Neurological Manifestations of Achondroplasia.

PURPOSE OF REVIEW: This review is to delineate the neurological complications seen in patients with achondroplasia. RECENT FINDINGS: As the understanding of the genetics of this disorder has advanced, the possibility of targets for intervention which might modify the development and management of the neurological complications of this disease may be identified. Achondroplasia is a hereditary short-limbed dwarfism which has been known for millennia. The genetic defect is a gain of function sequence variation in the fibroblast growth factor receptor 3 (FGFR3). This gene normally regulates (inhibits) bone growth thus the gain of function results in abnormal or excessive inhibition of growth. The resulting bone is subject to distortion and the result is that bone impinges on nervous tissue, most commonly at the foramen magnum, spinal canal, and nerve root outlet foramen. Awareness of the range of these complications will, hopefully, allow early and more effective intervention so as to ameliorate the nature and severity of the long-term effects of the neurological complications in patients with achondroplasia.

Copy number gain at Xp22.31 includes complex duplication rearrangements and recurrent triplications.

Genomic instability is a feature of the human Xp22.31 region wherein deletions are associated with X-linked ichthyosis, mental retardation and attention deficit hyperactivity disorder. A putative homologous recombination hotspot motif is enriched in low copy repeats that mediate recurrent deletion at this locus. To date, few efforts have focused on copy number gain at Xp22.31. However, clinical testing revealed a high incidence of duplication of Xp22.31 in subjects ascertained and referred with neurobehavioral phenotypes. We systematically studied 61 unrelated subjects with rearrangements revealing gain in copy number, using multiple molecular assays. We detected not only the anticipated recurrent and simple nonrecurrent duplications, but also unexpectedly identified recurrent triplications and other complex rearrangements. Breakpoint analyses enabled us to surmise the mechanisms for many of these rearrangements. The clinical significance of the recurrent duplications and triplications were assessed using different approaches. We cannot find any evidence to support pathogenicity of the Xp22.31 duplication. However, our data suggest that the Xp22.31 duplication may serve as a risk factor for abnormal phenotypes. Our findings highlight the need for more robust Xp22.31 triplication detection in that such further gain may be more penetrant than the duplications. Our findings reveal the distribution of different mechanisms for genomic duplication rearrangements at a given locus, and provide insights into aspects of strand exchange events between paralogous sequences in the human genome.

Ethical considerations in paediatric neurology: neuromuscular disease and epilepsy.

The pace of developing technology with respect to many diagnostic tests, as well as available treatments including artificial ventilation, may have progressed at a faster rate than our ethical, humane ability to decide on the optimal choices for our patients. In fact, who should make these choices; physicians or patients and families? Certain ethical aspects of neuromuscular disorders and epilepsy are reviewed. For neuromuscular disease, the example of Duchenne muscular dystrophy (DMD) with regards to genetic testing, relatively early wheelchair placement and individualised invasive ventilation is discussed. In epilepsy, performing neurosurgery in severely impaired children is probably appropriate in some cases if desired by the family. Financial and human costs restrict therapies and testing for epilepsy as well as other neurological and medical diseases. Whether it is ethical to consider costs in medical treatment or not, it is certainly a reality.

The evaluation of the hypotonic infant.

The pediatric neurologist is regularly asked to evaluate a hypotonic patient. This consultation request usually occurs in 2 different situations; the first is in the newborn period when the neurologist is asked to evaluate the "floppy infant," and the second is in the latter half of the first year of life and is usually accompanied by concern about the developmental progress of the infant and, in particular, the motor development of the infant. In this article, I will try to outline the factors related to the production of muscle tone in infants and children. The elements of the clinical evaluation of the hypotonic child including those clinical tests most helpful in the measurement of tone will be reviewed. A scheme for localizing the origin of the disturbance in muscle tone is presented, many of the known causes of the tone abnormalities are reviewed, and a rational approach to the diagnostic evaluation of these children is offered.

Pseudobulbar Affect in Survivors of Extreme Prematurity With Cerebellar Injury: Support for the Cerebellar Link in Pathologic Laughter and Crying.

Pseudobulbar affect, that is, pathologic laughter and crying is being increasingly recognized in adults and is seen in association with a number of diseases like Parkinson disease, dementia, traumatic encephalopathy, and others, but has not previously been described in children with cerebral palsy. The condition pseudobulbar affect may be due to lesions in (or degeneration of) the cerebro-ponto-cerebellar pathways. Here we report 2 children with cerebral palsy who have structural cerebellar injury because of their being born extremely premature who have pathologic crying and probably laughter.

Oro-facial-digital syndrome IX with severe microcephaly: a new variant in a genetically isolated population.

We describe four patients, two pairs of siblings, with a somewhat unique oro-facial-digital syndrome. The siblings come from the Navajo population which has undergone several genetic "bottlenecks." Thus, as would be anticipated, this syndrome seems to show autosomal recessive inheritance. The combination of the presence of retinal colobomata and the paucity of digital findings in these patients leads us to believe that their condition is best described as a variant of oro-facial-digital syndrome IX. In addition to retinal colobomata, these patients also show severe microcephaly, mental retardation and short stature.

Postterm closure of the cavum septi pellucidi and developmental outcome in premature infants.

The authors report the natural history of closure of the cavum Septi pellucidi in premature infants 26 to 27 weeks postconception at birth and compare the developmental outcome in these infants who had closure by 42 weeks postconception to those who still had a cavum septum pellucidi visualized on ultrasound at approximately term (35-42 weeks). Of 72 patients, 35 patients still had a cavum septum pellucidi visualized on the last ultrasound done between 35 and 42 weeks postconception, and the developmental outcome of these patients was no different from those with earlier closure. The authors conclude that persistence of a cavum septi pellucidi through term is not an independent risk factor for developmental delay.

Magnetic resonance imaging (MRI) findings in children surviving extremely premature delivery and extremely low birthweight with cerebral palsy.

To delineate the frequency, severity, and characteristics of the brain injury occurring in children surviving extremely premature birth, we reviewed brain magnetic resonance images (MRIs) of children with cerebral palsy whose birthweight was less than 1000 g and whose gestational age was less than 28 weeks. The patients were all enrolled in the state Children's Rehabilitative Services clinic, where cerebral palsy is an automatic qualifying condition. We tabulated the MRI findings with respect to the cerebellum, periventricular white matter, and corpus callosum. The inclusion criteria were met by 157 children; 94 had an MRI. The available scans were reviewed by the authors, and the findings were tabulated. Fifty scans were available for review. There were 4 totally normal scans, 18 scans had normal cerebellar imaging, and 8 scans were felt to have normal cerebral findings. The common cerebral abnormalities included decreased white-matter volume without gliosis (n = 36), periventricular leukomalacia (n = 16), and a thin corpus callosum (n = 18). Cerebellar abnormalities were found in 32. The cerebellar findings included destruction of major portions of the cerebellum (usually the inferior vermis and hemispheres) (n = 23) and focal or unilateral loss of cerebellar tissue (n = 4). The high incidence of injury to the cerebellum has not been previously appreciated. The most common cerebral injury is decreased volume of white matter in the periventricular regions without gliosis. The pattern of cerebellar injury suggests a vascular insult, and the deficient white matter without gliosis suggests immaturity of oligodendrogliocytes with limited response to injury. Both lesions are more or less unique to the age at which the insult occurred and represent an emerging, newly recognized type of cerebral palsy.

Leukoencephalopathy with bilateral anterior temporal lobe cysts.

Recently, several reports describing patients with a nonprogressive clinical course, increased signal in the cerebral white matter, and cystic changes in the anterior temporal lobes on magnetic resonance imaging (MRI) have appeared. To date, 25 patients with this very distinctive condition have been described. We report four new cases of this newly recognized entity. All have been identified primarily because of the distinctive MRI features consisting of the very unusual anterior temporal lobe cystic changes. The clinical features are characterized by severe, disabling, but nonprogressive mental and motor retardation. Magnetic resonance spectroscopy has shown increased myo-inositol and decreased N-acetylaspartate in the cerebral white matter. This is a distinctive, probably genetic, condition with characteristic neuroimaging and clinical features. In the appropriate clinical situation, the neuroimaging features are diagnostic.

Ontogeny and physiology of the cavum septum pellucidum in premature infants.

We report the natural history of the closure of the cavum septum pellucidum in 47 premature infants. In this study, a cavum septum pellucidum was present in all patients at 25 to 26 weeks' postconceptual age, in keeping with previous reports. The data from this study suggest that premature delivery does not change the natural history of the normal closure of the cavum septum pellucidum in most infants by 36 to 40 weeks' postconceptual age. Although not statistically significant, there is a suggestion from these data that higher grades of intraventricular hemorrhage are more frequently associated with loss (early closure) of the cavum septum pellucidum. One particularly illustrative case with a grade 4 intraventricular hemorrhage and subsequent hydrocephalus suggests that increases in pressure and volume in the lateral ventricles can cause the laminae of the septum pellucidum to approximate and appear to fuse earlier than expected. However, the fact that the cavum septum pellucidum reappeared in this case after ventricular pressure was decreased (postventricular shunt) suggests that approximation is not the sole factor in definitive fusion of the laminae of the septum pellucidum.

Pediatric Nerve Biopsy Diagnostic and Treatment Utility in Tertiary Care Referral.

BACKGROUND: Pediatric neuropathies are both unique and similar to their adult counterparts, with genetic varieties thought to be more common. The objective of this work was to assess the utility of nerve biopsy in children at a tertiary referral center in light of availability of current genetic testing. METHODS: We retrospectively reviewed the clinical, nerve biopsy, and genetic testing findings of 316 pediatric (age ≤18 years) patients. RESULTS: Median age at diagnosis was 9.8 years (4 days to 18 years). Nerve biopsy was nontargeted in 198 (182 whole sural, seven superficial peroneal, and nine other), targeted in 21 (14 fascicular sciatic and seven brachial plexus), and unknown in 97 cases. Prebiopsy localizations and diagnoses were diverse, most commonly with length-dependent localizations (n = 150). Median follow-up was 6 months (0 to 480 months). A distinctive histopathologic diagnosis was made in 106 cases (33%), including inflammatory or immune (n = 30), neoplastic (n = 19), hereditary (n = 41), vasculitis (n = 10), and other (n = 6). Nerve biopsy confirmed the suspected diagnosis in 91 (29%) individuals and changed or refined the initial diagnosis in 182 (58%). Treatment modifications as a result of biopsy occurred in 80 (25%) cases; 59 (19% of the entire cohort) with clinical improvements noted, most commonly by immunotherapy (n = 30). Low diagnostic yield occurred in "hypotonic infants" without nerve conduction abnormalities. Pain at the biopsy site beyond 1 month was rare (n = 3; 1%). Forty-four patients underwent genetic testing. Among demyelinating varieties, mutations were identified in five of 11 (46%) cases compared with only six of 33 (18%) cases of axonal varieties. CONCLUSION: Pediatric nerve biopsy provides diagnostic information that frequently alters treatment recommendations. Furthermore, it leads to clinical improvements, especially in inflammatory immune neuropathies. For suspected inherited varieties, genetic testing has the highest diagnostic yield in demyelinating phenotypes.

Cerebellar injury in the extremely premature infant: newly recognized but relatively common outcome.

Severe injury to the cerebellum as a complication of extreme prematurity with extremely low birthweight was recently described in 13 children with the clinical diagnosis of cerebral palsy. We report another 10 cases of this syndrome. The clinical features include striking motor impairment and variable degrees of ataxia and athetosis or dystonia, which represent a distinct clinical type of cerebral palsy. Most are severely damaged, with cognitive, language, and motor delays. All are microcephalic, except one with hydrocephalus. Neuroimaging studies demonstrate the absence of major portions of the cerebellum involving both the inferior vermis and hemispheres. Most also have injury of a less severe nature in the cerebrum. This report indicates that this is not an uncommon outcome of extremely low birthweight infants, and we hope to encourage further investigations into the relative frequency and likely etiologies of the condition.

Frequency and nature of cerebellar injury in the extremely premature survivor with cerebral palsy.

We report on the frequency and variable nature of magnetic resonance imaging-documented injury to the cerebellum in children with cerebral palsy who had survived a birth with a weight under 1000 g and/or a gestational age under 28 weeks. Thirty of 67 patients who had magnetic resonance images were found to have injury to the cerebellum. Those with cerebellar injury were much more likely to be microcephalic and to be unable to walk or talk. They did not demonstrate a greater frequency of observed injury to the cerebrum. From a larger collection of children with known cerebellar injury and cerebral palsy who had a history of being extremely premature, we found that 35 of 47 patients had prominent injury to the inferior cerebellum, suggesting infarction, whereas the remainder demonstrated varying degrees of cerebellar atrophy with or without asymmetry and four also had enlarged 4th ventricles. Injury to the cerebellum in the extremely premature survivor who has cerebral palsy is common and associated with a more adverse clinical picture. The etiology of this injury is obscure.

Neurologic complications associated with respiratory syncytial virus.

Encephalopathy has been demonstrated to be associated with respiratory syncytial virus bronchiolitis. In this study, the data on all patients less than 14 years of age hospitalized with respiratory syncytial virus bronchiolitis over the past 4 years was reviewed. Patients who had concomitant diagnoses consistent with neurologic disease underwent detailed chart review. There were 964 patients (age 0.1 to 13.6 years) with a diagnosis of respiratory syncytial virus bronchiolitis. Thirty-six of these patients had concurrent neurologic diagnoses. Twenty-four patients were excluded because of preexistent neurologic disorders, probable simple febrile seizures, or a history of epilepsy. Twelve respiratory syncytial virus-positive patients had definite neurologic complications without another recognized cause. Seven of these patients had seizures (predominantly generalized tonic-clonic and one with status epilepticus), three had generalized encephalopathy (marked hypotonia and decreased responsiveness) of whom two also developed esotropia. Two patients developed isolated esotropia. There was an incidence of neurologic complications of 1.2% (0.7% seizures) in a total of 964 patients with respiratory syncytial virus bronchiolitis. This percentage does not include presumed simple febrile seizures or exacerbations of preexisting seizure disorder (further 1.3%). Neurologic complications occur with respiratory syncytial virus bronchiolitis, and physicians and other caregivers should be aware of this entity as well as the favorable prognosis.

The beginnings of the Southern Child/Pediatric Neurology Society.

The founding and early development of the Southern Pediatric Neurology Society was in many ways parallel to that of the Child Neurology Society. The organization started out as the Southern Child Neurology Society but the name was changed at the time of incorporation so as to avoid confusion of identity and purpose with the larger Child Neurology Society. Although there are archives of early days and the later development of the Southern Pediatric Neurology Society, the details have never been set down in a narrative explaining the events that led to the development of the organization. In this paper, we try to produce a written record of the history of the founding and early development of the Southern Pediatric Neurology Society.

Congenital myopathies/dystrophies.

The congenital myopathies and congenital muscular dystrophies are a group of relatively infrequent neuromuscular disorders. Ultimate understanding of these disorders, however, will undoubtedly shed considerable light on skeletal muscle development and function. Three classical congenital myopathies are central core disease, nemaline myopathy, and centronuclear myopathy. The congenital muscular dystrophies are often distinguished by whether or not they are associated with clinically evident cerebral involvement.

Hypomagnesemic seizures: case report and presumed pathophysiology.

Hypomagnesemia has previously been recognized as an uncommon cause of seizures. The electrolyte abnormality is caused by poor gastrointestinal absorption or excessive renal wasting, both from a variety of causes. We report on a 5-week-old patient who developed hypomagnesemic seizures as a consequence of renal magnesium wasting. Although the exact pathophysiology of hypomagnesemic seizures remains uncertain, currently available information suggests that it is related to disinhibition of the N-methyl-D-aspartate-type glutamate receptor-sodium channel complex.

Hypotonia, congenital hearing loss, and hypoactive labyrinths.

The records of all patients attending a neurosensory genetics clinic over an 11-year period were reviewed. Of the 450 patients seen, 31 presented with sensorineural hearing loss, hypotonia, and delay in the acquisition of motor milestones. Of these, 4 children were found who did not have an etiologic diagnosis such as Down syndrome or cerebral palsy. Vestibular testing revealed hypoactive labyrinthine function in all 4 of the cases, and careful imaging of the temporal bone showed anomalous development of the cochlea, vestibule, and semicircular canals in 3 of the 4 cases. None of the patients had ataxia, tremor, or significant nystagmus. Over time, the hypotonia improved in all, and none were felt to have cognitive deficits. These cases demonstrate that hypoactive labyrinthine function may be associated with hypotonia that is severe enough to result in delayed acquisition of motor milestones. The patients followed the typical remitting course of "benign congenital hypotonia." The distinguishing clinical feature is the presence of moderate to profound sensorineural hearing loss in all of the patients.

Naegleria fowleri hemorrhagic meningoencephalitis: report of two fatalities in children.

Two cases of hemorrhagic meningoencephalitis secondary to Naegleria fowleri infection confirmed by postmortem analysis are described. The first patient is a 5-year-old boy who presented with a severe headache, neck stiffness, and lethargy. His neurologic examination was significant for somnolence and nuchal rigidity. Cerebrospinal fluid studies and structural neuroimaging were consistent with hemorrhagic meningoencephalitis. Another 5-year-old boy presented to a different institution 2 miles away in the same week with similar complaints. Both patients declined rapidly and expired within 48 hours of admission secondary to transtentorial herniation caused by the mass effect of inflammation, edema, and hemorrhage with displacement of the brain stem. Histopathologic and immunochemistry analysis of brain tissue revealed the presence of Naegleria trophozoites in both cases.

Agenesis of the corpus callosum is associated with feeding difficulties.

Our objective was to characterize the common occurrence of feeding and swallowing disorders noticed by our speech therapy department among patients with agenesis of the corpus callosum. All patients with suspected or presumed agenesis of the corpus callosum undergoing therapy for feeding and/or swallowing disorders, including oral and/or pharyngeal dysphagia and oral-sensory disorder, were identified. Their brain magnetic resonance imaging (MRI) studies and charts were reviewed in detail. Seven patients with striking oral-motor and oral-sensory disorder met the criteria for agenesis of the corpus callosum. Particular difficulties noted include oral-sensory defensiveness in five of these seven patients, oral dysphagia/weakness in all seven patients, and pharyngeal dysphagia with risk of aspiration in three of these seven patients. The oral-motor weakness observed in all of the patients affected the strength and coordination necessary for functional oral-phase swallowing. We conclude that feeding and swallowing disorders are significant in children with agenesis of the corpus callosum. Although the pathophysiologic mechanism is not known, recognition of this phenomenon is important because early detection and intervention can facilitate functional feeding and swallowing patterns earlier in these patients, therefore avoiding the adverse and more severe disorders that can arise when dysphagias and/or oral-sensory disorder persist over extended periods of time.