Epilepsy and fragile X gene mutations.

We used two strategies to investigate a possible link between predisposition for epilepsy and mutations in the fragile X mental retardation-1 gene. The first entailed performing electroencephalography on 14 patients with an amplification in the fragile X mental retardation-1 gene, and the second involved molecular genetic analysis of the fragile X mental retardation-1 gene in 16 children with benign childhood epilepsy with centrotemporal spikes (BECT, Rolandic epilepsy). Fourteen young male patients with fragile X syndrome, verified by a full mutation in exon 1 of the fragile X mental retardation-1 gene, were studied by electroencephalography. In eight boys aged between 4-8 years we observed focal sharp waves, activated by sleep. In six of these patients, partial seizures occurred during sleep. We detected no epileptiform electroencephalographic abnormalities under the age of 4 and over the age of 8. In 16 children with Rolandic epilepsy who were studied for fragile X gene mutations, one boy proved to carry a fragile X premutation. In the waking state electroencephalography of a 5-year-old girl with a premutation in one of her fragile X mental retardation-1 genes, we found groups of generalized spike wave complexes. Our observations suggest a possible impact of the fragile X mental retardation-1 gene mutations on brain maturation and epileptogenesis.

Nutritional influence on serum ammonia in young patients receiving sodium valproate.

Hyperammonemia is a common side effect of valproic acid (VPA) therapy. This study was designed to investigate a potential nutritional influence on serum ammonia levels during VPA therapy. In 10 VPA-treated young patients (5 receiving monotherapy, 5 receiving VPA-primidone polytherapy), venous serum ammonia, triglycerides, and cholesterol were measured on 3 consecutive days as follows: (a) after a 13-h overnight fast; (b) 2 h after an oral fat load with butter (1.2 g fat/kg body weight); and (c) 2 h after an oral protein load with fresh cheese (1 g protein/kg body weight). Ten young adults served as controls. After protein load VPA patients had significantly higher serum ammonia levels than controls (mean: 194 vs. 75 micrograms/dl in controls; p less than 0.006). Ammonia values were higher after protein load than after fat load or after fasting (p less than 0.0001). Patients receiving polytherapy had higher ammonia levels than patients receiving monotherapy (not significant). There was no correlation to the height of serum VPA levels. Clinical symptoms attributable to hyperammonemia (vomiting, apathy) were found in only one patient, and her serum ammonia was as high as 426 micrograms/dl. Triglycerides and cholesterol did not show any VPA-induced differences. We assume that VPA alters the short-term regulation of ureasynthesis. We recommend the avoidance of high protein intake in patients receiving VPA therapy, especially in young patients receiving polytherapy or comedication, or in risk situations like serious infections.

[Hyperammonemia in valproate therapy in children and adolescents]. / Hyperammonämie während Valproat-Therapie bei Kindern und Jugendlichen.

In order to evaluate significance and frequency of valproic acid (VPA)-induced hyperammonemia we measured venous serum ammonia, SGOT, G-GT, platelets and antiepileptic drug levels in three groups of subjects: 1.) 30 pediatric patients treated with VPA, alone or in combination 2.) 30 healthy age and sex matched subjects 3.) 30 pediatric unselected patients treated with various antiepileptic drugs except VPA. In the VPA group serum ammonia was significantly (p less than 0.01) higher than in controls and in the group 3. Patients on VPA-polytherapy had significantly higher serum ammonia values than patients on VPA-monotherapy (p less than 0.01). Hyperammonemia was found in 8 (27%) VPA-treated patients. A syndrome consisting of lethargy, stupor, hypotonia and increased seizure activity developed in 3 patients on VPA-therapy of whom two showed hyperammonemia. After discontinuing VPA this syndrome disappeared in all three cases. There was no direct correlation between VPA and ammonia levels. The etiology of hyperammonemia in VPA treated patients is not yet fully explained. It may be related to the fatal VPA induced hepatic failure reported in the literature. Some risk factors which may facilitate hepatic injury during VPA therapy (young age, co-medication, polytherapy, infectious disease, protein overload, low caloric intake) are discussed and some practical consequences are indicated.

Increased periventricular echogenicity (periventricular halos) in neonatal brain: a sonographic study.

This study was designed in order to evaluate frequency and natural development of periventricular increased echogenicity (periventricular halos) as a sonographic feature. Sixty healthy term neonates were examined sonographically through the open fontanel within the first twelve hrs of life (phase I). Out of this group, forty-three infants were again studied between the twenty-fourth and forty-eighth hr of life (phase II), forty between third and eighth day of life (phase III), twenty between third and sixth week of life (phase IV) and twelve between third and fifth months of life (phase V). Halos were found in occipital areas in 83% in I, in 86% in II, in 85% in III, in 35% in IV and in 0% in V. They presented as increased echogenicity predominantly occipitally and frontally at the external angles of both lateral ventricles. There was no correlation to the mode of delivery. The differential diagnosis (haemorrhage, hypoxicischaemic injury, oedema) is discussed. Periventricular increased echogenicity represents a common sonographic finding in clinically healthy term infants. When present in the typical form as described here it seems to have no pathological significance. Each clinician examining neonatal heads sonographically should be familiar with his phenomenon and its interpretation.

Outcome of persistent vegetative state following hypoxic or traumatic brain injury in children and adolescents.

Persistent vegetative state (PVS, apallic syndrome) has become a significant medical and social problem. The outcome of young people with PVS is a matter of great interest. Therefore, we analysed the outcome of 127 children and adolescents who were in PVS for at least 30 days following traumatic (n = 82) or hypoxic (n = 45) brain injury. After 19 months of follow-up, 84% of the patients of the traumatic brain injury (TBI) group, but only 55% of the hypoxic brain injury (HBI) group had left PVS (p < 0.001). The TBI patients regained consciousness earlier. Later than 9 months post trauma less than 5% of the patients of both groups left PVS. Hypoxic brain injury patients had a higher incidence of seizures (p = 0.01) and a higher seizure frequency. They had significantly more complications like pneumonia, gastrointestinal disturbance or myositis ossificans (= heterotopic ossification). Posttraumatic hyperthermia and autonomic dysfunctions were correlated with worse outcome in the TBI group, but not in the HBI group. Thirteen patients (16%) with TBI became independent in everyday life versus only two (4%) with HBI. These results underline the important contribution of hypoxia in severe and permanent brain impairment. They also may help to establish the prognosis of children in PVS.

[Systematic ultrasound measurements of the lateral ventricles: an A-scan/B-scan comparison]. / Systematische Ultraschallmessungen der Seitenventrikel: ein A-Scan/B-Scan-Vergleich.

In 100 newborn and infants the total diameter of both lateral ventricles in the region of cella-media was measured ultrasonographically by one-dimensional (A-Scan) and two-dimensional (B-Scan) technique. Comparison of the results of both methods showed good correlation (r = 0,945). Possible reasons of differing results are discussed. The importance of cella-media-index is emphasized. The transparietal A-Scan technique is sufficiently reliable in determining the width of the lateral ventricles. However, the B-Scan (through the open fontanel) will give many additional informations about intracranial structures and should be applied whenever possible.

[Cranial computer tomography in children. Correlation of echoencephalography and EEG to cranial computer tomography]. / Kraniale Computer-Tomographie im Kindesalter. Korrelation von Echoenzephalogramm und EEG zum kranialen Computer-Tomogramm.

The results of cranial ultrasound (A-scan) and computerized tomography (CT) in 81 children were corresponding in 90%, when ventricular diameter was determined, in 85% of intracerebral dysplasias, and in 12,5% of neonatal intracranial hemorrhagia. Comparison of EEG and CT findings in 70 of these children were corresponding in 54% of the cases with respect to "normal" and "abnormal". On the basis of these results routine one-dimensional ultrasound scanning still seems to be a useful procedure.

[Ultrasound echography (A-scan) of the cerebral ventricles in newborn infants: its relation to the degree of maturity and clinical significance]. / Ultraschallechographie (A-Scan) der Hirnventrikel bei Neugeborenen: Beziehungen zum Reifegrad und klinische Bedeutung.

Since during fetal development the intracerebral ventricular system shows characteristic changes wer tried to varify wether there is a relationship between the width of the ventricles of the newborn and the degree of maturity. In 304 neurologically healthy newborn infants (28. until 42. weeks of gestation) the ventricular diameters in the region of body of the lateral ventricles were measured by ultrasound (A-mode) once between the third and eight day of life. In addition the cella-media-indices were calculated. With increasing maturation we found wider ventricles. Also the cella-media-indices were higher in the more mature infants which we believe is the result from growth of cerebral substance in the last third of pregnancy. Small-for-date infants born at term showed significantly lower cella-media-indices than normal weight term babies (p less than 0,01). These results may help interprete sonographic and computertomographic measurements of the premature ventricles. The significance of ventricular diameters smaller or larger than our normal values is not yet exactly understood and further studies are needed.

Serum carnitine during valproic acid therapy.

This study was initiated to examine the influence of valproic acid (VPA) on serum carnitine, as well as the possible etiological role of carnitine in VPA-induced fatal hepatotoxicity. Free, total, and short-chain acylcarnitine were measured in the serum of 21 pediatric patients receiving VPA therapy, 21 healthy matched controls, and 21 patients receiving various antiepileptic drugs other than VPA. The free carnitine level was lowest in the VPA group (p less than 0.05), and the short-chain acylcarnitine/free carnitine ratio was highest in the VPA group (p less than 0.01). Patients receiving VPA polytherapy had lower total carnitine values than patients receiving VPA monotherapy (p less than 0.05). No correlation was found between serum ammonia and VPA drug levels. A 3 1/2-year-old girl developed hepatic failure under VPA therapy. Her serum carnitine values were normal. Despite the oral intake of L-carnitine this patient died. In this case, apparently VPA-induced hepatotoxicity was not associated with carnitine deficiency. The reduction of carnitine in the serum of VPA-treated patients is most probably due to alterations of fatty acid metabolism. However, neither primary carnitine deficiency nor VPA-induced secondary carnitine deficiency can be the only reason for the VPA-induced fatal hepatotoxicity.

[Abnormalities of the brain in childhood in nuclear magnetic tomography]. / Fehlbildungen des kindlichen Gehirns im Kernspintomogramm.

25 of about 300 infants and children, who had been examined by magnetic resonance imaging since 1984, had a congenital malformation of the brain. Cystic malformations (e.g. arachnoid cysts) were the most frequent lesion. Other findings were: Arnold-Chiari malformation, septo-optic dysplasia, Dandy-Walker syndrome, agenesis of the corpus callosum, migration disorders. The multiplanar slice orientation and the good tissue contrast in magnetic resonance imaging supplied a clear diagnosis in all cases. Compared with other imaging modalities (CT, ultrasonography) the depiction of the morphology was superior in MR imaging in most cases.

Retrobulbar cysts in Aicardi's syndrome.

Case report of a four-year-old girl with Aicardi's syndrome diagnosed from the triad: absence of the corpus callosum, focal seizures, and chorioretinal lacunae. In addition, MR scans and orbital ultrasonography detected retrobulbar cysts behind the right microphthalmic eye not described so far. Analyzing the histological data from two previous reports, it becomes likely that the cysts have formed from abnormal migration of neuroretinal tissue through the border of the optic disc coloboma that was also present. This pathomechanism is also known in isolated colobomatous microphthalmos in which cysts may occur.

[Neurologic rehabilitation in Bavaria. Study of the development of admission capacity of rehabilitation clinics 1992 to 1994]. / Neurologische Rehabilitation in Bayern. Untersuchung zur Entwicklung der Aufnahmekapazitäten der Rehabilitationskliniken 1992 bis 1994.

In order to get information about capacities of neurorehabilitation for patients with acquired brain injuries or stroke in Bavaria, a survey concerning the time interval between registration and admission of the patient (waiting period) was carried out. Structured interviews by telephone were performed and all departments of neurorehabilitation and neurosurgery in Bavaria were included. The waiting period was calculated for the last 3 years and for each phase of rehabilitation using rehabilitation phase model A-D, which was proposed by the Deutscher Verband Rentenversicherungsträger (Association of German social pension Insurancies). As a result, a significant shortening of the waiting period over the last 3 years for almost all phases of rehabilitation has been demonstrated. We therefore conclude that an over capacity may develop in Bavarian neurorehabilitation, at least in certain regions. Quantity seems to be obtained. Next goal required is control of quality.

Biotinidase Km-variants: detection and detailed biochemical investigations.

We describe a simple method for the detection of biotinidase Km-variants and detailed biochemical investigations in 5 such patient. They were detected among 103 patients with plasma biotinidase activity which ranged from undetectable to 30% of the mean normal value. Two different types of biotinidase Km-variants were found. (1) In 3 infants biotinidase had a single 105-430-fold elevated Km for biocytin. Biotinidase showed very low activities (0.2-4% of the mean normal value) in the routine colorimetric assay and was not functional in vivo. Accordingly, these patients presented with classical clinical illness. (2) In two patients biotinidase showed biphasic kinetics indicating the presence of one component with a normal Km and reduced Vmax (1.7% and 12%), and another with 330- and 59-fold elevated Km, respectively. In these two patients, biotinidase proved to be at least partially functional in vivo. However, the first patient developed severe symptoms and biotin deficiency late, at the age of 10-15 years, and the second had marginal biotin deficiency at the age of 2 years but no clinical symptoms. Comparative studies revealed that both patients had more severe biotin deficiency than age-matched patients with similar levels of residual biotinidase activity and a single normal Km. Therefore, all patients with residual biotinidase activity should be evaluated for the presence of a Km-mutation, since such patients should be treated with biotin. These can easily be detected by including a second substrate concentration (1.5 mmol/L) in the routine colorimetric biotinidase assay which is performed with 0.15 mmol/L biotin. Increased activity with the higher substrate concentration indicates the presence of a Km-mutation. Detailed kinetic studies are needed to evaluate the distinct forms of Km-variants.