Jan J. Rotteveel

Effect of Botulinum Toxin in the Treatment of Drooling: A Controlled Clinical Trial

Objective. To investigate the clinical effectiveness of botulinum neurotoxin type A (BoNT) to reduce drooling in children with cerebral palsy (CP). Methods. A controlled clinical trial was performed in which the results of single-dose BoNT injections in the submandibular glands were compared with treatment with scopolamine. Forty-five children who had CP and experienced severe drooling were enrolled. Drooling severity was measured at baseline, during application of scopolamine, and at different intervals after BoNT injections up to 24 weeks, using the Drooling Quotient (DQ), the Teacher Drooling Scale (TDS), and Visual Analog Scales (VAS). Results. Drooling was reduced during scopolamine application as well as after BoNT injections. Compared with baseline, the mean DQ showed a significant decrease throughout the study. Greatest reductions were achieved 2 to 8 weeks after BoNT injection. No significant differences were found between scopolamine measurements and those up to 24 months after BoNT injection. Using VAS, parents recorded the effect on drooling in which significant differences were found between baseline VAS score and all follow-up assessments. According to our definition of “success to therapy,” demanding a 2-point decrease on the TDS, 61.5% of patients responded to BoNT injections. Analysis of the DQ demonstrated a response rate of 53% of the patients to scopolamine and 48.7% to BoNT until 24 weeks after BoNT injections, the actual duration of this study. As a reaction to scopolamine, 71.1% of the patients had moderate to severe side effects. Only nonsevere, incidental side effects were reported after BoNT injections. Conclusions. During scopolamine application as well as after intraglandular BoNT injections, a clinically relevant reduction in drooling was achieved in children with CP, demonstrating maximum effect 2 to 8 weeks after injections. This is the first controlled clinical trial that confirmed a significant effect of BoNT injections in the treatment of drooling. General anesthesia was needed for all children. BoNT injections show fewer and less serious side effects than transdermal scopolamine treatment.

The treatment of drooling by ultrasound-guided intraglandular injections of botulinum toxin type A into the salivary glands.

Objective The aim of the study was to present the background, procedure, and technique of bilateral ultrasound‐guided, single‐dose injections of botulinum toxin type A (BTX) into the salivary glands in patients with severe drooling.

Botulinum toxin A: a new option for treatment of drooling in children with cerebral palsy. Presentation of a case series.

Abstract Drooling beyond the age of 4 years is pathological, particularly if it occurs in children with neurological and developmental impairment and disability. Considering the therapeutic spectrum of botulinum toxin A and in view of the innervation of the salivary glands, we postulated that intraglandular injections into the submandibular glands with botulinum toxin A could reduce the secretion of saliva and consequently decrease drooling. Three patients with cerebral palsy and severe drooling were selected and evaluated over a 4-month period. Under ultrasound guidance, one dose of botulinum toxin A was injected bilaterally into the submandibular glands. Saliva secretion was measured at baseline and repeated four times during the following 4 months. In the three patients, maximal salivary flow rate of the sublingual and submandibular glands was reduced by 51% to 63%. The time of the maximal effect differed among the three children. The parents reported a satisfactory reduction of drooling throughout the whole study period. No objectionable disturbances of oral functions were observed. There was mild transient thickening of saliva in one of the patients. Conclusion The application of botulinum toxin A to the submandibular gland is a promising technique to reduce salivary flow rate and probably an alternative in the treatment of drooling in children with cerebral palsy.

The maturation of the central auditory conduction in preterm infants until three months post term. II: The auditory brainstem responses (ABRs)

Auditory cortical evoked responses (ACRs) were recorded in 65 preterm infants, at least on 3 occasions in 48 of them. The infants were divided into 5 groups according to their gestational age (GA). The recording sessions were performed at 8 conceptional age (CA) levels, defined as the gestational age added to the chronological age. The last recordings were obtained at 50-52 weeks CA. The ACRs were analyzed for the primary complex containing middle latency components (MLR) and the secondary complex, containing the slow late components. The ACR records first appear at about 25 weeks CA, initiating the premature stage followed by a transitional stage around term date and the gradual development into the mature stage, achieved at 50-52 weeks CA. The detectability rate of the various components generally increased with increasing conceptional age, for some of the components, especially N2p and N2, this rate achieved a value of about 80%. The degree of prematurity did not influence appreciably the development of the ACR. The waveforms, and to a lesser extent the latency and amplitude values, are strongly age dependent. Remarkable topographic differences between the ACR parameter latency and more importantly amplitude values are found between the derivations from the vertex and the central temporal areas, supporting the theory of different generation sites for the ACR components. The premature and mature ACR appeared relatively insensitive to changes in the states of vigilance. The ACR in premature infants are useful in developmental studies with respect to the central audition in premature infants and might contribute in the clinical assessment on the quality of the premature central auditory system.

Clinical and biochemical effects of zileuton in patients with the Sjögren-Larsson syndrome

Abstract. The Sjögren-Larsson syndrome (SLS) is an inborn error of lipid metabolism, characterised clinically by congenital ichthyosis, mental retardation and spasticity. Patients also suffer from severe pruritus. The degradation of leukotriene (LT) B4 is one of the defective metabolic routes in SLS. Zileuton inhibits the synthesis of LTB4 and the cysteinyl leukotrienes. Five SLS patients were treated with zileuton for 3 months. Favourable effects were found on pruritus score (P=0.006), general well-being, and background activity of electroencephalographic studies. Neuropsychological test results did not change significantly. There was, however, a clinically important trend towards improvement in the speed of information processing. Results of cerebral MRI and proton magnetic resonance spectroscopy did not change during therapy. Urinary concentrations of LTB4 and ω-OH-LTB4 decreased significantly (P=0.02 and P=0.003 respectively), while their concentrations in CSF were normal at baseline and remained so after therapy. Conclusion: patients with Sjögren-Larsson syndrome might benefit from treatment with zileuton, especially with respect to the agonising pruritus. The findings reported here, point to a crucial role for leukotriene B4 in the pathogenesis of pruritus.

Calibrated parametric medical ultrasound imaging

The goal of this study was to develop a calibrated on-line technique to extract as much diagnostically-relevant information as possible from conventional video-format echograms. The final aim is to improve the diagnostic potentials of medical ultrasound. Video-output images were acquired by a frame grabber board incorporated in a multiprocessor workstation. Calibration images were obtained from a stable tissue-mimicking phantom with known acoustic characteristics. Using these images as reference, depth dependence of the gray level could fairly be corrected for the transducer performance characteristics, for the observer-dependent equipment settings and for attenuation in the examined tissues. Second-order statistical parameters still displayed some nonconsistent depth dependencies. The results obtained with two echoscanners for the same phantom were different; hence, an a posteriori normalization of clinical data with the phantom data is indicated. Prior to processing of clinical echograms, the anatomical reflections and echoless voids were removed automatically. The final step in the preprocessing concerned the compensation of the overall attenuation in the tissue. A ‘sliding window’ processing was then applied to a region of interest (ROI) in the ‘back-scan converted’ images. A number of first and second order statistical texture parameters and acoustical parameters were estimated in each window and assigned to the central pixel. This procedure results in a set of new ‘parametric’ images of the ROI, which can be inserted in the original echogram (gray value, color) or presented as a color overlay. A clinical example is presented for illustrating the potentials of the developed technique. Depending on the choice of the parameters, four full resolution calibrated parametric images can be calculated and simultaneously displayed within 5 to 20 seconds. In conclusion, an on-line technique has been developed to estimate acoustic and texture parameters with a reduced equipment dependence and to display acoustical and textural information that is present in conventional echograms.

Dihydropyrimidinase deficiency : structural organization, chromosomal localization, and mutation analysis of the human dihydropyrimidinase gene

Dihydropyrimidinase (DHP) deficiency (MIM 222748) is characterized by dihydropyrimidinuria and is associated with a variable clinical phenotype. This disease might be associated with a risk of 5-fluorouracil toxicity, although no cases have been reported. We present here both the molecular characterization of the human DHP gene and, for the first time, the mutations causing DHP deficiency. The human DHP gene spans >80 kb and consists of 10 exons. It has been assigned to 8q22, by FISH. We performed mutation analysis of genomic DNA in one symptomatic and five asymptomatic individuals presenting with dihydropyrimidinuria. We identified one frameshift mutation and five missense mutations. Two related Japanese adult subjects were homozygous for the Q334R substitution, whereas two other, unrelated Japanese infant subjects were heterozygous for the same mutation, but this mutation is not common in the Japanese population. A Caucasian pediatric patient exhibiting epileptic attacks, dysmorphic features, and severe developmental delay was homozygous for W360R. Using a eukaryotic expression system, we showed that all mutations reduced enzyme activity significantly, indicating that these are crucial DHP deficiency-causing mutations. There was no significant difference, in residual activity, between mutations observed in the symptomatic and those observed in the asymptomatic individuals.

Clinical practice: swallowing problems in cerebral palsy.

Cerebral palsy (CP) is the most common physical disability in early childhood. The worldwide prevalence of CP is approximately 2–2.5 per 1,000 live births. It has been clinically defined as a group of motor, cognitive, and perceptive impairments secondary to a non-progressive defect or lesion of the developing brain. Children with CP can have swallowing problems with severe drooling as one of the consequences. Malnutrition and recurrent aspiration pneumonia can increase the risk of morbidity and mortality. Early attention should be given to dysphagia and excessive drooling and their substantial contribution to the burden of a child with CP and his/her family. This review displays the important functional and anatomical issues related to swallowing problems in children with CP based on relevant literature and expert opinion. Furthermore, based on our experience, we describe a plan for approach of investigation and treatment of swallowing problems in cerebral palsy.

Social interaction and self-esteem of children with cerebral palsy after treatment for severe drooling

The impact of salivary flow reduction following medication (scopolamine and botulinum neurotoxin) on social interaction and emotional development (self-esteem) was evaluated in a group of 45 children with cerebral palsy who suffered from severe drooling. The children ranged in age from 3 to 16 years (median 9.1 years); 28 were male, 17 female. A questionnaire to document the impact of drooling on social interaction and self-esteem for both the children and their parents was developed and administered during the use of scopolamine and up to 24 weeks after intraglandular botulinum neurotoxin in the submandibular glands. The reduction of drooling was related to increased social contacts with peers. In addition, parents perceived that the impact of drooling on the level of the child’s satisfaction on physical appearance, relations within the extended family, and life in general increased. Although medication led to (temporary) positive changes, many social and emotional consequences remained unchanged. Conclusion: Interventions to treat drooling should not only be evaluated using measurements of drooling, but the consequences on social interaction and self-esteem should also be assessed.

Defective metabolism of leukotriene B4 in the Sjögren-Larsson syndrome

The Sjögren-Larsson Syndrome (SLS) is a neurocutaneous disorder, caused by deficient activity of the microsomal enzyme fatty aldehyde dehydrogenase (FALDH). FALDH catalyzes the oxidation of medium- and long-chain fatty aldehydes to their corresponding carboxylic acids. SLS is diagnosed by demonstrating the enzyme deficiency or by mutation analysis of the FALDH gene, while laboratory investigations of plasma, urine, and cerebrospinal fluid do not reveal any diagnostic abnormality. Leukotriene (LT) B4 is a pro-inflammatory mediator synthesized from arachidonic acid. LTB4 is inactivated by microsomal omega-oxidation, successively yielding 20-OH-LTB4, 20-CHO-LTB4 and 20-COOH-LTB4. Since FALDH is involved in LTB4 degradation, we have analyzed LTB4 and its metabolites in urine and cerebrospinal fluid as well as the degradation capacity for LTB4 in fresh polymorphonuclear leukocytes (PMN) of SLS patients. The urinary concentrations of LTB4, 20-OH-LTB4 and 20-COOH-LTB4 are below the detection limit in healthy controls. The urine of all SLS patients (n=13) exhibited highly elevated concentrations of LTB4 and 20-OH-LTB4, while 20-COOH-LTB4 was absent. Cerebrospinal fluid levels of LTB4, 20-OH-LTB4 and 20-COOH-LTB4 were found to be normal (n=7). PMN isolated from four patients were shown to be unable to convert 20-OH-LTB4 to 20-COOH-LTB4. Our findings provide unambiguous evidence for defective LTB4 degradation in SLS patients, and offer new and non-invasive diagnostic tools. Moreover, they open new pathophysiological considerations, with the prospect of rational treatment strategies.