which are safe for healthy volunteers, may lead to a higher risk for seizure occurrence in chronic stroke patients. SIGNIFICANCE: rTMS at rates of 20 and 25 Hz using above threshold stimulation potentially increases the risk of seizures in patients with chronic stroke.

Hypertrophic chronic pachymeningitis as a localized immune process in the craniocervical region.

Hypertrophic chronic pachymeningitis (HCP) is a rare disorder that causes intracranial or spinal thickening of the dura mater. This report describes a patient with progressive HCP in the craniocervical region associated with signs of rheumatic disease. A ventricular-atrial shunt had to be inserted because of increased intracranial pressure. The patient improved after suboccipital craniotomy, C1 to C6 laminectomy, and removal of the thickened dura. Additional therapy with methotrexate stopped progression, which was documented by MRI and PET.

The impact of blepharospasm and cervical dystonia on health-related quality of life and depression.

The aim of the study was to evaluate and compare health-related quality of life (HR-QoL) and depression in essential blepharospasm (BSP) and idiopathic cervical dystonia (CD), to identify the clinical and demographic factors associated with poor HR-QoL in both disorders and to analyse the effect of Botulinum Toxin A (BtxA) therapy. Two hundred-twenty consecutive patients with BSP (N = 89, 62 % women, mean age 64 years, mean disease duration 7 years) and CD (N = 131, 64 % women, mean age 53 years, mean disease duration 8 years) recruited from routine referrals to eight Austrian dystonia clinics were included. HR-QoL was measured by the Short Form 36 (SF-36) and depression by the Beck Depression Inventory (BDI). At baseline, patients with CD and BSP scored significantly worse in all eight SF-36 domains compared with an age-matched community sample. In addition, 47 % of patients with CD and 37 % of those with BSP were depressed. Women with BSP scored significantly lower in all SF-36 domains and were more depressed than male patients. In contrast, there was no significant effect of gender on HR-QoL and depression in CD. Neck pain had a significant impact on all SF-36 domains and represented the main determinant of depression in CD. Although BtxA therapy resulted in a significant improvement of clinical symptoms in BSP and CD, HR-QoL did not improve in BSP and only two of the eight SF-36 domains improved significantly in patients with CD. The present study for the first time demonstrated that BSP has a substantial impact on health status emphasizing the need for psychological support with interventions aimed at treating depression in these patients. Our results provide further evidence for the profound impact of CD on HR-QoL and indicate the importance of an adequate management of neck pain in addition to reducing the severity of dystonia in CD. The mismatch between objective BtxA derived improvement of dystonia and lack of change of HR-QoL as determined by the SF-36 illustrates the need for optimized disease specific quality of life rating scales in patients with craniocervical dystonia.

Cortical control of voluntary blinking: a transcranial magnetic stimulation study.

OBJECTIVE: To investigate cortical regions related to voluntary blinking. METHODS: Transcranial magnetic stimulation (TMS) was applied to the facial motor cortex (M1) and the midline frontal region (Fz) in 10 healthy subjects with eyes opened and closed. Motor-evoked potentials were recorded from the orbicularis oculi (OOC), orbicularis oris (OOR), abductor digiti minimi and tibialis anterior using surface and needle electromyography electrodes. Facial M waves and blink reflex were measured using supramaximal electrical stimulation of the facial and supraorbital nerves. RESULTS: TMS at Fz elicited 3 waves in OOC with no response in other tested muscles except for the early wave in OOR. Facial M1 stimulation produced only early and late waves. Because of their latencies, shapes, and relationship to coil position and stimulation intensity, early and late waves appeared to be analogous to the facial M wave and R1 component of the blink reflex. The intermediate wave at 6-8 ms latency was elicited in OOC by Fz stimulation with eyes closed. CONCLUSIONS: Since its latency matches the central conduction time of other cranial muscles and it has characteristic of muscle activation-related facilitation, the intermediate wave is presumably related to cortical stimulation. This result provides evidence that the cortical center for the upper facial movements, including blinking, is not principally located in the facial M1, but rather in the mesial frontal region.

[Treatment of the spastic drop foot with botulinum toxin type A in adult patients]. / Behandlung des spastischen Spitzfusses mit Botulinum Toxin Typ A bei erwachsenen Patienten.

Spastic drop foot can be managed by physical measures, local pharmacological agents, oral anti-spastic drugs and surgical procedures. Recent studies have documented the clear effect of botulinum toxin type A (BTX-A) in the treatment of the spastic drop foot, particularly by reducing the resistance against passive movement and increasing the range of motion. Functional benefit and pain reduction have also been observed. The use of BTX-A is safe and free of serious side effects. Individual realistic treatment goals must be defined by the rehabilitation team before the treatment. Possible purposes of the treatment are the achievement of a straight foot to allow weight bearing or application of an orthosis and to reduce the premature activation of the calf muscles during gait. Other treatment goals are the facilitation of nursing care, as well as physical and occupational therapy. BTX-A injections can reduce pain, and prevent pressure ulcers or surgical interventions. Early physiotherapy or occupational therapy may increase the treatment effect of BTX-A. Close cooperation between the neurologist, physiotherapist, occupational therapist, nursing staff and other multidisciplinary rehabilitation team members is essential to maximize the benefit for the patients.

[Botulinum toxin in the treatment of focal hyperhidrosis]. / Intradermale Botulinumtoxininjektionen in der Behandlung fokaler Hyperhidrosen.

INTRODUCTION: Botulinum A toxin (BTX-A) acts primarily at peripheral cholinergic synapses, inhibiting the release of acetylcholine. Initially it has been used to block the neuromuscular junction in focal dystonic and spastic syndromes. Recently there has been suggestions for potential clinical indications in non-muscular diseases where cholinergic terminals play a role. GUSTATORY SWEATING: In 1995 physicians reported a long-lasting anhidrotic effect of intracutaneous BTX-A injections in patients suffering from gustatory sweating (Frey's syndrome). Consequently, a number of clinical studies demonstrated good efficacy of intradermal injections of botulinumtoxin in patients with focal hyperhidrosis. FOCAL HYPERHIDROSIS OF THE PALMS AND AXILLAE: Focal hyperhidrosis is usually confined to the palms and axillae. Excessive sweating may be a social handicap and an occupational hazard. The management of focal hyperhidrosis remains controversial. Topical antiperspirants are only effective in very mild cases. Iontophoresis with tap water or anticholinergic drugs is messy and time consuming with only short-lived effect. Sympathectomy, the cornerstone of surgical management, is usually effective in palmar hyperhidrosis. Complications of this technique include surgical risks, postoperative and cosmetic problems and compensatory hyperhidrosis. AXILLARY HYPERHIDROSIS: Several studies confirmed that intracutaneous injections of botulinum toxin are useful in the majority of patients with axillary hyperhidrosis resistant to conventional treatment. In axillary hyperhidrosis total doses are ranging from 200-400 mU Dysport or from 80 to 130 mU Botox to reach a good clinical response. Injections are usually well tolerated and no serious side-effects have been observed. The mean duration of anhidrotic effect ranges between 3 and 9 weeks. PALMAR HYPERHIDROSIS: The use of botulinumtoxin in patients with palmar hyperhidrosis is rather difficult. The therapeutic window is smaller because injections are complicated by transient weakness of the small hand-muscles. Furthermore the injections at the palms are painful which can be overcomed by application of local anaesthetics or the blockade of the ulnar and median nerves. The duration of anhidrotic effect ranges from 20 to 50 weeks. CONCLUSION: Intracutaneous injections of botulinum-toxin should be offered to patients with focal hyperhidrosis of the palms and axillae causing serious social, psychologic and occupational problems, resistant to other conventional treatment options.

Type of edema in posterior reversible encephalopathy syndrome depends on serum albumin levels: an MR imaging study in 28 patients.

PRES is a clinicoradiologic entity, combining seizures, blindness, and coma with MR imaging findings of predominantly vasogenic and occasional cytotoxic edema. In this clinical report, we determined the type of edema by using DWI and FLAIR sequences on MR imaging as well as ADC maps in 28 patients with PRES. The neuradiologic findings were correlated with levels of serum albumin, which is a main contributor to colloid osmotic pressure and vascular integrity. The presence of vasogenic edema was significantly associated with decreased serum albumin levels, which may be a particular risk factor for the development of PRES.

Blepharospasm and the modulation of cortical excitability in primary and secondary motor areas.

BACKGROUND: Traditionally, benign essential blepharospasm (BEB) is considered a disorder caused by basal ganglia dysfunction. Electrophysiologic and brain imaging studies suggest pathologic changes in excitability in the primary motor cortex (MC), anterior cingulate (AC), and secondary motor areas, such as premotor (PMC) and supplementary motor cortices (SMA). METHODS: In this pilot study of 7 patients with BEB, we experimentally reduced cortical excitability of 4 areas: MC (first dorsal interosseus area), PMC, SMA, and AC, each with 3 noninvasive techniques: low-frequency repetitive transcranial magnetic stimulation (lfrTMS), continuous theta burst stimulation (cTBS), and cathodal transcranial direct current stimulation (tDCS). Primary outcome was the clinical effects on blepharospasm (blink rate observation by an investigator blinded to the intervention and subjective rating by the patient); secondary outcome was the blink reflex recovery curve (BRR). RESULTS: lfrTMS resulted in a significant improvement over all 4 brain areas for physician rating, patient rating, and BRR, whereas cTBS and tDCS showed only trends for improvement in physician rating, but no improvements for patient rating and BRR. lfrTMS had a significantly higher effect over AC than MC for physician rating, but no differences were seen for other pairwise comparisons of stimulated brain areas. CONCLUSIONS: Electrophysiologic and clinical improvements by functional inhibition of the medial frontal areas using low-frequency repetitive transcranial magnetic stimulation suggests that hypersensitivity of the anterior cingulate is directly or indirectly involved in the pathophysiology of benign essential blepharospasm. Inhibition of these areas using low-frequency repetitive transcranial magnetic stimulation could provide a therapeutic tool and is worthy of a larger study.

Neutralizing antibodies in dystonic patients who still respond well to botulinum toxin type A.

BACKGROUND: Complete secondary therapy failure due to antibodies against botulinum toxin A (BoNT/A-ABs) may raise extensive treatment difficulties. We tested whether neutralizing BoNT/A-ABs can be detected in dystonic patients with good clinical responses to botulinum toxin A (BoNT/A) treatment. METHODS: We used the ninhydrin sweat test (NST) and the mouse diaphragm test (MDT) in 28 subjects. Of 119 dystonic patients who responded well to BoNT/A, we randomly selected 14 and compared the results of the NST and MDT with 14 healthy controls. RESULTS: Higher BoNT/A-AB titers correlated significantly with smaller anhidrotic areas. We found seven patients with borderline antibody (AB) values (MDT 0.4 to 0.8 mU/mL) with significantly smaller anhidrotic areas (NST) compared with healthy controls and AB-negative patients. Risk factors for smaller anhidrotic areas were short injection intervals but not prolonged exposure to BoNT/A or high injection doses. CONCLUSIONS: These data demonstrate that >40% of dystonic patients who respond well to botulinum toxin A (BoNT/A) show partial nonresponsiveness on the ninhydrin sweat test and have low titers of neutralizing BoNT/A antibodies.

To do or not to do? Magnetic resonance imaging in mild traumatic brain injury.

Clinical quantification of mild traumatic brain injury (MTBI) patients should be based on Glasgow coma scale (GCS) score, duration of loss of consciousness (LOC) and post-traumatic amnesia (PTA). In addition, a short practicable neuropsychological test might be useful in detecting minor memory and attentional deficits. MRI appears to be the most sensitive imaging method for assessing MTBI so far, but information regarding a visualized lesion is not usually utilized in the classification of MTBI. Magnetic resonance imaging (MRI) should, therefore, play a major role in any MTBI classification scheme. An appropriate MRI protocol has to be chosen using at least T1 weighted, T2 weighted, proton density and gradient-echo (GRE) sequence images, all in at least two planes, in order to detect and classify all lesions precisely. Owing to the fact that acute lesions may be missed, it is advisable to perform MRI in the first 2 weeks following trauma. Further research is necessary to clarify the relationship between chronic symptoms after MTBI and MRI abnormalities. It may, thus, be possible to provide optimal strategies for emergency department management, to define a group of patients with a need for acute and rehabilitative intervention after MTBI, and to predict their outcome.

[The Neuro-Mental Index. An addition to the Barthel Index for detection of impairments in basic psychological-mental diemsnions in neurorehabilitation]. / Der Neuromentalindex. Ein Additivinstrument zum Barthel-Index zur Erfassung von Fähigkeitsstörungen der psychisch-mentalen Grunddimensionen in der Neurorehabilitation.

The Barthel Index (BI) is the most commonly used scale for assessing impairment of activities of daily living (ADL). For a global view of patients' abilities and the care needed in everyday neurorehabilitation practice, additional information about basic psychological and cognitive functions is essential. We therefore designed a new disability scale comprised of assessments of consciousness, approachability, orientation, memory, behaviour, emotions, communication, problem solving, perception, and behaviour at night. The scale shows exactly the same inner structure as the BI, with ten items and a score of up to 20 in steps from 0-100% (or 0-20 points). By a careful weighing of the items, the final score of the neuromental index (NMI) should create a clearer picture of both the disabilities and the needed resources. A second aim was to cover a broad range of patients including those in coma and coma remission states and those with only slight neuropsychological or behavioural symptoms. The NMI was examined with a group of 179 neurorehabilitation inpatients and proved to be highly valid, reliable, and practicable. It was designed to enable a global assessment of disability as well as the care resources needed, even in patients with different disability levels in ADL and psychological and cognitive functions.

Treatment of focal hyperhidrosis with botulinum toxin type A: long-term follow-up in 61 patients.

BACKGROUND: The blocking action of botulinum toxin type A (BTX-A) on cholinergically innervated sweat glands has been used successfully to treat patients with focal hyperhidrosis. OBJECTIVES: To investigate the long-term efficacy and safety of intradermal injections of BTX-A. METHODS: We performed an open-label study in 61 patients treated over a period of 3 years for axillary or palmar hyperhidrosis. A total dose of 400 mU BTX-A (Dysport) was injected into both axillae or 460 mU BTX-A (Dysport) into both palms. The injections were repeated after relapse. Objective quantification of sweat production was performed using digitized ninhydrin-stained sheets. RESULTS: Four weeks after BTX-A treatment the median reduction in sweat production was 71% compared with baseline (P < 0.001) in the axillary group and 42% (P = 0.005) in the palmar group. Subjective assessment of sweat production by the patients using a visual analogue scale (0, no sweating; 100, the most severe sweating) showed a significant reduction in both the axillary (P < 0.001) and palmar groups (P < 0.001). Secondary disturbances due to focal hyperhidrosis interfering with daily activities were markedly improved in both groups. The median time interval between the sets of injections was 34 weeks for axillary hyperhidrosis and 25 weeks for palmar hyperhidrosis. The treatment of palmar hyperhidrosis was complicated by transient but not disabling weakness of the small hand muscles in nine of 21 patients. CONCLUSIONS: Repeated intradermal injections of BTX-A in patients with axillary and palmar hyperhidrosis are as effective as first treatments.

Neuropsychological, MRI and EEG findings after very mild traumatic brain injury.

Neuropsychological performance, magnetic resonance imaging (MRI) and electroencephalography (EEG) were investigated in 12 consecutive patients with very mild traumatic brain injury (MTBI) (Glasgow coma score 15) within 24 hours and 6 weeks after injury. The data were compared to 14 control subjects. There was a significant impairment in neuropsychological performance (verbal memory, arithmetic abilities and psychomotor reaction time) at onset and after 6 weeks, whereas verbal fluency and non-verbal memory test revealed no significant differences matching the control values. In MRI scans, three patients showed traumatic lesions (slight epidural haematoma, haemorrhagic contusions and white matter lesions indicating diffuse axonal injury). In the EEG recordings, no generalized slowing or focal changes were found. Structural and functional impairment can be identified using neuroimaging and neuropsychological examination, even in very MTBI patients.

Plasma progestagen concentrations in the normal and dysmature newborn foal.

Radioimmunoassay (RIA) and gas chromatography-mass spectrometry (GC-MS) were used to determine plasma progestagen concentrations in the normal and premature foal. Radioimmunoassay provides a profile of plasma progestagens with respect to time but, due to the non-specific nature of the technique and without prior chromatographic purification, quantitative data based on RIA analysis must be interpreted with caution. In contrast, the greater specificity of GC-MS allows identification of specific plasma progestagens and measuring of multiple analytes in a single analysis. Both techniques demonstrated a marked difference in plasma progestagen concentrations between the normal and abnormal foal. GC-MS studies demonstrated that the plasma steroid profile was dominated by pregnenolone and 5-pregnene-3 beta, 20 beta-diol. Measuring the amounts of these 2 steroids in a single analysis demonstrated persistent high concentrations in premature foals, whereas concentrations decreased rapidly in the first few hours following birth in the normal foal. Preliminary analyses of urinary concentrations in the 2 steroids demonstrated again differences between normal and abnormal foals.

Craniocervical dystonia questionnaire (CDQ-24): development and validation of a disease-specific quality of life instrument.

OBJECTIVE: To develop and test a questionnaire for measuring quality of life in patients with craniocervical dystonia. METHODS: A 29-item pool was developed based on semi-structured interviews of patients with cervical dystonia (CD) and blepharospasm (BSP). This preliminary questionnaire was administered to 203 consecutive patients with CD and BSP from Austrian dystonia and botulinum toxin outpatient clinics. For scale generation, a combination of exploratory factor and cluster analysis was applied. This resulted in the 24-item version of the instrument (CDQ-24) based on five subscales: Stigma, Emotional wellbeing, Pain, Activities of daily living, and Social/family life. The validity and reliability of the CDQ-24 was assessed in 231 consecutive patients with CD and BSP different from those examined with the preliminary questionnaire. This second survey included the CDQ-24, a generic QoL instrument (SF-36) and clinical rating scales. Sensitivity to change was analysed in 51 previously untreated (de novo) patients four weeks and one year following the first botulinum toxin treatment. RESULTS: Internal consistency reliability was satisfactory for all subscales, with values of Cronbach's alpha ranging from 0.77 to 0.89. The CDQ-24 subscales showed moderate to high correlations with those SF-36 subscales measuring similar aspects (Pearson's correlation r = 0.50-0.73; p<0.001, each). Sensitivity to change was confirmed by highly significant improvements of all CDQ-24 subscores in the de novo patients from baseline to four week follow up. One year follow up data revealed a stable improvement. CONCLUSION: The CDQ-24 is the first fully validated and disease specific questionnaire to evaluate quality of life of patients with cervical dystonia and blepharospasm and we propose its use in clinical trials as well as in daily clinical practice.

Effect of CI-949 and CI-959 on immune function and lymphoid organs in rats.

The immunotoxic properties of two experimental antiallergic drugs, CI-949 and CI-959, were investigated. Wistar rats were gavaged once (CI-949) or twice (CI-959) daily for 21 days with the drugs. Immunotoxicity was assessed using the enzyme-linked immunoabsorbant assay (ELISA) for humoral immunity, a delayed-type hypersensitivity (DTH) procedure for cell-mediated immunity, and natural killer cell (NKC) activity to evaluate spontaneous cytotoxicity. Ratios of body weight to spleen, thymus, liver and kidney weights were determined. Routine histopathology was performed on lymphoid tissue and other body organs. Although 100 mg/kg/day of CI-949 had some stimulating effect on antibody production and NKC cytotoxicity, no consistent immunomodulation was apparent. Except for a significant increase in liver weight at the 100 mg/kg dose of CI-949, no other toxic effects were observed. In contrast to CI-949, CI-959 significantly (P less than 0.05) suppressed antibody production at the 100 mg/kg dose and impaired the DTH reaction, although not significantly. Natural killer cell cytotoxicity was unaffected by 100 mg/kg CI-959. Decreased body weight and histopathological lesions were observed in the thymus and spleen of rats administered 100 mg/kg CI-959. These lesions ranged from mild to severe lymphoid depletion which was also reflected in significantly (P less than 0.05) reduced spleen and thymus organ weight to body weight ratios. Since 100 mg/kg of CI-959 produced toxicological and pathological alterations in the exposed rats, these data suggest that CI-959 is not highly or specifically immunotoxic at dosages lower than those that alter conventional toxicological parameters used in new drug testing programs.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized, double-blind, placebo controlled study on analgesic effects of botulinum toxin A.

OBJECTIVE: Botulinum toxin type A (BTXA) is used to treat neurologic disorders associated with increased muscle tone. Its use is often associated with pain relief. METHODS: A possible direct analgesic effect of BTXA on C and Adelta fibers was studied on 16 healthy volunteers receiving 30 U BTXA into one forearm and pure saline into the other. To exclude the secondary effect due to muscular tone reduction, BTXA was injected intradermally. Thermal sensory testing of heat pain (threshold and tolerance) and neuroselective current sensory testing of current pain threshold/tolerance were performed at baseline and 3, 14, and 28 days after treatment. Thereafter, on day 28, capsaicin was administered simultaneously into both forearms to evaluate a possible peripheral effect and central effect on pain processing and on the axon reflex flare. RESULTS: The authors observed no significant difference in any of the perception outcome measures between BTXA and placebo pretreated areas. Flare areas as a result of the release of neuropeptides after capsaicin application showed no differences. CONCLUSIONS: The results suggest that pain reduction after BTXA treatment is mediated through its effect on muscle tone rather than a direct analgesic effect.