Spasticity, dyskinesia and ataxia in cerebral palsy: Are we sure we can differentiate them?

OBJECTIVE: Cerebral palsy (CP) can be classified as spastic, dyskinetic, ataxic or combined. Correct classification is essential for symptom-targeted treatment. This study aimed to investigate agreement among professionals on the phenotype of children with CP based on standardized videos. METHODS: In a prospective, observational pilot study, videos of fifteen CP patients (8 boys, mean age 11 ± 5 y) were rated by three pediatric neurologists, three rehabilitation physicians and three movement disorder specialists. They scored the presence and severity of spasticity, ataxia or dyskinesias/dystonia. Inter- and intraobserver agreement were calculated using Cohen's and Fleiss' kappa. RESULTS: We found a fair inter-observer (κ = 0.36) and moderate intra-observer agreement (κ = 0.51) for the predominant motor symptom. This only slightly differed within the three groups of specialists (κ = 0.33-0.55). CONCLUSION: A large variability in the phenotyping of CP children was detected, not only between but also within clinicians, calling for a discussing on the operational definitions of spasticity, dystonia and ataxia. In addition, the low agreement found in our study questions the reliability of use of videos to measure intervention outcomes, such as deep brain stimulation in dystonic CP. Future studies should include functional domains to assess the true impact of management options in this highly challenging patient population.

The effect of cerebral hypothermia on white and grey matter injury induced by severe hypoxia in preterm fetal sheep.

Prolonged, moderate cerebral hypothermia is consistently neuroprotective after experimental hypoxia-ischaemia; however, it has not been tested in the preterm brain. Preterm (0.7 gestation) fetal sheep received complete umbilical cord occlusion for 25 min followed by cerebral hypothermia (fetal extradural temperature reduced from 39.4 +/- 0.3 to 29.5 +/- 2.6 degrees C) from 90 min to 70 h after the end of occlusion or sham cooling. Occlusion led to severe acidosis and profound hypotension, which recovered rapidly after release of occlusion. After 3 days recovery the EEG spectral frequency, but not total intensity, was increased in the hypothermia-occlusion group compared with normothermia-occlusion. Hypothermia was associated with a significant overall reduction in loss of immature oligodendrocytes in the periventricular white matter (P < 0.001), and neuronal loss in the hippocampus and basal ganglia (P < 0.001), with suppression of activated caspase-3 and microglia (isolectin-B4 positive). Proliferation was significantly reduced in periventricular white matter after occlusion (P < 0.05), but not improved after hypothermia. In conclusion, delayed, prolonged head cooling after a profound hypoxic insult in the preterm fetus was associated with a significant reduction in loss of neurons and immature oligodendroglia, with evidence of EEG and haemodynamic improvement after 3 days recovery, but also with a persisting reduction in proliferation of cells in the periventricular region. Further studies are required to evaluate the long-term impact of cooling on brain growth and maturation.

Relationship between evolving epileptiform activity and delayed loss of mitochondrial activity after asphyxia measured by near-infrared spectroscopy in preterm fetal sheep.

Early onset cerebral hypoperfusion after birth is highly correlated with neurological injury in premature infants, but the relationship with the evolution of injury remains unclear. We studied changes in cerebral oxygenation, and cytochrome oxidase (CytOx) using near-infrared spectroscopy in preterm fetal sheep (103-104 days of gestation, term is 147 days) during recovery from a profound asphyxial insult (n= 7) that we have shown produces severe subcortical injury, or sham asphyxia (n= 7). From 1 h after asphyxia there was a significant secondary fall in carotid blood flow (P < 0.001), and total cerebral blood volume, as reflected by total haemoglobin (P < 0.005), which only partially recovered after 72 h. Intracerebral oxygenation (difference between oxygenated and deoxygenated haemoglobin concentrations) fell transiently at 3 and 4 h after asphyxia (P < 0.01), followed by a substantial increase to well over sham control levels (P < 0.001). CytOx levels were normal in the first hour after occlusion, was greater than sham control values at 2-3 h (P < 0.05), but then progressively fell, and became significantly suppressed from 10 h onward (P < 0.01). In the early hours after reperfusion the fetal EEG was highly suppressed, with a superimposed mixture of fast and slow epileptiform transients; overt seizures developed from 8 +/- 0.5 h. These data strongly indicate that severe asphyxia leads to delayed, evolving loss of mitochondrial oxidative metabolism, accompanied by late seizures and relative luxury perfusion. In contrast, the combination of relative cerebral deoxygenation with evolving epileptiform transients in the early recovery phase raises the possibility that these early events accelerate or worsen the subsequent mitochondrial failure.

Polyuria and impaired renal blood flow after asphyxia in preterm fetal sheep.

Renal impairment is common in preterm infants, often after exposure to hypoxia/asphyxia or other circulatory disturbances. We examined the hypothesis that this association is mediated by reduced renal blood flow (RBF), using a model of asphyxia induced by complete umbilical cord occlusion for 25 min (n = 13) or sham occlusion (n = 6) in chronically instrumented preterm fetal sheep (104 days, term is 147 days). During asphyxia there was a significant fall in RBF and urine output (UO). After asphyxia, RBF transiently recovered, followed within 30 min by a secondary period of hypoperfusion (P < 0.05). This was mediated by increased renal vascular resistance (RVR, P < 0.05); arterial blood pressure was mildly increased in the first 24 h (P < 0.05). RBF relatively normalized between 3 and 24 h, but hypoperfusion developed again from 24 to 60 h (P < 0.05, analysis of covariance). UO significantly increased to a peak of 249% of baseline between 3 and 12 h (P < 0.05), with increased fractional excretion of sodium, peak 10.5 +/- 1.4 vs. 2.6 +/- 0.6% (P < 0.001). Creatinine clearance returned to normal after 2 h; there was a transient reduction at 48 h to 0.32 +/- 0.02 ml.min(-1).g(-1) (vs. 0.45 +/- 0.04, P < 0.05) corresponding with the time of maximal depression of RBF. No renal injury was seen on histological examination at 72 h. In conclusion, severe asphyxia in the preterm fetus was associated with evolving renal tubular dysfunction, as shown by transient polyuria and natriuresis. Despite a prolonged increase in RVR, there was only a modest effect on glomerular function.

The metabolic effects of endotoxin are differentially affected by the pattern of GH administration in the rat.

GH treatment can increase the mortality and morbidity of critically ill patients. The mechanisms of these harmful effects of GH are unknown but have been, in part, ascribed to interactions between GH and the immune system. Because GH has pattern-dependent actions we have now compared the dose-related effects of continuous and intermittent GH treatment given with or without an endotoxin (lipopolysaccharide; LPS) challenge. Male Wistar rats (n=6 per group) were treated for 5 days with recombinant human GH (0, 10, 100 or 1000 microg/kg per day) using either continuous s.c. infusion by osmotic minipump or intermittent twice daily s.c. injections. On day 4, endotoxin (5 mg/kg, i.p.) was injected and the animals monitored for a further 16 h. LPS administration alone led to neutrophilia and lymphopoenia, with increased plasma concentrations of urea, cholesterol, triglyceride, insulin and leptin, and decreased levels of IGF-I. High dose GH infusion (1000 microg/kg per day) followed by LPS caused greater increases in plasma urea, cholesterol, triglyceride, sodium and magnesium, but lower plasma glucose and insulin levels, than treatment with LPS alone. In contrast, twice daily injections of GH did not enhance these effects of endotoxin. In conclusion, the effects of endotoxin on plasma electrolytes, lipids, urea, glucose and insulin are differentially affected by the pattern of GH administration in the rat.

Insulin-like growth factor binding protein (IGFBP) displacers: relevance to the treatment of renal disease.

Chronic renal failure (CRF) results in complex metabolic and hormonal derangements, particularly in the GH-IGF-IGFBP axis, which can be manifest in children as growth retardation. The decreased glomerular filtration rate (GFR) in CRF is associated with increased plasma IGFBP levels, which may have an important role in inhibiting the bioavailability of IGF-I. There is a large literature from both animal and human studies showing that the administration of IGF-I can affect structure and function of normal and compromised kidneys. We propose an alternative therapeutic approach: activating bound IGF by administering molecules that bind to the IGFBPs. In initial animal studies we used a mutant IGF, an IGF displacer, that binds to IGFBPs but not to IGF receptors. In the rat this molecule activated the IGF system and produced IGF-like effects in vivo, such as increased kidney size, reduced serum creatinine, increased bone growth and increased body weight. Novel synthetic peptides have also been discovered which bind to specific IGFBPs, and we believe such molecules hold promise as therapeutic agents in renal disease.