Christine Bonnier

Outcome and prognosis of whiplash shaken infant syndrome; Late consequences after a symptom-free interval

Long‐term follow‐up five to 13 (mean seven years) of 13 cases of whiplash‐shaken‐infant syndrome (WSIS) demonstrated long sign‐free intervals. Full clinical appearance of neurological deficits takes four months tor the interruption of brain growth, six to 12 months for lesions of the central nervous system long pathways, up to two years for epilepsy, and three to six years for behavioural and neurospychological signs. In our series, WSIS ocurred at a mean postnatal age of 5.5 months and caused intracranial, retinal and preretinal haemorrhages, intracranial haematomas, oedema, contusional tears, and developmental disturbances interfering with the growth and differentiation of neural tissue and with synaptic stabilisation. These mechanisms account for the long sign‐free interval that makes its impossible to formulate a precise and final neurological prognosis before the age of school entrance. Only one of our patients seems to have remained normal even several years after the shaking.

Does in utero exposure to heavy maternal smoking induce nicotine withdrawal symptoms in neonates

Maternal drug use during pregnancy is associated with fetal passive addiction and neonatal withdrawal syndrome. Cigarette smoking—highly prevalent during pregnancy—is associated with addiction and withdrawal syndrome in adults. We conducted a prospective, two-group parallel study on 17 consecutive newborns of heavy-smoking mothers and 16 newborns of nonsmoking, unexposed mothers (controls). Neurologic examinations were repeated at days 1, 2, and 5. Finnegan withdrawal score was assessed every 3 h during their first 4 d. Newborns of smoking mothers had significant levels of cotinine in the cord blood (85.8 ± 3.4 ng/mL), whereas none of the controls had detectable levels. Similar findings were observed with urinary cotinine concentrations in the newborns (483.1 ± 2.5 μg/g creatinine versus 43.6 ± 1.5 μg/g creatinine; p = 0.0001). Neurologic scores were significantly lower in newborns of smokers than in control infants at days 1 (22.3 ± 2.3 versus 26.5 ± 1.1; p = 0.0001), 2 (22.4 ± 3.3 versus 26.3 ± 1.6; p = 0.0002), and 5 (24.3 ± 2.1 versus 26.5 ± 1.5; p = 0.002). Neurologic scores improved significantly from day 1 to 5 in newborns of smokers (p = 0.05), reaching values closer to control infants. Withdrawal scores were higher in newborns of smokers than in control infants at days 1 (4.5 ± 1.1 versus 3.2 ± 1.4; p = 0.05), 2 (4.7 ± 1.7 versus 3.1 ± 1.1; p = 0.002), and 4 (4.7 ± 2.1 versus 2.9 ± 1.4; p = 0.007). Significant correlations were observed between markers of nicotine exposure and neurologic-and withdrawal scores. We conclude that withdrawal symptoms occur in newborns exposed to heavy maternal smoking during pregnancy.

Prenatal and Early Postnatal Intoxication by Inorganic Mercury Resulting from the Maternal Use of Mercury Containing Soap

A case of slight renal tubular dysfunction associated with cataract and anaemia was diagnosed in a 3-month-old black boy in whom high levels of mercury were found in blood and urine. Several arguments suggest that the renal, ocular and haematological defects may have resulted from exposure to mercury during foetal life and the 1-month lactation period due to the extensive use of inorganic mercury containing cosmetics by the mother.

Delayed white matter injury in a murine model of shaken baby syndrome.

Shaken baby syndrome, a rotational acceleration injury, is most common between 3 and 6 months of age and causes death in about 10 to 40% of cases and permanent neurological abnormalities in survivors. We developed a mouse model of shaken baby syndrome to investigate the pathophysiological mechanisms underlying the brain damage. Eight‐day‐old mouse pups were shaken for 15 seconds on a rotating shaker. Animals were sacrificed at different ages after shaking and brains were processed for histology. In 31‐day‐old pups, mortality was 27%, and 75% of survivors had focal brain lesions consisting of hemorrhagic or cystic lesions of the periventricular white matter, corpus callosum, and brainstem and cerebellar white matter. Hemorrhagic lesions were evident from postnatal day 13, and cysts developed gradually between days 15 and 31. All shaken animals, with or without focal lesions, had thinning of the hemispheric white matter, which was significant on day 31 but not earlier. Fragmented DNA labeling revealed a significant increase in cell death in the periventricular white matter, on days 9 and 13. White matter damage was reduced by pre‐treatment with the NMDA receptor antagonist MK‐801. This study showed that shaking immature mice produced white matter injury mimicking several aspects of human shaken baby syndrome and provided evidence that excess release of glutamate plays a role in the pathophysiology of the lesions.

Glycine antagonist and NO synthase inhibitor protect the developing mouse brain against neonatal excitotoxic lesions.

The prevention of cerebral palsy and neuroprotection of the immature brain continue to be health care priorities. The pathophysiology of perinatal brain lesions associated with cerebral palsy seems to be multifactorial and includes pre- and perinatal factors such as preconceptional events, hormone and growth factors deficiencies, maternal infections with production of cytokines, and hypoxic/ischemic perfusion failures. Excitotoxic cascade could represent a common pathway that leads to neural cell death and subsequent brain damage. Brain injuries induced by ibotenate, a glutamatergic analog, which are essentially mediated through the N-methyl-D-aspartate receptor, mimic some aspects of the white matter cysts and transcortical necrosis observed in human perinatal brain damage. The purpose of the present study was to assess the protective role of several pharmacological agents, administered in conjunction with ibotenate, against induced excitotoxic lesions. We injected ibotenate in the developing mouse brain 5 d postnatally, after the full settlement of neuronal layers. Co-treatment with kynurenic acid, and antagonist of the facilitating glycine site of the N-methyl-D-asparate receptor, or with NG-nitro-L-arginine, an inhibitor of nitric oxide synthesis, induced a dose-dependent neuroprotective effect. Conversely, zinc gluconate, a blocking agent of the channel linked to the N-methyl-D-aspartate receptor, and a free radical scavenger (U74389F), were unable to protect the developing brain against excitotoxic attack. These data help to clarify some molecular mechanisms involved in excitotoxic lesions of the developing mouse brain and permit us to envision new strategies in the prevention of cerebral palsy.

Fructose-1,6-biphosphate prevents excitotoxic neuronal cell death in the neonatal mouse brain

The excitotoxic cascade may represent an important pathway leading to brain damage and cerebral palsy. Brain lesions induced in newborn mice by ibotenate (acting on N-methyl-D-aspartate receptors) and by S-bromowillardiine (acting on alpha-3-amino-hydroxy-5-methyl-4-isoxazole propionic acid and kainate receptors) mimic some aspects of white matter cysts and transcortical necrosis observed in human perinatal brain damage. Fructose 1,6-biphosphate (FBP) is a high-energy glycolytic pathway intermediate which, in therapeutic doses, is non-toxic and neuroprotective in hypoxic-ischemic models of brain injury. Mechanisms of action include modulation of intracellular calcium through phospholipase C (PLC) activation. The goal of this study was to determine the neuroprotective effects of FBP in a mouse model of neonatal excitotoxic brain injury. Mice that received intraperitoneal FBP had a significant reduction in size of ibotenate-induced (80% reduction) or S-bromowillardiine-induced (40% reduction) cortical plate lesions when compared with control animals. Studies of fragmented DNA and cleaved caspase 3 confirmed the survival promoting effects of FBP. FBP had no detectable effect on excitotoxic white matter lesions. The effects of FBP were antagonized by co-administration of PLC, protein kinase C or mitogen-associated protein kinase inhibitors but not by protein kinase A inhibitor. A moderate, transient cooling of pups immediately after the insult extended the therapeutic window for FBP, as FBP administered 24 h after ibotenate was still significantly neuroprotective in these pups. This data extends the neuroprotective profile of FBP in neonatal brain injury and identifies gray matter lesions involving N-methyl-D-aspartate receptors as a major target for this promising drug.

Animal models of shaken baby syndrome: revisiting the pathophysiology of this devastating injury

To better understand outcomes after early brain injuries, studies must address multiple variables including age at injury, the mechanisms and severity of injury, environmental factors (before and after injury) and developmental factors. Animal models are helpful for elucidating these different aspects. First, this paper describes a new model of shaken baby syndrome (SBS) in mice, without impact or hypoxia. Mortality was 27%; 75% of survivors had focal brain lesions consisting of haemorrhagic or cystic lesions of the white matter, corpus callosum and cerebellum. All shaken animals, with and without focal lesions, showed delayed white matter atrophy. White matter damage and atrophy were reduced by pre-treatment with an NMDA receptor antagonist, indicating that excess glutamate release contributed to the pathophysiology of the lesions. Secondly, it discusses data on neuroprotection after early brain injuries; drugs targeting the NMDA receptors cannot be used in clinical practice but indirect neuroprotection strategies including anti-NO, anti-free radicals and trophic factors hold promise for limiting the excitotoxic white matter damage induced by early injury, in particular caused by shaking, during brain development. Thirdly, it describes two experimental models in which SBS outcomes are determined when the trauma is combined with environmental influences, namely medications during the acute phase, most notably anti-epileptic drugs and rearing conditions.

Leiomyoma of the suprarenal gland in a child with ataxia-telangiectasia.

We report the occurrence of a leiomyoma of the suprarenal gland in a 10-year-old girl with ataxia-telangiectasia (A-T). Muscle cell tumors are very uncommon in this gland as they are in A-T. Possible reasons for developing nonhematologic tumors in this syndrome are reviewed. A defect in DNA repair mechanisms probably favors, in young children, the expression of tumors normally expected in the aged.

Prolonged dysphagia caused by congenital pharyngeal dysfunction.

We describe two patients with severe, isolated, congenital dysphagia caused by paralysis of the pharyngeal muscles, who recovered at the ages of 40 months and 20 months, respectively. No other evidence of neurologic or muscular dysfunction was present except for a transient paralysis of the adductors of the vocal cords in one child. Radiocinematographic studies showed paralysis of the pharyngeal stage of swallowing, with minimal involvement of the oral stage. One child refused oral feeding for several months after apparent radiologic recovery. Two other patients with a similar disorder died of tracheal aspiration at the ages of 8 months and 4 months, respectively. Autopsies showed no abnormality of the central nervous system, and the cranial nerves involved in swallowing were normal. Only five other well-studied cases of this syndrome have been reported. These observations demonstrate the existence of a type of severe, idiopathic, congenital dysphagia related to paralysis of the constrictor muscles of the pharynx, with a propensity to recover after several months or years if properly managed. The cause of the disorder is obscure, but it is probably related to a dysfunction of the central nervous system.

Early bifrontal brain injury: disturbances in cognitive function development.

We describe six psychomotor, language, and neuropsychological sequential developmental evaluations in a boy who sustained a severe bifrontal traumatic brain injury (TBI) at 19 months of age. Visuospatial, drawing, and writing skills failed to develop normally. Gradually increasing difficulties were noted in language leading to reading and spontaneous speech difficulties. The last two evaluations showed executive deficits in inhibition, flexibility, and working memory. Those executive abnormalities seemed to be involved in the other impairments. In conclusion, early frontal brain injury disorganizes the development of cognitive functions, and interactions exist between executive function and other cognitive functions during development.