Anna Illner

TM4SF20 Ancestral Deletion and Susceptibility to a Pediatric Disorder of Early Language Delay and Cerebral White Matter Hyperintensities

White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ~70% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles.

No significant improvement in the rate of accurate ventricular catheter location using ultrasound-guided CSF shunt insertion: a prospective, controlled study by the Hydrocephalus Clinical Research Network

OBJECT Cerebrospinal fluid shunt ventricular catheters inserted into the frontal horn or trigone are associated with prolonged shunt survival. Developing surgical techniques for accurate catheter insertion could, therefore, be beneficial to patients. This study was conducted to determine if the rate of accurate catheter location with intraoperative ultrasound guidance could exceed 80%. METHODS The authors conducted a prospective, multicenter study of children (< 18 years) requiring first-time treatment for hydrocephalus with a ventriculoperitoneal shunt. Using intraoperative ultrasound, surgeons were required to target the frontal horn or trigone for catheter tip placement. An intraoperative ultrasound image was obtained at the time of catheter insertion. Ventricular catheter location, the primary outcome measure, was determined from the first postoperative image. A control group of patients treated by nonultrasound surgeons (conventional surgeons) were enrolled using the same study criteria. Conventional shunt surgeons also agreed to target the frontal horn or trigone for all catheter insertions. Patients were triaged to participating surgeons based on call schedules at each center. A pediatric neuroradiologist blinded to method of insertion, center, and surgeon determined ventricular catheter tip location. RESULTS Eleven surgeons enrolled as ultrasound surgeons and 6 as conventional surgeons. Between February 2009 and February 2010, 121 patients were enrolled at 4 Hydrocephalus Clinical Research Network centers. Experienced ultrasound surgeons (> 15 cases prior to study) operated on 67 patients; conventional surgeons operated on 52 patients. Experienced ultrasound surgeons achieved accurate catheter location in 39 (59%) of 66 patients, 95% CI (46%-71%). Intraoperative ultrasound images were compared with postoperative scans. In 32.7% of cases, the catheter tip moved from an accurate location on the intraoperative ultrasound image to an inaccurate location on the postoperative study. This was the most significant factor affecting accuracy. In comparison, conventional surgeons achieved accurate location in 24 (49.0%) of 49 cases (95% CI [34%-64%]). The shunt survival rate at 1 year was 70.8% in the experienced ultrasound group and 66.9% in the conventional group (p = 0.66). Ultrasound surgeons had more catheters surrounded by CSF (30.8% vs 6.1%, p = 0.0012) and away from the choroid plexus (72.3% vs 58.3%, p = 0.12), and fewer catheters in the brain (3% vs 22.4%, p = 0.0011) and crossing the midline (4.5% vs 34.7%, p < 0.001), but they had a higher proportion of postoperative pseudomeningocele (10.1% vs 3.8%, p = 0.30), wound dehiscence (5.8% vs 0%, p = 0.13), CSF leak (10.1% vs 1.9%, p = 0.14), and shunt infection (11.6% vs 5.8%, p = 0.35). CONCLUSIONS Ultrasound-guided shunt insertion as performed in this study was unable to consistently place catheters into the frontal horn or trigone. The technique is safe and achieves outcomes similar to other conventional shunt insertion techniques. Further efforts to improve accurate catheter location should focus on prevention of catheter migration that occurs between intraoperative placement and postoperative imaging. Clinical trial registration no.: NCT01007786 ( ClinicalTrials.gov ).

Diagnosing cranial fasciitis based on distinguishing radiological features : Report of 4 cases

Primary skull lesions, albeit rare in the pediatric population, have been well described and classified. These lesions are usually benign and commonly present as a painless mass. The most common lesions are epidermoid, dermoid, and Langerhans cell histiocytosis. Cranial fasciitis, encountered less frequently, is usually not considered in this differential diagnosis. Given such few cases reported, it is commonly misdiagnosed preoperatively. The authors retrospectively reviewed data obtained in 4 patients with cranial fasciitis in whom the diagnosis was based on histopathological findings. In 2 patients the onset of the lesion was spontaneous. One patient had a lesion 4 months following a vacuum extraction and subsequent cephalohematoma formation. One patient developed a lesion following a previous craniectomy. Presentation, imaging studies, and histopathological findings were all reviewed and analyzed. All patients presented with a firm nontender mass. Radiological features included a lytic bone lesion with a mildly sclerotic margin, T1 isodensity, T2 heterogeneous hyperdensity, and heterogeneous enhancement. The enhancing portion was not bright on T2-weighted MR images, likely representing the fibrous component; the nonenhancing portion was bright on T2-weighted images, likely representing the myxoid matrix. Histopathological examination revealed proliferating fibroblasts in a myxoid matrix. Cranial fasciitis is a benign, painless but rapidly growing lesion of the skull mainly limited to the pediatric population. It is histologically similar to nodular fasciitis, a fibroblastic proliferation of varying size. These lesions are often related to trauma but can also be insidious or can develop at a prior craniectomy site. The appropriate clinical picture and distinguishing radiographic features may help to differentiate cranial fasciitis from other lesions of the skull allowing for earlier intervention.

Primary Lesions of the Root of the Tongue

In the assessment of the head and neck, differential diagnoses can be formulated by subdividing the anatomy into spaces along identifiable and logical boundaries. In the oral cavity, the root of the tongue is notably unlike adjacent regions due to structural and tissue-specific differences. The majority of lesions found in the root of the tongue are congenital and benign, representing ectopic tissues of thyroidal, epidermal, dermal, foregut, venous, and lymphatic origin. A greater number of acquired neoplasms and infections are seen in the adjacent sublingual, submandibular, and oropharyngeal regions of the base of the tongue, presumably due to their greater exposure to mucosal surfaces and lymphatic tissues. Many lesions of the root of the tongue have clinical and imaging characteristics that can help narrow the differential diagnosis, and surgical management may be required. Familiarity with these lesions and how they differ from other lesions of the oral cavity and oropharynx can significantly aid in their diagnosis and treatment.

Infected lumbar dermoid cyst mimicking intramedullary spinal cord tumor: Observations and outcomes.

We report two unusual cases of a 17-month-old boy with a previously undiagnosed lumbar dermal sinus tract terminating in an intradural dermoid cyst and holocord edema or syrinx, presenting with paraparesis and sphincter dysfunction secondary to an intramedullary abscess and a 26-month-old boy with a previously undiagnosed lumbar dermal sinus tract terminating in an infected dermoid cyst and intramedullary abscess, presenting with recurrent episodes of meningitis and hydrocephalus. Pre-operative magnetic resonance imaging (MRI) studies in these patients were initially confused for an intramedullary spinal cord tumor; however, the presence of an associated dermal sinus tract made this diagnosis of neoplasm less likely. Total excision of the dermal sinus tract, debulking of the dermoid cyst and drainage of the intramedullary abscess through an L1-L5 osteoplastic laminoplasty and midline myelotomy, followed by long-term antibiotic therapy resulted in a good functional recovery. Post-operative MRI of the spine showed removal of the dermoid cyst, decreased inflammatory granulation tissue and resolution of the holocord edema or syrinx. We also performed a literature review to determine the cumulative experience of management of intramedullary abscess in this rare clinical setting.

Posterior reversible encephalopathy syndrome during posterior fossa tumor resection in a child

Posterior reversible encephalopathy syndrome (PRES) has been described in the setting of malignant hypertension, renal disease, eclampsia, and immunosuppression. In addition, a single case of intraoperative (posterior fossa craniotomy) PRES has been reported; however, this case occurred in an adult. The authors present a clinically and radiographically documented case of intraoperative PRES complicating the resection of a posterior fossa tumor in a 6-year-old child. During tumor resection, untoward force was used to circumferentially dissect the tumor, and excessive manipulation of the brainstem led to severe hypertension for a 10-minute period. An immediate postoperative MR image was obtained to rule out residual tumor, but instead the image showed findings consistent with PRES. Moreover, the patients postoperative clinical findings were consistent with PRES. Aggressive postoperative management of blood pressure and the institution of anticonvulsant therapy were undertaken. The patient made a good recovery; however, he required a temporary tracheostomy and tube feedings for prolonged lower cranial nerve dysfunction. Posterior reversible encephalopathy syndrome can occur as a result of severe hypertension during surgery, even among young children. With prompt treatment, the patient in the featured case experienced significant clinical and radiographic recovery.

Ventricular catheter entry site and not catheter tip location predicts shunt survival: a secondary analysis of 3 large pediatric hydrocephalus studies

OBJECTIVE Accurate placement of ventricular catheters may result in prolonged shunt survival, but the best target for the hole-bearing segment of the catheter has not been rigorously defined. The goal of the study was to define a target within the ventricle with the lowest risk of shunt failure. METHODS Five catheter placement variables (ventricular catheter tip location, ventricular catheter tip environment, relationship to choroid plexus, catheter tip holes within ventricle, and crosses midline) were defined, assessed for interobserver agreement, and evaluated for their effect on shunt survival in univariate and multivariate analyses. De-identified subjects from the Shunt Design Trial, the Endoscopic Shunt Insertion Trial, and a Hydrocephalus Clinical Research Network study on ultrasound-guided catheter placement were combined (n = 858 subjects, all first-time shunt insertions, all patients < 18 years old). The first postoperative brain imaging study was used to determine ventricular catheter placement for each of the catheter placement variables. RESULTS Ventricular catheter tip location, environment, catheter tip holes within the ventricle, and crosses midline all achieved sufficient interobserver agreement (κ > 0.60). In the univariate survival analysis, however, only ventricular catheter tip location was useful in distinguishing a target within the ventricle with a survival advantage (frontal horn; log-rank, p = 0.0015). None of the other catheter placement variables yielded a significant survival advantage unless they were compared with catheter tips completely not in the ventricle. Cox regression analysis was performed, examining ventricular catheter tip location with age, etiology, surgeon, decade of surgery, and catheter entry site (anterior vs posterior). Only age (p < 0.001) and entry site (p = 0.005) were associated with shunt survival; ventricular catheter tip location was not (p = 0.37). Anterior entry site lowered the risk of shunt failure compared with posterior entry site by approximately one-third (HR 0.65, 95% CI 0.51-0.83). CONCLUSIONS This analysis failed to identify an ideal target within the ventricle for the ventricular catheter tip. Unexpectedly, the choice of an anterior versus posterior catheter entry site was more important in determining shunt survival than the location of the ventricular catheter tip within the ventricle. Entry site may represent a modifiable risk factor for shunt failure, but, due to inherent limitations in study design and previous clinical research on entry site, a randomized controlled trial is necessary before treatment recommendations can be made.

Hyperperfusion on Magnetic Resonance Imaging in Acute Chemotherapy-Related Leukoencephalopathy

Acute chemotherapy-related leukoencephalopathy can present similar to acute stroke with symptoms including aphasia, dysarthria, and hemiplegia. Differentiation based on clinical appearance is challenging, and physicians must distinguish between the 2 conditions rapidly to institute appropriate therapies. An 8-year-old male with acute lymphoblastic leukemia receiving chemotherapy, including intrathecal methotrexate, presented to our emergency center with 2 hours of expressive aphasia and flaccid right hemiplegia. Emergent magnetic resonance imaging (MRI) was obtained, demonstrating diffusion restriction within bilateral corona radiata and centrum semiovale. Magnetic resonance perfusion revealed mildly increased perfusion, a finding inconsistent with ischemic stroke and previously unreported in acute chemotherapy-related leukoencephalopathy without necrosis. This increased perfusion conclusively eliminated stroke from the clinical differential. Magnetic resonance perfusion imaging proved valuable to rapidly distinguish acute chemotherapy-related leukoencephalopathy from ischemia, and the evaluation of perfusion alterations in this disorder may provide further insight into the pathophysiology of this entity.

A child with Friedreich's ataxia and epilepsy.

Epilepsy in Friedreichs ataxia is rare. We describe a 9-year-old boy with Friedreichs ataxia who had onset of symptoms in the second year of life and developed a generalized epilepsy at age 5 years. On cerebral magnetic resonance imaging, he has a subependymal gray-matter heterotopia. We suggest that his gray-matter heterotopia might be related to his diagnosis of Friedreichs ataxia and that his early onset of symptoms might be related to the length of his guanine - adenine - Adenine (GAA) triplet repeat expansion. ( J Child Neurol 2005;20:248—250).

Spinal Column Tumors

Spinal column tumors in the growing spine are rare and diverse lesions. Most present with pain with or without neurological deficit. When evaluating a child with persistent back pain, tumor should be considered in the differential diagnosis and investigated. When identified, common goals of treatment are removal of the lesion, preservation of neurological function, and maintenance of spinal column instability.