Cervical spinal cord atrophy in the atraumatically born neonate: one form of prenatal or perinatal ischaemic insult?

After atraumatic birth, three neonates presented with muscle hypotonia and weakness. Flaccid paresis of the upper extremities, spasticity of the lower extremities, dissociate sensory loss and autonomic dysfunction developed later. This ruled out the initial, tentative diagnoses of cerebral palsy, spinal muscular atrophy or hereditary neuropathy. Diagnostic imaging revealed marked thinning of the cervical spinal cord in all patients. The possible aetiology of these lesions is considered. In all cases, an antenatal or perinatal infarction is thought to be the most probable cause. Different clinical pictures following intrauterine spinal cord ischemia are discussed. Spinal cord lesion must be considered even after atraumatic birth.

Acetazolamide treatment for infantile central sleep apnea.

Central sleep apnea is a common respiratory pattern in healthy neonates. Nevertheless, frequent central sleep apnea associated with drops in oxygen saturation may contribute to infantile morbidity. Recently, low-dose acetazolamide was shown to reduce symptomatic central sleep apnea in adults. We treated 12 infants, median conceptional age 42 weeks (range, 40-44 weeks), with central sleep apnea. In all cases, the central apnea index was >40/h total sleeping time (apnea > or = 3 sec). The cumulative duration of drops in oxygen saturation below 90% was more than 3 min/h total sleeping time. All individuals received acetazolamide 7 mg/kg/day (orally, divided in three doses) for 11 weeks. Polysomnography was begun 10 hours before the first dose and continued for 10 hours after the third dose. Polysomnography was repeated after 6 weeks of treatment and 1 week after acetazolamide therapy was discontinued. Comparison of the respiratory patterns before and after treatment (10-hour recording after the third dose) showed a decrease in the median central apnea index from 74/h (range, 42-152/h) to 13/h (range, 6-49/h). The median of the cumulative duration of drops in oxygen saturation below 90% decreased from 3.6 min/h (range, 3.1-9.2 min/h) to 0.07 min/h (range, 0-0.5 min/h). Basal oxygen saturation increased from 95 (92-97%) to 98% (96-99%). This improvement was maintained in the final polysomnography (12 weeks after therapy was begun and 1 week after completion of the 11-week course). No adverse effects were noted. We conclude that low-dose acetazolamide treatment may be useful for the treatment of central infantile sleep apnea associated with hypoxemia.

2-Amino-6-arylsulfonylbenzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1.

A series of 2-amino-5-arylthiobenzonitriles (1) was found to be active against HIV-1. Structural modifications led to the sulfoxides (2) and sulfones (3). The sulfoxides generally showed antiviral activity against HIV-1 similar to that of 1. The sulfones, however, were the most potent series of analogues, a number having activity against HIV-1 in the nanomolar range. Structural-activity relationship (SAR) studies suggested that a meta substituent, particularly a meta methyl substituent, invariably increased antiviral activities. However, optimal antiviral activities were manifested by compounds where both meta groups in the arylsulfonyl moiety were substituted and one of the substituents was a methyl group. Such a disubstitution led to compounds 3v, 3w, 3x, and 3y having IC50 values against HIV-1 in the low nanomolar range. When gauged for their broad-spectrum antiviral activity against key non-nucleoside reverse transcriptase inhibitor (NNRTI) related mutants, all the di-meta-substituted sulfones 3u-z and the 2-naphthyl analogue 3ee generally showed single-digit nanomolar activity against the V106A and P236L strains and submicromolar to low nanomolar activity against strains E138K, V108I, and Y188C. However, they showed a lack of activity against the K103N and Y181C mutant viruses. The elucidation of the X-ray crystal structure of the complex of 3v (739W94) in HIV-1 reverse transcriptase showed an overlap in the binding domain when compared with the complex of nevirapine in HIV-1 reverse transcriptase. The X-ray structure allowed for the rationalization of SAR data and potencies of the compounds against the mutants.

Severe congenital myasthenic syndrome due to homozygosity of the 1293insG epsilon-acetylcholine receptor subunit mutation.

Recently, a congenital myasthenic syndrome (CMS) with end-plate acetylcholine receptor (AChR) deficiency due to missense mutations in the genes for the AChR subunit was described. The first observed patient with this CMS was heteroallelic for the two epsilon-AChR subunit mutations epsilon1101insT and epsilon1293insG. This patient had only a moderate phenotype with mild muscle weakness and abnormal fatigue. We have now found homozygosity for the epsilon1293insG mutation in a severely affected CMS patient, who lost the ability to walk in midchildhood and shows profound weakness and muscle wasting. Our observation allows a genotype-phenotype correlation illustrating how differences in the AChR mutation haplotype can profoundly influence disease severity.

Ischemic stroke and migraine in childhood: coincidence or causal relation?

Although migraine is an accepted cause of cerebral infarction in adults, this association is less well recognized in children. We present two children with migraine and cerebral infarction, which we regard as migrainous stroke, though neither patient fulfills all criteria of the International Headache Society for the diagnosis of migrainous infarction. Review of the literature concerning examples of migraine-associated stroke in childhood suggests that these criteria are too restrictive to comprise the majority of migrainous strokes, especially in this age group.

Basilar artery occlusion and the dense artery sign in the newborn.

A child with basilar artery occlusion in the neonatal period is reported. The occlusion was documented by unenhanced computed tomography performed in the neonatal period demonstrating a "dense" artery at the tip of the basilar artery. The pattern of cerebral damage on MRI scan at 10 years of age confirmed the site of the vascular occlusion. The evidence suggests that embolization was the operating pathogenic mechanism of cerebral vascular occlusion. Neonatal arterial thrombosis involving the carotid circulation has been well documented and may be due to many pathological factors including direct trauma to the carotid artery and embolization from remote sites. Thrombosis of the vertebral artery in the neonate is only rarely reported and only in association with significant cervical trauma. A second child with a similar pattern of cerebral injury demonstrated on neuroimaging is described suggesting that this event may be more common than recognized. The clinical features of basilar artery occlusion as seen in the adult are not apparent in the neonate. Recognition of the neuroimaging characteristics seen in this condition may help to provide the clinician with a reasonable pathogenetic explanation for unexplained cerebral injury.

Hamartoma of the triceps surae muscle.

A 9-year-old, otherwise healthy girl presented with a 5-year history of pain in her right calf with retarded growth and development of an equinus contracture of her right leg. Magnetic resonance imaging showed an irregular mass with heterogeneous enhancement after contrast in her right triceps surae muscles, especially the soleus. Histological studies of this triceps surae muscle tissue revealed a haphazard distribution of adipose and connective tissue, striated and smooth muscle cells, vessels and lymphoid follicles, as well as nerve bundles which, together, were considered components of a hamartoma.

[Cataplexy in type C Niemann-Pick disease]. / Kataplexie bei Morbus Niemann-Pick Typ C.

Cataplexy usually occurs as a part of the tetrad of clinical phenomena of idiopathic narcolepsy. Symptomatic cases are rare. A 4 years old girl from consangineous parents had recurrent loss of muscle tone and fell to the ground, when she laughed. The EEG was normal. Prolonged neonatal jaundice with cholestasis, hepatosplenomegaly, mental regression, supranuclear ophthalmoplegia, and foam cells led to the diagnosis of Niemann-Pick disease type C with symptomatic cataplexy. Symptomatic forms of the narcolepsy-cataplexy complex should be considered, when there is an early onset before puberty, cataplectic attacks predominate the narcoleptic attacks, and when additional neurological symptoms occur. Symptomatic cataplexy occurs in Niemann-Pick disease type C. It is considered to be the result of lesions of the pontine reticular formation.

Glycosyl-phosphatidylinositols of Trypanosoma congolense: two common precursors but a new protein-anchor.

The parasitic protozoan Trypanosoma congolense exhibits a dense surface coat which is pivotal for immunoevasion of the parasite. This dense surface coat is made of a single protein species, the variant surface glycoprotein, which is present in a high copy number. The protein is anchored to the plasma membrane by a glycosyl-phosphatidylinositol membrane anchor. A detailed study of the structure of T. congolense strain 423 (clone BENat 1.3) variant surface glycoprotein glycosyl-phosphatidylinositol membrane anchor was performed. Radioactively labelled core-glycan prepared by dephosphorylation, deamination and reduction was analysed by high-pH anion-exchange chromatography, size-exclusion and lectin affinity chromatography. Additionally the glycosyl-phosphatidylinositol membrane anchor core-glycan was purified from a bulk preparation of variant surface glycoprotein and subjected to mass spectrometry and methylation analysis. Using these methods we could identify a novel galactose-beta 1,6-N-acetyl-glucosamine-beta 1,4-branch modifying the mannose adjacent to the glucosamine of the mannose-alpha 1,2-mannose-alpha 1,6-mannose-alpha 1,4-glucosamine core-glycan of the variant surface glycoprotein glycosyl-phosphatidylinositol membrane anchor. Furthermore the biosynthetic pathway leading to this novel structure was investigated. Two putative glycosyl-phosphatidylinositol anchor precursors were identified having structures identical to the previously characterized Trypanosoma brucei brucei glycolipids P2 and P3 (also designated glycolipid A and C) consistent with a trimannosyl core and a dimyristoyl-glycerol. Both glycosyl-phosphatidylinositol anchor precursors of T. congolense do not possess the side-branch modification found on the mature protein membrane anchor, implying that the sugar side-chain is added to the anchor during its passage through the Golgi-apparatus.

Dystrophinopathies.

The discovery of the subsarcolemmal muscle fiber protein dystrophin has, to a certain extent, replaced former nosological terms of Duchenne (DMD) and Becker (BMD) muscular dystrophies by the term dystrophinopathies. The immunohistochemical and Western blot analysis of dystrophin has not only enlarged the clinical spectrum of dystrophinopathies, but has also made carrier detection of DMD more reliable, particularly in manifesting carriers without family history. Moreover, prenatal muscle biopsy, under selected circumstances, can show presence or absence of dystrophin, ie, in the latter case an affected male fetus. Molecular genetics have provided a wealth of genetic details in the dystrophinopathies, but therapy has not yet succeeded to a similar extent, on the contrary, myoblast transplantation has not resulted in any clinical improvement.

Prenatal diagnosis of infantile neuronal ceroid-lipofuscinosis: a combined electron microscopic and molecular genetic approach.

Based on two unrelated index patients afflicted with INCL, fetal chorion tissues were studied from subsequent pregnancies of the two respective mothers resulting in the prenatal diagnosis of INCL in two of the three pregnancies. Documentation of INCL was based on electron microscopy and DNA studies of the biopsied chorion tissue, later confirmed in the two affected fetuses after termination of their pregnancies by demonstrating INCL-specific lipopigments in post-mortem tissues, in the liver of both aborted fetuses and, additionally, in spleen and skeletal muscle of one of the affected fetuses. The autolysis of the aborted tissues, however, precluded a systematic documentation of all affected cell types and tissues. Thus, prenatal diagnosis of INCL is feasible and reliable for both Finnish and non-Finnish families.

Deflazacort vs. prednisone in Duchenne muscular dystrophy: trends of an ongoing study.

Several studies have demonstrated the slowing effect of corticosteroids on the decline of muscle strength in Duchenne muscular dystrophy (DMD). Deflazacort (DFC) is supposed to have fewer side effects than prednisone (PRED). An ongoing double blind multicenter study is comparing the effects and side effects of deflazacort (0.9 mg/kg/day) and prednisone (0.75 mg/kg/day) in DMD. This interim report includes data for 67 boys between age 5 years and loss of ambulation. Besides the common clinical and laboratory data for chronic corticoid treatment, motor performance has been tested. Interim results, 3-15 months after starting the medication, show some scattering but no grouping of data for all the functions tested: timed motor functions, sum of the strength of 20 muscles according to a 10-point scale on manual testing, weight gain, osteocalcin and alkaline phosphatase. Only the changes in CK activity after 3 months medication might reflect two equal groups without any correlation with the initial activity or with other parameters. On average, there was no clear-cut loss of muscle strength or performance. Except for in 4 patients, who were excluded due to unacceptable weight gain and/or loss of ambulation, there were no side effects considered to be serious. The results suggest that (i) DFC and PRED in equal anti-inflammatory dosage are similarly or equally efficient in slowing down the decline of muscle strength in DMD; (ii) benefits outweigh the side effects. This allows the study to continue as designed.

[Multi-segmental fusion of scoliosis in Duchenne's muscular dystrophy]. / Mehrsegmentale Fusion der Skoliose bei Duchenne-Muskeldystrophie.

Operations in scoliosis in patients suffering from an advanced stage of Duchenne muscular dystrophy are associated with a higher risk due to the extent of the curves, the respiratory insufficiency and frequent cardiomyopathia. Progressive scolioses in 20 wheelchair patients with an age between 10.5-18.3 years (mean 14.6 years) were treated by CDI. The mean preoperative angle in this group was 70.6 degrees, the postoperative angle 31.2 degrees (mean correction 39.4 degrees or 55.8%). The preoperative lordosis of the lumbar spine (mean angle 4.1 degrees) was corrected to 17.8 degrees postoperatively. The average intraoperative blood loss (2300 ccm) was evident more compared with idiopathic scoliosis. One neurologic complication (postoperative disturbance of bladder function) was observed. Nowadays early surgical correction and stabilization (Cobb angle > 20 degrees) has to be recommended as the treatment of choice for scolioses in Duchenne muscular dystrophy using multisegmental instrumentation methods to enable rapid mobilisation and a postoperative care without brace or cast. This conception allows a prophylactic operation including the following targets: prolongation of life expectancy, improvement of sitting position and prevention of rapid deterioration of lung function including assisted mechanical ventilation in late stages.

Tethered cord after spina bifida aperta: a longitudinal study of somatosensory evoked potentials.

Progressive neurological deterioration may occur after meningomyelocele repair. Magnetic resonance imaging almost invariably demonstrates a conus medullaris in an abnormally low position, whether neurological symptoms develop or not. Surgery of a secondary tethered cord is indicated when progression of neurological symptoms is documented. We performed a longitudinal study of posterior tibial nerve somatosensory evoked potentials (SSEPs) in children and adolescents after neonatal meningomyelocele repair. All patients were able to walk. Declining or negative posterior tibial nerve SSEPs were recorded in 15 patients; 14 of these had clinical signs of a secondary tethered cord. After surgery of the tethered cord, the SSEPs improved in 8 of 10 patients. Posterior tibial nerve SSEPs may contribute to the diagnosis of secondary tethered cord. After untethering, the evoked potentials demonstrate recovery of spinal cord function and might help to delineate prognosis.

Aplasia of the retinal vessels combined with optic nerve hypoplasia, neonatal epileptic seizures, and lactic acidosis due to mitochondrial complex I deficiency.

A newborn male with mitochondrial complex I deficiency suffered from neonatal epileptic seizures, which later developed into infantile spasms. The infant was blind due to aplasia of the retinal vessels and hypoplasia of the optic nerve. There was congenital lactic acidosis, which persisted in later life. The boy was microcephalic and retarded. Muscular hypotonia later shifted to spasticity. Succinic acid was increased in urine. We assume that the aplasia of the retinal vessels is due to damage of the retinal ganglion cells caused by the mitochondrial disease in the first 3 to 4 months of pregnancy.

[The automated determination of the dibucaine number using the Greiner G450 selective analyzer. A routine parameter of significance?]. / Die automatisierte Bestimmung der Dibucainzahl am selektiven Analyzer GREINER G450. Ein Routineparameter von Bedeutung?

UNLABELLED: Patients who are homozygous for an atypical pseudocholinesterase enzyme (PCHE) suffer a prolonged neuromuscular block after succinylcholine application. In order to determine which patients have atypical PCHE preoperatively, an automated method using the Greiner G450 analyzer was developed. PATIENTS AND METHODS: The contribution of blocked and unblocked PCHE by dibucaine hydrochloride (optimal concentration 10(-4) mol/l;) was determined in 113 patients (ASA groups 1-2) and the dibucaine number (DN) was evaluated. RESULTS: According to the DN, the patients were subdivided into three groups: group A (PCHE 5.01 +/- 1.64 kU/l, DN 74.47 +/- 0.87); group B (PCHE 4.28 +/- 3.41 kU/l, DN 64.95 +/- 3.41); group C (PCHE 1.33 +/- 0.54 kU/l, DN 13.08 +/- 2.19;). PCHE and DN of group A corresponded with normal standard values, whereas the patients in groups B and C could be considered to be patients with heterozygous and homozygous atypical PCHE, respectively. CONCLUSIONS: Our data indicate that an automated analysis of blocked and unblocked PCHE with the Greiner G450 can be easily done in a routine laboratory. By interpreting the DN, the possible risks of delayed succinylcholine degradation can probably be prevented.

[Progressive Duchenne muscular dystrophy: general practice aspects of diagnostic assessment]. / Progressive Muskeldystrophie Duchenne: Praxis der Diagnosefindung.

The analysis of 57 cases of Duchenne muscular dystrophy (DMD) from W.-Germany outlined an average delay in motor development with an extended period of time between learning to stand and to walk. 33 patients could not walk when they were 16 months old. At the age of 27 months people without medical training generally noticed first symptoms. Unexpectedly often quantitative deficiencies in movements became evident. On average 26 months passed until DMD was diagnosed. To improve the situation, the authors propose a selective screening of boys who are not able to walk without help when they are 16 months old (90th percentile for healthy children).