ASPP2 deficiency causes features of 1q41q42 microdeletion syndrome.

Chromosomal abnormalities are implicated in a substantial number of human developmental syndromes, but for many such disorders little is known about the causative genes. The recently described 1q41q42 microdeletion syndrome is characterized by characteristic dysmorphic features, intellectual disability and brain morphological abnormalities, but the precise genetic basis for these abnormalities remains unknown. Here, our detailed analysis of the genetic abnormalities of 1q41q42 microdeletion cases identified TP53BP2, which encodes apoptosis-stimulating protein of p53 2 (ASPP2), as a candidate gene for brain abnormalities. Consistent with this, Trp53bp2-deficient mice show dilation of lateral ventricles resembling the phenotype of 1q41q42 microdeletion patients. Trp53bp2 deficiency causes 100% neonatal lethality in the C57BL/6 background associated with a high incidence of neural tube defects and a range of developmental abnormalities such as congenital heart defects, coloboma, microphthalmia, urogenital and craniofacial abnormalities. Interestingly, abnormalities show a high degree of overlap with 1q41q42 microdeletion-associated abnormalities. These findings identify TP53BP2 as a strong candidate causative gene for central nervous system (CNS) defects in 1q41q42 microdeletion syndrome, and open new avenues for investigation of the mechanisms underlying CNS abnormalities.

Implications for Australian anaesthetists and proceduralists of a recent court decision regarding informed consent and patient positioning.

This article discusses the medicolegal implications of a recent judgment in relation to a patient who suffered significant morbidity as a result of patient positioning during an operative procedure. The patient developed an unexpected serious complication following surgery, in the context of a preoperative consent that did not cover every potential complication or contingency. The court held that the failure to warn of a particular risk that would have prevented the patient from undergoing a procedure but did not occur will not necessarily result in a finding of negligence in relation to another risk where the harm did occur. This finding is well aligned to current clinical practice and at the same time does not abrogate the practitioner's duty to provide a comprehensive list of possible complications during the consent process for any proceduralist. In the context of a procedure requiring anaesthesia, the importance of communication and understanding between the anaesthetist and proceduralist as to which aspects of the consent process are undertaken by whom, and to ensure the process is done comprehensively, is of great importance and is indirectly highlighted by this recent judgment.

[Evaluation of current assessment tools in early detection of developmental deviations in speech and language in the German preventive paediatric examination (Kindervorsorgeuntersuchung U8)]. / Analyse aktueller Untersuchungsinstrumente zur Früherkennung von Auffälligkeiten in Sprechen und Sprache in der pädiatrischen Vorsorgeuntersuchung U8.

OBJECTIVE: The current analysis is a contribution to application information and quality assurance. It is intended to evaluate and optimise the use of German developmental screening instruments to identify deficits in speech, speech fluency and language during the early paediatric toddler check-up Kindervorsorgeuntersuchung U8 in the age of 43-50 months. METHODS: A systematic literature search was conducted seeking current specific, standardised, norm-referenced assessment tools, particularly those relevant to the early detection of developmental speech and language retardation. They were subsequently evaluated quantitatively and qualitatively with specific regard to 15 psychometric criteria and construction features. RESULTS: 4 assessment tools (ETS 4-8; KiSS; SSV; TSVK-Screen) resulted from literature search. They were subjected to a detailed and rigorous comparative analysis. Quantitatively they met 7-12 of the 15 psychometric criteria whose quality was partly low or demonstrated survey standard to a lesser degree. CONCLUSION: These developmental screening instruments utilised in the paediatric toddler check-up U8 cannot be recommended without reservation with regard to a dichotomous decision (suspected disorder versus no suspected disorder). More qualificatory research focusing specifically on the existing screenings and the construction of new screening tools is required in order to gain vital developmental psychological information of the speech/language status of a child during the preventive paediatric examination U8. Alternatively, it should be evaded to the approach of taking diagnostic language developmental tests.

20p11 deletion in a female child with panhypopituitarism, cleft lip and palate, dysmorphic facial features, global developmental delay and seizure disorder.

Deletions of 20p are rare with the majority of reported cases involving individuals with 20p12 deletions associated with Alagille syndrome. We report on a child with a de novo mosaic 20p11 deletion who presents with panhypopituitarism; hypoplastic pituitary gland and ectopic posterior pituitary gland on MRI of the brain; cleft lip and palate; kyphosis with anterior beaking of L1 and L2 vertebral bodies; pulmonic stenosis; dysmorphic facial features including flat nasal bridge, hypoplastic premaxilla, hypotelorism, preauricular pit, and cupped ears; seizure disorder; variable muscle tone; and global developmental delay. Array comparative genomic hybridization revealed this deletion to be approximately 5.4 Mb in size, containing 35 genes. Previously, an infant with 20p11.22 deletion who had panhypopituitarism, craniofacial, and genital abnormalities was reported, but the precise parameters of that deletion are unavailable. Several other reported cases of 20p11 deletions also have phenotypic overlap with our case. The similarities in clinical features of these patients suggest that the genes at 20p11 have a critical role in development of midline brain structures.

[Evaluation of current assessment tools in the early detection of language retardation in the German preventive paediatric examinations (Kindervorsorgeuntersuchung U7/U7A)]. / Vergleichende Analyse aktueller Untersuchungsinstrumente zur Früherkennung von Sprachentwicklungsretardationen in den pädiatrischen Vorsorgeuntersuchungen U7/U7A.

OBJECTIVE: The current analysis is a contribution to user orientation and quality assurance that seeks to evaluate and optimise the use of German language development assessment tools during early paediatric toddler check-ups ( KINDERVORSORGEUNTERSUCHUNG U7 OR U7A). METHODS: All current, standardised assessment tools, particularly those relevant to early detection of developmental language retardation - normed on German speaking children - were evaluated quantitatively and qualitatively with particular regard to their psychometric criteria (13 criteria) and design features. RESULTS: 8 assessment tools (ELAN; ELFRA-2; Short Form ELFRA-2; FRAKIS; FRAKIS-K; SBE-2-KT; SBE-3-KT; SETK-2) were located in the literature and subjected to a detailed and rigorous comparative analysis. Quantitatively they met 9 to 11 of the 13 psychometric criteria. CONCLUSION: In Germany, there are several assessment tools for dichotomous identification of language retardations on high levels of psychometric criteria that can be used in the above-mentioned preventive paediatric examinations. Nevertheless, the collecting of actual norm scores of representative samples should be kept in mind.

[Phenotyping specific language impairment in kindergarten children]. / Phänotypisierung von Vorschulkindern mit spezifischer Sprachentwicklungsstörung.

OBJECTIVE: For phenotyping specific language impairment (SLI) in kindergarten children in clinical practice and research issues, we need a valid diagnostic method for dichotomous classification (language impaired, normal developing). PATIENTS AND METHODS: 27 kindergarten children belonged to SLI-group, 36 to control-group. The diagnostic accuracy of a composed language test battery was examined in comparison to a clinical assessment. The test battery was composed of 8 subtests of German norm-referenced, standardized tests. RESULTS: Several discriminant analyses showed acceptable levels of accuracy with over 80% for sensitivity and specificity. Using a single subtest the subtest "Phonologisches Arbeitsgedächtnis für Nichtwörter" (phonological short-term memory of nonwords) from Sprachentwicklungstest für drei- bis fünfjährige Kinder (SETK 3-5; Grimm, 2001) showed best classification rates between the two groups using a Cut-off point of -0,39 SD. Means of the 8 used subtests showed significant differences for the two groups. CONCLUSION: The described method for phenotyping SLI can identify children with normal language and those with impaired language with acceptable levels of diagnostic accuracy. When using a norm-referenced standardized test for the assessment of language abilities, it is important to have empirically derived information about diagnostic accuracy (sensitivity, specificity, Cut-off score).

Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.

OBJECTIVE: To systematically review evidence bearing on the management of patients with amyotrophic lateral sclerosis (ALS). METHODS: The authors analyzed studies from 1998 to 2007 to update the 1999 practice parameter. Topics covered in this section include breaking the news, multidisciplinary clinics, symptom management, cognitive and behavioral impairment, communication, and palliative care for patients with ALS. RESULTS: The authors identified 2 Class I studies, 8 Class II studies, and 30 Class III studies in ALS, but many important areas have been little studied. More high-quality, controlled studies of symptomatic therapies and palliative care are needed to guide management and assess outcomes in patients with ALS. RECOMMENDATIONS: Multidisciplinary clinic referral should be considered for managing patients with ALS to optimize health care delivery and prolong survival (Level B) and may be considered to enhance quality of life (Level C). For the treatment of refractory sialorrhea, botulinum toxin B should be considered (Level B) and low-dose radiation therapy to the salivary glands may be considered (Level C). For treatment of pseudobulbar affect, dextromethorphan and quinidine should be considered if approved by the US Food and Drug Administration (Level B). For patients who develop fatigue while taking riluzole, withholding the drug may be considered (Level C). Because many patients with ALS demonstrate cognitive impairment, which in some cases meets criteria for dementia, screening for cognitive and behavioral impairment should be considered in patients with ALS (Level B). Other management strategies all lack strong evidence.

Transcallosal resection of hypothalamic hamartoma for gelastic epilepsy.

INTRODUCTION: Hypothalamic hamartomas (HHs) are commonly associated with severe epilepsy resistant to anticonvulsant therapy. Historically, surgical resection of HHs resulted in considerable morbidity. DISCUSSION: Two series of patients who successfully underwent resection using a transcallosal approach have now been published; we report the first UK experience of this technique in a series of five patients with HHs and gelastic epilepsy resistant to anticonvulsant therapy. Patients were assessed pre- and postoperatively for seizure activity, endocrine function, ophthalmology, and neurocognitive function. Two patients had precocious puberty and all had evidence of developmental delay and behavioral problems. Postoperatively, all children experienced at least a 50% reduction in seizure frequency with abolition of major seizure types; one child remains seizure-free. One child developed a mild postoperative right hemiparesis and one developed transient diabetes insipidus. CONCLUSION: There were no adverse developmental effects of surgery. Transcallosal resection of HHs ameliorates resistant epilepsy syndromes associated with HH.

Glioblastoma of the optic chiasm.

Primary malignant gliomas of the optic nerve and chiasm are rare, and are usually rapidly fatal in adults. We report a 48-year-old woman with a glioblastoma multiforme arising from the optic chiasm. Following radiotherapy, our patient survived nearly 14 months, which is the longest survival reported in patients with this diagnosis. There have only been four other reports of glioblastoma multiforme arising from the optic chiasm as distinct from secondary involvement of the chiasm, in the last 40 years.

Surgical management of spinal tuberculosis in Papua New Guinea.

Two cases of spinal tuberculosis (TB) presented with deteriorating myelopathy despite chemotherapy. Surgery of anterior decompression and fusion was successfully carried out resulting in both the patients ambulating and being continent on discharge. This highlights the importance of early surgery and a multidisciplinary approach to the management of this condition.

Big heads in Port Moresby General Hospital: an audit of hydrocephalus cases seen from 2003 to 2004.

BACKGROUND: Hydrocephalus is a common neurosurgical problem in Port Moresby General Hospital (PMGH) contributing to 27 (24%) of the 114 neurosurgical operations done in 2003 and 2004. During the same period it was responsible for 25% of the cases seen in the neurosurgery clinic. AIM: To prospectively audit and follow up hydrocephalus cases in PMGH over 2 years from January 2003 to December 2004 and ascertain the causes and the outcome of treatment. METHOD: All cases of hydrocephalus seen in 2003 and 2004 were categorized according to cause. The associated findings on ultrasound scan or CT (computed tomography) scan when available were noted. The subsequent progress was documented with and without treatment for at least 6 months. RESULTS: 61 cases of hydrocephalus were seen for surgical opinion. The age ranged from 4 weeks to 56 years. The commonest age group affected was in the first year of life (61% of cases). There were 34 cases (56%) of congenital hydrocephalus followed by 19 (31%) post meningitis and 8 (13%) due to tumour. There was only one case of myelomeningocele with concomitant hydrocephalus. Ventriculoperitoneal (VP) shunts were inserted in 24 cases. 3 shunts were bypasses from the posterior horn to the cisterna magna, making a total of 27 shunt operations. 9 shunts were performed for post-meningitic hydrocephalus, 15 for congenital stenosis and 3 for a posterior fossa tumour. 24 out of the 27 shunt operations were in children aged <9 months. Post-VP-shunt infection of 2 cases reported within 6 weeks of operation gave an infection rate of 7%. There was cerebrospinal fluid (CSF) leak in 2 cases with Pundez-type shunts. There were 2 shunt blocks needing revision. CONCLUSION: Shunt operations can be done in PMGH with good outcomes. The decision-making about surgery can be made on the basis of the enlarging head and the ultrasound findings.

Health related quality of life and psychological outcome in patients treated for craniopharyngioma in childhood.

UNLABELLED: Patients with craniopharyngioma are at risk for many adverse effects related to the tumour's invasive behaviour and its proximity to many vital structures. Profound psychosocial problems, memory impairment, pituitary and hypothalamic dysfunction in addition to the physical handicap of visual loss are frequently recognized sequelae of craniopharyngioma treatment. OBJECTIVES: To examine health related quality of life (QoL) and psychological outcomes of patients treated for craniopharyngioma at the Royal Children's Hospital, Melbourne, between January 1980 and September 2003. PATIENTS: Seven (17.4%) of 46 (26 male) had died. Thirty-nine remained, of whom 30 were contactable. Eighteen of 30 (8 male), mean age 21.2 +/- 6.7 years, agreed to evaluation, of whom 16/18 (88.9%) had three or more pituitary hormone deficiencies, 11/18 had visual impairment and 9/18 obesity. MEASUREMENTS: The Adult GH-Deficient Assessment (AGHDA) and Psychological General Well-Being (PGWB) questionnaires were employed to assess quality of life in patients and age- and sex-matched healthy controls. Additional psychological assessment, including intellectual and academic skills, emotional function, and adaptive behaviour, had been undertaken in 12 patients at a previous time. RESULTS: High levels of physical morbidity and psychological disability were described. The General Health score of patients was significantly worse than for controls on PGWB (p = 0.025), anxiety was higher in those who had surgery alone (p = 0.008) and subjective QoL associated with GHD using AGHDA was lower (p = 0.006). Few craniopharyngioma survivors (18/30) were available for evaluation, demonstrating difficulties in attempts to assess this complex group. The discrepancy between results of objective and subjective measures of QoL is discussed in terms of adaptation to illness, disabilities and changed perception of life fulfilment. CONCLUSIONS: Craniopharyngioma and its treatment result in significant, complex medical, social, psychological and emotional difficulties. The degree of global disability is not reflected in subjective QoL reports for this group, highlighting the need for careful selection of assessment instruments.

Generalized epilepsy in hypothalamic hamartoma: evolution and postoperative resolution.

OBJECTIVE: To better understand the epileptogenesis of symptomatic generalized epilepsy in patients with hypothalamic hamartoma and intractable epilepsy, many of whom experience remission of generalized seizures and slow spike-wave discharges following surgery. METHODS: The authors documented the evolution of symptomatic generalized epilepsy in 12 of 20 children who underwent transcallosal microsurgical hypothalamic hamartoma resection. In seven patients they recorded intraoperative EEG from the hamartoma and simultaneously from the scalp and frontal cortex before, during, and after resection. RESULTS: Gelastic seizures began on average at 6 months of age (range birth to 3 years); tonic seizures began at 6 years (range 2 months to 9 years). Normal EEG were reported in early childhood; thereafter, abnormalities were progressive. Interictal spike-wave was recorded intraoperatively over the scalp and cortex in six patients, but not from the hypothalamic hamartoma. Hamartoma resection had no immediate effect on cortical spike-wave, but waking spike-wave was absent in seven patients on subsequent postoperative EEG. Tonic seizures ceased in 11 of 12 patients, but 6 of these had postoperative generalized seizures that resolved over 1 to 6 months. CONCLUSION: Gelastic seizures in hypothalamic hamartoma arise from the hamartoma itself; the interictal spike-wave does not. The evolution of EEG abnormalities, the development of generalized seizures years after onset of gelastic seizures, and the postoperative running down of interictal spike-wave and generalized seizures in these patients may reflect secondary epileptogenesis.

James IV Lecture. Epilepsy surgery, hypothalamic hamartomas and the quest for a cure.

This presentation reviews the epidemiology of epilepsy, the evolution of epilepsy surgery, the selection of cases for surgery, the range and results of epilepsy surgery, and the future development of this burgeoning field. Hypothalamic hamartoma (HH) is a rare developmental lesion which causes intractable gelastic epilepsy which is refractory to medical therapy. Hypothalamic hamartoma presents a formidable surgical challenge. The application of a midline transcallosal interforniceal approach to resect the HH from within the third ventricle, in a series of 28 patients, is presented. This has produced excellent results with minimal morbidity. This surgery is placed within the context of epilepsy surgery in general.

Awake craniotomy in an adolescent.

We present our approach to management of awake craniotomy for epilepsy surgery for an adolescent. The importance of patient selection and preoperative preparation is stressed. Anaesthetic management included regional scalp block and preincisional surgical infiltration of local anaesthetic and light sedation with propofol, fentanyl and midazolam. The patient remained responsive to voice for all but a small part of the procedure.

Evaluation and treatment of galactorrhea.

Galactorrhea, or inappropriate lactation, is a relatively common problem that occurs in approximately 20 to 25 percent of women. Lactation requires the presence of estrogen, progesterone and, most importantly, prolactin. Stress, suckling, sleep, sexual intercourse and medications may increase prolactin levels, whereas dopamine inhibits its release. The differential diagnosis of galactorrhea includes pituitary adenomas, neurologic disorders, hypothyroidism, numerous medications, breast stimulation, chest wall irritation and physiologic causes. The evaluation includes a thorough history and physical examination, as well as selected laboratory and imaging studies to rule out secondary causes such as an intracranial mass or a tumor. Diagnostic studies include a pregnancy test, a prolactin level, renal and thyroid function tests and, if indicated, magnetic resonance imaging of the brain. Treatment options for prolactinomas include observation, dopamine agonists, surgery and radiation therapy, depending on tumor size and associated symptoms. Fortunately, the prognosis for patients with prolactinomas is good: most prolactinomas remain stable or regress. In pregnant women, prolactinomas must be observed closely because the lesions may greatly increase in size.

Frontoethmoidal encephaloceles: reconstruction and refinements.

Frontoethmoidal encephaloceles are herniations of the intracranial contents through a defect in the skull at the junction of the frontal and ethmoidal bones. They are generally classified as nasofrontal, nasoethmoidal, and naso-orbital, although there may be some overlap or multiplicity. The records of 35 patients treated for frontoethmoidal encephaloceles were examined. Of these, 12 cases with complete and accurate medical records were evaluated in detail. The successful correction of frontoethmoidal encephaloceles was shown to depend on the following: a detailed understanding of the pathological anatomy (such as interorbital hypertelorism rather than true orbital hypertelorism and the presence of secondary trigonocephaly), careful planning of the bone movements to correct these deformities, and attention to detail regarding the placement of scars, positioning of the medial canthi, and the nasal reconstruction. Avoiding the "long-nose" deformity often seen after repair should be a priority. In general, the authors recommend a one-stage repair with both a transcranial and external approach.

Transcallosal resection of hypothalamic hamartomas, with control of seizures, in children with gelastic epilepsy.

OBJECTIVE: Hypothalamic hamartomas (HHs) are associated with precocious puberty and gelastic epilepsy; the seizures are often refractory to antiepileptic medications and associated with delayed development and disturbed behavior. The current opinion is that surgery to treat intrahypothalamic lesions is formidable and that complete excision is not technically achievable. We report our experience with a transcallosal approach to the resection of HHs. METHODS: Five children (age, 4-13 yr) with intractable epilepsy and HHs underwent preoperative clinical, electroencephalographic, and imaging evaluations. Two patients experienced only gelastic seizures, and three patients experienced mixed seizure disorders with drop attacks; all experienced multiple daily seizures. Patients were evaluated with respect to seizures, cognition, behavior, and endocrine status 9 to 37 months (mean, 24 mo) after surgery. The HHs were approached via a transcallosal-interforniceal route to the third ventricle and were resected using a microsurgical technique and frameless stereotaxy. RESULTS: Complete or nearly complete (>95%) excision of the HHs was achieved for all patients, with no adverse neurological, psychological, or visual sequelae. Two patients experienced mild transient diabetes insipidus after surgery. Two patients developed appetite stimulation, but no other significant endocrinological sequelae were observed. Three patients are seizure-free and two patients have experienced only occasional, brief, mild gelastic seizures after surgery, all with reduced antiepileptic medications. On the basis of parental reports and our own subjective observations, the children also exhibited marked improvements in behavior, school performance, and quality of life. CONCLUSION: Complete or nearly complete resection of HHs can be safely achieved via a transcallosal approach, with the possibility of seizure freedom and neurobehavioral improvements.