Deborah Alcorn

REPORT OF THE DIAGNOSTIC-CRITERIA COMMITTEE OF THE NATIONAL-TUBEROUS-SCLEROSIS-ASSOCIATION

Special Article Criteria: Tuberous Sclerosis Complex Diagnostic Editorial Note: This issue of the Journal of Child Neu- carries the consensus report of the the Diagnostic Criteria Committee of the National Tuberous Sclerosis Associa- tion. Reliable diagnostic criteria for tuberous sclerosis complex are important for a number of reasons. If we are to identify specific gene markers for tuberous sclerosis, it is essential that we accurately identify those patients with definite tuberous sclerosis and not include in our research individuals whose diagnosis is open to question. Debates about the validity of a gene marker should not fall on the issue of the accuracy of the diagnosis of tuberous sclerosis in those patients in whom a marker is first identified. Likewise, clinically useful laboratory tests for tuberous sclerosis complex based on these markers can not be developed rology without a carefully screened homogeneous population of patients with tuberous sclerosis. Eventually these same concerns will arise in conjunction with therapeutic issues. Thus, it is only through the use of a well-defined patient population that we can hope to develop the tools for the diagnosis, evaluation, therapy related to tuberous sclerosis. and The National Tuberous Sclerosis Association now sponsors and supports tuberous sclerosis clinics in 11 medical centers around the country. Tuberous sclerosis clinics are ideal sites at which to collect patients with tuberous sclerosis and investigate the combinations and constellations of stigmata of tuberous scle- rosis. The clinics provide an ideal opportunity to test many of the assumptions in the tuberous sclerosis diagnostic criteria, then to improve the criteria. The availability of large numbers of tuber- Report of the Diagnostic sclerosis patients and a uniform system of diagnosis and clas- sification should in turn promote research and eventually therapy. Thus, the development of uniform diagnostic criteria for tuberous sclerosis promotes better use of the tuberous sclerosis clinics for research. Any attempt to arrive at a consensus stimulates debate about the validity and veracity of cherished assumptions which have not before been submitted to critical scrutiny. Debate often draws attention to the emperor’s new clothes and recognition of his true form. Over the last 12 months, committee members real- ous ized that we do not have a consensus on what tuberous sclerosis really looks like. The disease is extremely variable from patient to patient, and there are few data on the general incidence of many of the stigmata of tuberous sclerosis. We are unsure how many of the phenomena are necessary or sufficient for the diagnosis of tu- berous sclerosis. This debate forced the committee to make some assumptions about the specificity of lesions, assumptions which will need to be tested during the next decade. Are facial angiofi- bromas, subependymal giant cell astrocytomas, or ungual fibro- mas pathognomonic of tuberous sclerosis? Hypomelanotic macules, cysts, and seizures seem to be less reliable witnesses of tuberous sclerosis than the former group. The committee intends these criteria to be adaptable, susceptible to modification as data are collected by empiricism. It is our fervent wish that the criteria for the diagnosis of tuberous sclerosis will metamorphose into a stable support for molecular diagnosis and treatment of tuberous sclerosis complex.-Robert M. Shuman, MD Criteria Committee of the National Tuberous Sclerosis Association E.S. Roach, MD; Moyra Smith, MD, PhD; Peter Huttenlocher, MD; Mohandes Bhat, DDS; Deborah Alcorn, MD; Louise Hawley, PhD uberous sclerosis complex is a genetic disor- Tder with protean clinical manifestations. Since there is presently no reliable molecular marker for tuberous sclerosis, we must rely on clinical diag- nostic criteria, especially for patients with atypical features or subtle forms of the disorder. Accurate di- agnosis underpins the clinical approach to individ- ual tuberous sclerosis patients, influences the From the University of Texas Southwestern Medical School (Dr Roach), Dallas, TX, the University of California (Dr Smith), Irvine, CA, the University of Chicago (Dr Huttenlocher), Chicago, IL, the National Institute of Dental Research (Dr Bhat), Bethesda, MD, Stanford University (Dr Alcorn), Stanford, CA, and the Uni- versity of Minnesota (Dr Hawley), Minneapolis, MN. Address correspondence to Dr E.S. Roach, University of Texas Southwestern Medical School, Department of 5323 Harry Hines Blvd, Dallas, TX 75235. Neurology, estimated recurrence risk figures provided to fami- lies in the course of genetic counseling, and affects the validity of the results of clinical and basic re- search on tuberous sclerosis. The need for accurate diagnosis in research is critical; even if a definite di- agnosis can not be established, it would be helpful to estimate the probability that an individual family member is affected. Unfortunately, there are few population-based studies of the various clinical fea- tures of tuberous sclerosis, and it is not always pos- sible to establish a firm diagnosis on clinical grounds alone. A definitive diagnosis of tuberous sclerosis is easy when many features of the disorder are present. However, fined to clinical since findings, present day criteria it is are con- impossible to absolutely Downloaded from jcn.sagepub.com at UNIV CALIFORNIA IRVINE on March 23, 2015

Wernicke Encephalopathy and Beriberi During Total Parenteral Nutrition Attributable to Multivitamin Infusion Shortage

Objective. Wernicke encephalopathy (WE) is an acute neurologic disorder characterized by a triad of ophthalmoplegia, ataxia, and mental confusion. WE is attributable to thiamine (vitamin B1) deficiency. Beriberi is the systemic counterpart of thiamine deficiency and often manifests in cardiovascular collapse. WE is usually associated with alcoholism and malnutrition. It has also been seen in people with gastrointestinal diseases with malabsorption. Patients who have received total parenteral nutrition (TPN) without proper replacement of thiamine have also developed WE. Since November 1996, there has been a shortage of multivitamin infusion (MVI). Many patients who were on chronic TPN with MVI ceased to receive the MVI and were converted to an oral form of the multivitamin. As a result, there have been several reports of children and adults on TPN who have developed WE as a result of thiamine deficiency. With this case report, we bring to attention the association of the MVI shortage and WE. Early diagnosis of WE is important, because if it is treated with thiamine in the acute stages, the neurologic and cardiovascular abnormalities can be reversed. Case Report. We report a 20-year-old female patient with Crohns disease who developed WE as a result of thiamine deficiency. She had Crohns disease since age 9 years and was on chronic TPN. Two months before admission, MVI was discontinued in the TPN because of the shortage of its supply. An oral multivitamin tablet was substituted instead. She was admitted to the hospital for persistent vomiting. In the hospital, she continued to receive TPN without MVI, but continued taking an oral multivitamin preparation. Two weeks after admission, she developed signs of WE including diplopia, ophthalmoplegia, nystagmus, and memory disturbance. She also developed hypotension that was thought to be caused by beriberi. She was treated with 50 mg of intravenous thiamine. Within hours of the intravenous thiamine, her hypotension resolved. The day after the infusion, she no longer complained of diplopia, and her ophthalmoplegia had improved dramatically. Magnetic resonance imaging showed several areas of abnormally high signal on T2-weighted images in the brainstem, thalamus, and mamillary bodies. The topographic distribution of these changes was typical of WE. After 2 months, her mental status and neurologic status had recovered completely. Conclusion. WE and thiamine deficiency should be considered in all patients with malabsorption, malnutrition, and malignancies. WE from thiamine deficiency can occur as a result of cessation of MVI in the TPN infusion. Even if an oral multivitamin preparation is given instead of MVI, patients with malabsorption may not absorb thiamine adequately. Prompt diagnosis of WE is important because it is potentially fatal and readily treatable with thiamine supplementation. Early recognition of WE may be more difficult in children, because the classic triad of symptoms may not develop fully. Magnetic resonance imaging may be useful in these cases to confirm the diagnosis of WE. Because the shortage of MVI is expected to be a long-term, there are likely to be more cases of WE in the pediatric population of TPN-dependent children. Because there is no shortage of intravenous thiamine, it should be administered with TPN even if MVI is not available.

Partial rectus muscle–augmented transpositions in abduction deficiency

PURPOSE Lateral posterior fixation sutures increase the effect of full rectus extraocular muscle transpositions. Partial rectus muscle transposition may be indicated to minimize the risk of anterior ischemia when multiple rectus muscles require surgery to achieve ocular alignment. PURPOSE To report a modification of full vertical rectus muscle transposition with lateral posterior fixation sutures for use in patients at risk for anterior segment ischemia. METHODS Ten cases of unilateral split rectus muscle transposition augmented with lateral posterior fixation sutures were analyzed. Five patients had Duanes syndrome with esotropia in primary position, and five patients had sixth-nerve palsy. RESULTS Seven patients had a history of ipsilateral rectus muscle surgery, and three patients underwent simultaneous surgery on ipsilateral horizontal rectus muscles. In Duanes syndrome patients, the preoperative angle of deviation at distance was 15.8 +/- 5.8 prism diopters (PD) (range, 10 to 25) compared with 3.2 +/- 4.4 PD (range, 0 to 8) postoperatively (P =.005). In patients with sixth-nerve palsy, the preoperative angle of deviation at distance was 45.2 +/- 23.9 PD (range, 16 to 80) compared with -5 +/- 14.1 PD (range, -30 to 5) postoperatively (P =.004). Postoperative binocular single visual fields enlarged in seven of seven patients. CONCLUSION Partial rectus muscle-augmented transposition allows surgery on multiple ipsilateral rectus muscles in (1) Duanes syndrome patients with esotropia, marked cocontraction, and/or limitation to both horizontal rotations and in (2) sixth-nerve palsy patients with ipsilateral medial rectus tightness. Augmented partial rectus muscle transpositions improve ocular alignment and may enlarge binocular single fields in patients with persistent deviations despite previous muscle surgery.

Churg-Strauss syndrome in a child: retina and optic nerve findings

Allergic granulomatosis and angiitis, also known as Churg-Strauss syndrome (CSS) is predominantly a disease of adults.1 Ocular involvement is rare.2 We describe a case of CSS in a child that resulted in bilateral optic neuropathy with vasculitis and multiple branch retinal artery occlusions affecting the macula. A 10 year old African-American girl developed sudden painless loss of vision in both eyes over 2 days. The child was an inpatient admitted for examination of a multisystem disorder, affecting her pulmonary, gastrointestinal, muscular, and renal systems. On examination the best corrected vision was hand movement in both eyes. Confrontation visual fields were full bilaterally. Pupils were normal, without an afferent papillary defect. Anterior segment examination was completely …

Sclerocornea associated with the chromosome 22q11.2 deletion syndrome

Reported ocular findings in the 22q11.2 deletion syndrome (which encompasses the phenotypes of DiGeorge, velocardiofacial, and Takao (conotruncal‐anomaly‐face) syndromes) have included posterior embryotoxon (prominent, anteriorly displaced Schwalbes line at the corneal limbus or edge), retinal vascular tortuosity, eyelid hooding, strabismus, and astigmatism. We present seven 22q11.2 patients from multiple centers with sclerocornea, an eye finding previously unreported in the literature. Four boys and three girls were identified with sclerocornea, systemic DGS/VCFS findings, and fluorescence in situ hybridization (FISH)‐confirmed microdeletion at chromosome 22q11.2. FISH diagnosis was perinatal in six patients but at 2 years of age in one child. Sclerocornea was bilateral in five patients. Findings included descemetocele (five eyes), microophthalmos (one eye), iridocorneal adhesions (one bilateral case), and severe anterior segment dysgenesis (one eye). Two patients underwent bilateral corneal transplantation; another two were scheduled for possible unilateral transplant. Sclerocornea is a static congenital condition in which the cornea is opaque and vascularized and resembles the sclera. The novel finding of sclerocornea suggests that a genetic locus at 22q11.2 may be involved in anterior segment embryogenesis. In most of our patients, the diagnostic process was underway, but in one patient 22q11.2 deletion was not suspected until after the child had already been undergoing treatment for sclerocornea for 2 years. Sclerocornea should be added to the clinical manifestations of the 22q11.2 deletion syndrome. Ophthalmologists diagnosing sclerocornea in children with systemic findings suggestive of 22q11.2 deletion should ensure appropriate genetic referral.

Stereopsis Testing in a Preschool Vision Screening Program

We conducted a preschool vision screening study using stereopsis testing with the Random Dot E and Lang stereotests as a complement to visual acuity measurement. Over 6000 children were screened. Stereopsis testing at a threshold of 600 seconds of arc was cognitively easier for the children than visual acuity measurement. At this threshold there was no effect on reducing the rate of visual acuity overreferrals, but ten children with abnormal binocular vision were detected who were not referred by visual acuity criteria. Though a large number of children passed only one of the two stereotests, there was no significant difference in their degree of difficulty. Stereopsis testing with these two stereotests may be a useful adjunct to preschool vision screening programs though further studies are required.

Diffuse unilateral hemorrhagic retinopathy associated with accidental perinatal strangulation. A clinicopathologic report.

Objective To report an unusual case of diffuse retinal hemorrhage associated with strangulation in a neonate with a tightly wrapped nuchal cord around his neck at birth who was noted to have eyelid and subconjunctival petechial hemorrhages upon delivery. Methods Clinical diagnostic examination as well as postmortem gross and histopathologic examination of ocular and central nervous system structures was performed. Results Funduscopic and gross pathologic examination of the eyes revealed extensive unilateral retinal hemorrhage of the right eye only. This was corroborated by histopathologic studies, which revealed unilateral diffuse hemorrhage throughout all nuclear layers of the retina with a particularly dense nerve fiber layer and sub-internal limiting membrane hemorrhage in the macula along with extraocular muscle and episcleral hemorrhage. Clinical, gross, and microscopic examination also revealed multiple areas of hemorrhage involving the right side of the brain and throughout the cerebellum. Conclusion Although retinal findings in nonaccidental trauma are common, accidental strangulation retinopathy in neonates is a rare occurrence. To the authors’ knowledge, this case is the only documented histopathologic study of hemorrhagic retinopathy associated with strangulation in the literature.

Visual loss caused by pseudotumor cerebri in an infant on peritoneal dialysis

Abstract Infants with chronic renal insufficiency have multiple risk factors for developing pseudotumor cerebri (PTC) and are at particular risk for being diagnosed with PTC late, because of their inability to express symptoms. We describe a 13-month-old infant dependent on peritoneal dialysis, without evidence of central nervous system infection or inflammation, who developed acute vision loss secondary to PTC. Signs of PTC in infants include torticollis, inattentiveness, inability to track, facial paresis, or new-onset strabismus. Physicians responsible for the care of children with renal failure should be aware of the potential for PTC, as the diagnosis should be made as early as possible to prevent permanent visual loss.

Retinal Glioneuronal Hamartoma in Neurofibromatosis Type 1

Report of a Case. Our patient was born at term with buphthalmos and proptosis of her right eye, accompanied by corneal clouding and increased tearing. She was subsequently noted to have right sphenoid wing dysplasia, multiple cutaneous plexiform neuromas of the right eyelids and face (fifth nerve distribution), right hemispheric dysplastic polymicrogyria, and a seizure disorder. She was diagnosed as having NF1. The left eye was within normal limits. The patient received a Baerveldt glaucoma drainage implant at age 5.5 months. At age 8 months, a dilated fundus examination revealed temporal retinal whitening and posterior retinal hemorrhages, which were initially attributed to a retinal vein occlusion. Four months later, the patient was diagnosed clinically as having a CHRRPE (Figure 1). Enlargement of the retinal tumor was noted over the following 8 months, accompanied by the development of a vitreous hemorrhage, tractional retinal detachment, and proliferative vitreoretinopathy. At age 20 months, the right eye was enucleated owing to it being blind and painful with a fixed pupil and corneal haze. Postoperatively, she was more comfortable, no longer photophobic, and without tearing. Gross pathologic examination revealed a buphthalmic eye with a Baerveldt glaucoma drainage implant on the superonasal sclera. On oblique sectioning, the cornea was clear but thinned. The anterior chamber was filled with a tan, milky fluid. The pupil was widely dilated and the iridocorneal angle was closed by peripheral anterior synechiae. The lens and uveal tract were unremarkable. There was a funnel-shaped retinal detachment. Microscopic examination revealed an absent Bowman layer, which was replaced by an area of thin cellular fibrosis. A membrane composed of corneal endothelial cells was present over the surface of the severely contracted iris and ciliary body. The lens showed cataract formation with anterior calcific degeneration and posterior migration of the lens epithelium. The uvea was thickened by a diffuse neurofibroma typical for eyes involved with NF1. The predominant spindle cells within the neurofibroma reacted positively with S-100 protein and microtubule-associated protein 2 but were negative for glial fibrillary acidic protein, CD56 (neural cell adhesion molecule—a marker of neurons, astrocytes, and nonmyelinating Schwann cells), neurofilament, and Ki-67. Scattered clusters of larger neuronal cells with comparatively more abundant cytoplasm and large round nuclei with prominent nucleoli were also present and were positive for synaptophysin, microtubuleassociated protein 2, and neurofilament (Figure 2). The detached retina was displaced anteriorly and centrally by a fibrovascular proliferation in the vitreous. A retinal tumor replaced a broad area of the inner retina

Prenatal treatment of ornithine transcarbamylase deficiency

PURPOSE OF STUDY Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul®) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor. METHODS USED Two heterozygote OTCD mothers carrying male fetuses with a prenatal diagnosis of OTCD received intravenous Ammonul, arginine and dextrose-containing fluids shortly before birth. Maintenance Ammonul and arginine infusions and high-caloric enteral nutrition were started immediately after birth. Ammonul metabolites were measured in umbilical cord blood and the blood of the newborn immediately after delivery. Serial ammonia and biochemical analyses were performed following delivery. SUMMARY OF RESULTS Therapeutic concentrations of Ammonul metabolites were detected in umbilical cord and neonatal blood samples. Plasma ammonia and glutamine levels in the postnatal period were within the normal range. Peak ammonia levels in the first 24-48h were 53mcmol/l and 62mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3months and 5months. The patients show normal development at ages 7 and 3years. CONCLUSION Prenatal treatment of mothers who harbor severe OTCD mutations and carry affected male fetuses with intravenous Ammonul and arginine, followed by immediate institution of maintenance infusions after delivery, results in therapeutic levels of benzoate and phenylacetate in the newborn at delivery and, in conjunction with high-caloric enteral nutrition, prevents acute hyperammonemia and neurological decompensation. Following initial medical management, early liver transplantation may improve developmental outcome.