Spleen phenotype in autosomal dominant polycystic kidney disease.

AIM: To evaluate splenic phenotype in autosomal dominant polycystic kidney disease (ADPKD) including presence of cysts and splenomegaly to determine if these are ADPKD related or represent unrelated incidental findings. MATERIALS AND METHODS: The axial/coronal T2-weighted images of ADPKD patients (n=215) and age/gender-matched controls (n=215) were evaluated for the presence of T2-bright splenic lesions by three blinded observers. Spleen volume (SV) was evaluated in the context of clinical and imaging features as well as results of gene testing for PKD1 and PKD2 mutations. RESULTS: T2-bright splenic lesions were found in 16 of 215 (7%) ADPKD patients compared to 11 of 215 (5%) control patients (p=0.32) and their prevalence was similar in patients with either PKD1 or PKD2 mutations. Median SV was significantly higher in ADPKD patients than controls (236 [182; 313 ml] versus 176 [129; 264 ml], p<0.0001). In multivariable analysis, height-adjusted SV (htSV) was not associated with the presence of liver cysts, haemorrhagic cysts, or infections; however, htSV was directly associated with height-adjusted total kidney volume (htTKV), a biomarker for ADPKD disease severity. CONCLUSIONS: The prevalence of T2-bright splenic lesions is similar in ADPKD patients and non-ADPKD controls, suggesting no relation to the diagnosis of ADPKD; however, splenic enlargement in ADPKD compared to controls could not be explained by liver cystic involvement, by infection/inflammatory conditions, or by haemorrhagic renal cysts. This combined with direct correlation of htSV with htTKV, a biomarker of ADPKD severity, suggests splenomegaly may be related to the pathogenesis of ADPKD.

Autosomal dominant polycystic kidney disease caused by somatic and germline mosaicism.

Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder caused by loss of function mutations of PKD1 or PKD2 genes. Although PKD1 is highly polymorphic and the new mutation rate is relatively high, the role of mosaicism is incompletely defined. Herein, we describe the molecular analysis of ADPKD in a 19-year-old female proband and her father. The proband had a PKD1 truncation mutation c.10745dupC (p.Val3584ArgfsX43), which was absent in paternal peripheral blood lymphocytes (PBL). However, very low quantities of this mutation were detected in the father's sperm DNA, but not in DNA from his buccal cells or urine sediment. Next generation sequencing (NGS) analysis determined the level of this mutation in the father's PBL, buccal cells and sperm to be ∼3%, 4.5% and 10%, respectively, consistent with somatic and germline mosaicism. The PKD1 mutation in ∼10% of her father's sperm indicates that it probably occurred early in embryogenesis. In ADPKD cases where a de novo mutation is suspected because of negative PKD gene testing of PBL, additional evaluation with more sensitive methods (e.g. NGS) of the proband PBL and paternal sperm can enhance detection of mosaicism and facilitate genetic counseling.

Aberrant PKD2 splicing due to a presumed novel missense mutation in autosomal-dominant polycystic kidney disease.

Autosomal-dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder characterized by abnormal proliferation of renal tubular epithelium, leading to massive kidney enlargement and progressive chronic kidney disease. ADPKD is caused by mutations in PKD1 and PKD2 genes. Herein, we describe and characterize a novel missense mutation in the PKD2 gene (c.1320G>T) in a 41-year-old White man with kidney cysts and a family history of ADPKD. This mutation abolishes a conserved acceptor splice site of intron 5, resulting in a premature termination following the addition of three aberrant amino acids (PKD2 p.L441C fsX4). We demonstrate that the aberrantly spliced transcript is found in substantial amounts in the patient's peripheral blood leukocytes (PBL), and show that this alternative splicing of exon 6 occurs, to a lesser magnitude, in other patients with ADPKD and in normal control individuals. The biological and clinical significance of this splice variant in ADPKD is currently unknown.

Effects of an 11ß-hydroxysteroid dehydrogenase type 1 inhibitor, MK-0916, in patients with type 2 diabetes mellitus and metabolic syndrome.

AIM: We examined the effects of the 11ß-hydroxysteroid dehydrogenase type 1 (HSD1) inhibitor, MK-0916, on the multiple components of the metabolic syndrome (MetS) in patients with type 2 diabetes (T2DM) and MetS. METHODS: This was a 12-week, multicentre, randomized, double-blind, placebo-controlled study. Patients with T2DM (mean baseline A1C: 7.3%) and National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III)-defined MetS were randomized 1 : 1 : 1 : 1 to 0.5, 2 or 6 mg/day MK-0916 or placebo. The primary efficacy endpoint was a change from baseline at week 12 in fasting plasma glucose (FPG). Secondary endpoints included glycosylated haemoglobin A(1c) (A1C), 2-h postprandial glucose (2-h PPG), body weight, waist circumference, blood pressure and lipid profile. RESULTS: Treatment with MK-0916 had no significant effect relative to placebo on FPG at week 12. Compared to placebo, 6 mg MK-0916 produced a modest, significant (p = 0.049) reduction in A1C of 0.3% at week 12, but no significant difference was observed in 2-h PPG. Six milligram MK-0916 increased LDL-C relative to placebo by 10.4% (p = 0.041). Treatment with MK-0916 led to modest dose-dependent decreases in blood pressure and body weight. Overall, MK-0916 was generally well tolerated. MK-0916 produced mechanism-based activation of the hypothalamic-pituitary-adrenal axis, resulting in mean increases in adrenal androgen levels that remained within the normal range at all doses tested. CONCLUSIONS: Inhibition of HSD1 with MK-0916 was generally well tolerated in patients with T2DM and MetS. Although no significant improvement in FPG was observed with MK-0916 compared to placebo, modest improvements in A1C, body weight and blood pressure were observed.

Effect of bolus and divided feeding on urine ions and supersaturation in genetic hypercalciuric stone-forming rats.

Because urine ion excretion varies throughout the day, clinicians monitor 24 h urine samples to measure ion excretion and supersaturation in kidney stone patients. However, these results are averages and may not reflect maximal supersaturation which drives stone formation. We measured ion excretion and saturation in genetic hypercalciuric stone-forming rats on both a normal or low calcium diet over 0-3, 3-6 and 6-24 h using two feeding protocols, where the daily food allotment was fed either as a bolus or divided into three portions. With a normal calcium diet, urine calcium, oxalate, volume, and calcium oxalate supersaturation were significantly greater on the bolus compared to the divided feeds in the prandial and postprandial periods. Bolus eaters also excreted more calcium and oxalate and had increased volume over 24 h. Maximal calcium oxalate supersaturation was greater during the initial time periods than during the entire 24 h, regardless of the feeding schedule. With the low calcium diet, the effect of bolus feeding was reduced. Thus, urine ion excretion and supersaturation vary with the type of feeding. If these results are confirmed in man, it suggests that eating as a bolus may result in greater prandial and postprandial calcium oxalate supersaturation. This may increase growth on Randall's plaques and promote stone disease.

Implications of ICD-10 for Sarcopenia Clinical Practice and Clinical Trials: Report by the International Conference on Frailty and Sarcopenia Research Task Force.

Establishment of an ICD-10-CM code for sarcopenia in 2016 was an important step towards reaching international consensus on the need for a nosological framework of age-related skeletal muscle decline. The International Conference on Frailty and Sarcopenia Research Task Force met in April 2017 to discuss the meaning, significance, and barriers to the implementation of the new code as well as strategies to accelerate development of new therapies. Analyses by the Sarcopenia Definitions and Outcomes Consortium are underway to develop quantitative definitions of sarcopenia. A consensus conference is planned to evaluate this analysis. The Task Force also discussed lessons learned from sarcopenia trials that could be applied to future trials, as well as lessons from the osteoporosis field, a clinical condition with many constructs similar to sarcopenia and for which ad hoc treatments have been developed and approved by regulatory agencies.

Mitochondrial DNA ligase function in Saccharomyces cerevisiae.

The Saccharomyces cerevisiae CDC9 gene encodes a DNA ligase protein that is targeted to both the nucleus and the mitochondria. While nuclear Cdc9p is known to play an essential role in nuclear DNA replication and repair, its role in mitochondrial DNA dynamics has not been defined. It is also unclear whether additional DNA ligase proteins are present in yeast mitochondria. To address these issues, mitochondrial DNA ligase function in S.cerevisiae was analyzed. Biochemical analysis of mitochondrial protein extracts supported the conclusion that Cdc9p was the sole DNA ligase protein present in this organelle. Inactivation of mitochondrial Cdc9p function led to a rapid decline in cellular mitochondrial DNA content in both dividing and stationary yeast cultures. In contrast, there was no apparent defect in mitochondrial DNA dynamics in a yeast strain deficient in Dnl4p (Deltadnl4). The Escherichia coli ECO:RI endonuclease was targeted to yeast mitochondria. Transient expression of this recombinant ECO:RI endonuclease led to the formation of mitochondrial DNA double-strand breaks. While wild-type and Deltadnl4 yeast were able to rapidly recover from this mitochondrial DNA damage, clones deficient in mitochondrial Cdc9p were not. These results support the conclusion that yeast rely upon a single DNA ligase, Cdc9p, to carry out mitochondrial DNA replication and recovery from both spontaneous and induced mitochondrial DNA damage.

Infantile infection and diabetes insipidus in children with optic nerve hypoplasia.

BACKGROUND: Bilateral optic nerve hypoplasia (BONH) is often associated with other central nervous system midline abnormalities (septo-optic dysplasia). Hormonal dysfunction, caused by anterior (cortisol) and posterior (ADH) pituitary involvement, can be sudden, severe, and life threatening. METHODS: Case series. Three cases of septo-optic dysplasia (SOD) presenting as infantile infection with associated diabetes insipidus are reported. The diagnosis of SOD was suspected only after ophthalmological evaluation; further evaluation led to the diagnosis of panhypopituitarism. CONCLUSIONS: A high index of suspicion is required to diagnose SOD in children when the disorder presents with infantile infection and hypernatraemia. Early warning signs of neonatal jaundice and hypoglycaemia should prompt ophthalmological evaluation.

Quantification of HIV-1-specific T-cell responses at the mucosal cervicovaginal surface.

OBJECTIVE: To characterize HIV-1 specific cellular immune responses at mucosal surfaces using a rapid, sensitive enzyme-linked immuno-spot (ELISPOT) technique. DESIGN: Cervicovaginal mononuclear cells obtained from cytobrush and cervicovaginal lavage were assessed for production of interferon-gamma (IFN-gamma) in response to stimulation by HIV-1 antigens. HIV-1 specific responses were compared in a cross-sectional study of two HIV-1-positive patient groups: women not currently on antiretroviral therapy with peripheral CD4 cell counts > 250 x 10(6)/l (n = 12); and women on highly active antiretroviral therapy (HAART) (n = 9). METHODS: Mononuclear cells from peripheral blood or cervicovaginal specimens were assessed in an ELISPOT assay for responses to HIV-1 antigens expressed by recombinant vaccinia viruses. This assay detects primarily CD8 T cells and shows good correlation with MHC class I tetramer staining of cytotoxic T lymphocytes. RESULTS: HIV-1 specific IFN-gamma spot-forming cells were detected in cervicovaginal samples of one out of nine women (11%) on HAART and five out of 12 women (42%) not currently on HAART. In peripheral blood mononuclear cells, HIV-1 specific IFN-gamma spot-forming cells were significantly more numerous in women not currently on HAART than in women on HAART (P = 0.009). In most cases, antigens recognized by mucosal T cells were also recognized by PBMC; however, there were exceptions. CONCLUSIONS: HIV-1-specific antigen-reactive T cells may be detected in routine, noninvasive gynecological specimens. The results suggest that cervicovaginal HIV-1-specific T cells may be less numerous in individuals on HAART than in those not on HAART, as shown previously for HIV-1-specific cytotoxic T lymphocytes in the peripheral blood.

Ticlopidine inhibits phenytoin clearance.

Because cases of phenytoin toxicity during concomitant ticlopidine therapy have been reported, we investigated the effects of multiple doses of ticlopidine on phenytoin pharmacokinetics in six patients receiving phenytoin monotherapy. Two steady-state dosing rate and serum phenytoin minimum concentration (Cmin) pairs were obtained for each patient administered oral phenytoin alone, then phenytoin plus 250 mg ticlopidine twice daily. All patients had serum Cmin ticlopidine values of 0.06 to 0.25 microg/mL when receiving ticlopidine. Individual pharmacokinetic parameters for phenytoin were calculated. The Michaelis-Menten constant (Km) was determined as the slope and maximum velocity (Vmax; equivalent to the maximal rate of elimination or the maximum daily dose that can be metabolized) as the y-intercept of the linear Michaelis-Menten plot. Mean phenytoin Km significantly increased from 5.8 to 12.3 during ticlopidine coadministration compared with administration of phenytoin alone (P = .02). Mean phenytoin Vmax was not significantly changed by the coadministration of ticlopidine. These data indicate that ticlopidine inhibits the clearance and alters the clinical pharmacokinetics of phenytoin so that dosage adjustment of phenytoin should be considered when ticlopidine is coadministered. The results are consistent with previous human liver microsome findings that ticlopidine is a potent inhibitor of CYP2C19, a P450 isozyme that is significantly responsible for phenytoin metabolism.

Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19.

A patient who had taken a stable dose of phenytoin for 2 years had a coronary stent placed for unstable angina and ticlopidine was added to his therapeutic regimen. Twenty-five days later, he was hospitalized with acute symptomatic phenytoin toxicity and a serum concentration of 46.5 micrograms/ml. Determination of metabolic genotype revealed that the patient had a wild-type genotype for CYP2C9, CYP2C19, and CYP2D6. Using human liver microsomes, we showed that ticlopidine is a potent inhibitor of cytochrome P450 2C19, with an estimated inhibition constant (Ki) of 3.7 +/- 0.2 mumol/L. The influence of ticlopidine on CYP2C9, the other cytochrome P450 isoform that metabolizes phenytoin, is relatively weak, with a calculated Ki of 38.8 +/- 27 mumol/L. These data suggest that, in this patient, phenytoin toxicity was caused by inhibition of CYP2C19 by ticlopidine, and the data emphasize the importance of CYP2C19 in the metabolism of phenytoin.

Thalidomide does not alter the pharmacokinetics of ethinyl estradiol and norethindrone.

OBJECTIVE: To evaluate the effect of thalidomide on the plasma pharmacokinetics of ethinyl estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone). METHODS: Ten women who had undergone surgical sterilization were enrolled in an open-label crossover study conducted in the Georgetown University Clinical Research Center. The pharmacokinetics of single doses of 0.07 mg ethinyl estradiol and 2 mg norethindrone were measured at baseline and after 3 weeks of 200 mg thalidomide. Compliance with the thalidomide regimen was assessed with use of Medication Event Monitoring System (MEMS) caps. RESULTS: No changes were observed in the pharmacokinetics of ethinyl estradiol or norethindrone with thalidomide therapy. The mean +/- SD area under the plasma concentration-time curve (AUC0-infinity) for ethinyl estradiol was 6580 +/- 1100 ng.h/L at baseline and 5970 +/- 1560 ng.h/L after the thalidomide regimen (paired t test, P > .05). The values for norethindrone were 103 +/- 54 micrograms.h/L and 107 +/- 58 micrograms.h/L (paired t test, P > .05). No changes were observed for other pharmacokinetic parameters assessed for either ethinyl estradiol or norethindrone. No accumulation of thalidomide was seen after 21 days of therapy: day 1 AUC0-infinity 41.1 +/- 13.9 micrograms.h/mL; day 21 AUC0-infinity 59.6 +/- 27.3 micrograms.h/mL (paired t test, P > .05). No changes were observed for other pharmacokinetic parameters assessed for thalidomide between days 1 and 21. Thalidomide was well tolerated but caused variable degrees of sedation. The average thalidomide compliance rate was 97%. CONCLUSIONS: The pharmacokinetics of thalidomide do not change with 3 weeks of daily dosing. Thalidomide does not alter the pharmacokinetics of ethinyl estradiol or norethindrone. Therefore there is no drug interaction between thalidomide and these 2 drugs. The efficacy of oral contraceptives containing ethinyl estradiol and norethindrone should not be affected by concomitant thalidomide therapy.

PIP: An open-label crossover study was conducted to evaluate the effect of thalidomide on the plasma pharmacokinetics of ethinyl estradiol (INN, ethinyl estradiol) and norethindrone (INN, norethisterone) among 10 women who had undergone surgical sterilization at Georgetown University Clinical Research Center. The pharmacokinetics of single doses of 0.07 mg ethinyl estradiol and 2 mg norethindrone were measured at baseline and after 3 weeks of 200 mg thalidomide. Compliance with the thalidomide regimen was assessed with the use of Medication Event Monitoring System caps. The results showed that there were no changes in the pharmacokinetics of ethinyl estradiol or norethindrone with thalidomide therapy. Furthermore, no changes were seen for other pharmacokinetic parameters assessed for thalidomide between days 1 and 21. Thalidomide was well tolerated, but caused variable degrees of sedation. The average compliance rate of thalidomide was 97%. This study concluded that there was no drug interaction between thalidomide and the other two drugs (ethinyl estradiol and norethindrone). The efficacy of oral contraceptives containing ethinyl estradiol and norethindrone should not be affected by concomitant thalidomide therapy.

Response of IGF-1 to nutritional support in malnourished hospital patients: a possible indicator of short-term changes in nutritional status.

IGF-1 is a circulating growth factor with hepatic release dependent on nutritional status. To determine if IGF-1 could be a useful nutritional index, 15 malnourished patients were assessed during nutritional support. Patients with protein or protein-calorie malnutrition had lower IGF-1 (39 +/- 7 micrograms/L) than did patients with calorie-only malnutrition (109 +/- 25 micrograms/L, p less than 0.005); transferrin concentrations did not differ between the two groups. Nutritional supplementation produced an increase in IGF-1 (123 +/- 32 micrograms/L, p less than 0.005); the relative increase in IGF-1 (264 +/- 62%, p less than 0.001) exceeded increases in albumin or transferrin (9 +/- 6% and 59 +/- 16%, NS and p less than 0.005, respectively). Reduction or termination of support was followed by a decrease in IGF-1 to 59 +/- 9% of peak values (p less than 0.001) but neither albumin nor transferrin decreased significantly. Changes in IGF-1 were correlated with nitrogen balance (r = 0.45, p less than 0.005). The strong relationship between IGF-1 and nutritional status suggests that IGF-1 determinations may be useful in guiding nutritional therapy in patients whose nitrogen balance is difficult to assess.

Unusual ocular motility disturbances with increased intracranial pressure.

We evaluated nine patients with external ophthalmoparesis and increased intracranial pressure. The eye movements normalized when the intracranial pressure was controlled. Investigations for an underlying cause of elevated cerebrospinal fluid pressure are warranted when ocular motility disorders are present.

Visual field defects after temporal lobe resection: a prospective quantitative analysis.

OBJECTIVE: To evaluate and quantify prospectively visual field changes in patients undergoing temporal lobe resections for intractable epilepsy. BACKGROUND: Visual field abnormalities occur after temporal lobe resections for epilepsy; however, we have not encountered published reports using automated static visual field analysis. METHODS: Humphrey visual fields (program 30-2) were obtained before and after partial temporal lobe resection in 32 consecutive patients with intractable epilepsy. A quantitative point-by-point analysis was made in the affected superior quadrant, and the defects were averaged for the whole patient group. RESULTS: Thirty-one patients developed a visual field defect, but none was aware of the defect. The points nearest fixation were relatively spared. The defects were greatest in the sector closest to the vertical meridian in the eye ipsilateral to the resection. The ipsilateral and contralateral mean field defects also differed in both topography and depth. A significant correlation was found between the extent of lateral temporal lobe resection and the degree of the defect in the contralateral eye. CONCLUSIONS: There are differences in the shape and depth of the ipsilateral and the contralateral field defects not previously reported. These findings demonstrate that certain fibers from the ipsilateral eye travel more anteriorly and laterally in Meyer's loop, and support the hypothesis that visual field defects due to anterior retrogeniculate lesions are relatively incongruous because of anatomic differences in the afferent pathways. Automated perimetry is a sensitive method of evaluating and quantifying visual field defects.

Bone strain and microcracks at stress fracture sites in human metatarsals.

Microcracks in bone have been implicated in the development of stress fractures. The goal of this study was to evaluate bone strain and microcracks at locations where stress fractures are common (second metatarsal diaphysis) and rare (fifth metatarsal diaphysis) in an attempt to increase our understanding of the pathogenesis of stress fractures. A dynamic gait simulator was used to simulate normal walking with cadaver feet. The feet were loaded over the entire stance phase of gait and diaphyseal strains were recorded in second and fifth metatarsals. Microcrack density (Cr.Dn) and surface density (Cr.S.Dn) were determined in metatarsal cross sections from the contralateral feet. Bone strain was significantly higher in second metatarsals (-1897 +/- 613 microstrain) than in fifth metatarsals (-908 +/- 503 microstrain). However, second metatarsal Cr.Dn (0.23 +/- 0.15 #/mm(2)) was not significantly different from fifth metatarsal Cr.Dn (0.35 +/- 0.19 #/mm(2)). There was also no significant difference between Cr.S.Dn in second (17.64 +/- 10.99 microm/mm(2)) and fifth (26.70 +/- 15.53 microm/mm(2)) metatarsals. There were no significant relationships between the microcrack parameters and peak strain in either metatarsal. Cracks that occurred in trabecular struts (92 +/- 33 microm) were significantly longer than those found ending at cement lines (71 +/- 15 microm) and within osteons (57 +/- 16 microm). There were no significant relationships between the microcrack parameters and age in either metatarsal. Peak strain was more than twofold greater in second metatarsals than in fifth metatarsals for simulations of normal walking; however, microcrack parameters were unable to explain the greater incidence of second metatarsal stress fractures.

Tenotomy delays both synapse elimination and myogenesis in rat lateral gastrocnemius.

To investigate a possible relationship between synapse elimination and myogenesis, we examined both phenomena during the first 2 weeks of postnatal life in the rat lateral gastrocnemius muscle. Synapse elimination and myogenesis occur simultaneously. Sixty per cent of the number of fibers observed in adult muscles is generated during the first 10 days of postnatal life; during this time, the majority of muscle cells in lateral gastrocnemius also become singly innervated. We delayed synapse elimination by cutting the tendon of insertion of lateral gastrocnemius (tenotomy) on the day of birth. Both synapse elimination and postnatal myogenesis were slowed by tenotomy. Tenotomized muscles contained fewer detectable cells than unoperated contralateral control muscles. These results suggest that synapse elimination may be altered by altering postnatal muscle fiber addition.

Common ocular infections. A prescriber's guide.

While most ocular infections are benign, others can be associated with devastating visual consequences. Most patients present with either ocular discharge, visual symptoms or a red or painful eye. The primary care physician is usually the first to evaluate these patients. We have separated ocular infections into 3 groups. Infections affecting the cornea and conjunctiva often present with eye pain and a red eye; noninfectious aetiologies can have a similar presentation. Infections inside the eye (endophthalmitis) often have devastating consequences. They usually occur following penetrating ocular trauma or after intraocular surgery. Prompt referral to an ophthalmologist is crucial. Infections in the soft tissue surrounding the eye (ocular adnexa and orbit) can involve the eye indirectly and can spread from the orbit into the brain. The purpose of this article is to review ocular infections and current opinion regarding treatment. A general guideline should be that the approach to treatment be governed by the severity of symptoms and the magnitude of possible consequences. Mild external infections can be typically treated empirically. Severe conjunctivitis, and any corneal infection, require aggressive management, often including cultures and broad spectrum antibiotics; cultures are often used to guide treatment. Devastating vision loss can occur, even with aggressive management. Preseptal cellulitis in adults and older children can be managed conservatively with oral antibiotics if the orbit and optic nerve are not involved and the patient is otherwise healthy. Orbital or optic nerve involvement, on the other hand, demands orbital imaging and more aggressive intervention. Patients who have had recent surgery are at risk for developing endophthalmitis. Complaints of pain or a red eye must be taken very seriously. These patients must be considered to have an intraocular infection until it can be ruled out, and should be aggressively managed by a physician trained in eye diseases and surgery.

Primary oblique muscle overaction: the brain throws a wild pitch.

BACKGROUND: Sensorimotor and orbital anatomical mechanisms have been invoked to explain primary oblique muscle overaction. METHODS: Review of primitive visuo-vestibular reflexes and neuroanatomical pathways corresponding to vestibulo-ocular reflexes, and correlation with known clinical abnormalities in patients with primary oblique muscle overaction. RESULTS: Bilateral superior oblique muscle overaction, which corresponds to a backward pitch in lateral-eyed animals, can occur when structural lesions involving the brainstem or cerebellum increase central otolithic input to the extraocular muscle subnuclei that modulate downward extraocular muscle tonus. Bilateral inferior oblique overaction, which corresponds to a forward pitch in lateral-eyed animals, may result from visual disinhibition of central vestibular pathways to the extraocular muscle subnuclei that modulate upward extraocular muscle tonus. CONCLUSIONS: Primary oblique muscle overaction recapitulates the torsional eye movements that occur in lateral-eyed animals during body movements or directional luminance shifts in the pitch plane. These primitive ocular motor reflexes become manifest in humans when early-onset strabismus or structural lesions within the posterior fossa alter central vestibular tone in the pitch plane.

Prognostic indicators for vision and mortality in shaken baby syndrome.

OBJECTIVE: To study ocular and nonocular signs of patients diagnosed as having "shaken baby syndrome" and determine prognostic indicators for vision and mortality. METHODS: Medical records of child abuse cases involving bilateral retinal hemorrhages were reviewed. Particular attention was paid to visual function and pupillary light reaction at the time of admission as well as the location of retinal hemorrhages, neuroimaging findings, ventilatory requirement, and associated skeletal injuries. These findings were correlated with visual prognosis and mortality. RESULTS: Thirty consecutive cases met the criteria for review. At the initial visit, mean age of the children was 9.3 months (range, 1-39 months) and 12 children (40%) had at least fix-and-follow vision. Preretinal and intraretinal hemorrhages (93% [n = 28] and 100% [n = 30]) were more common than vitreous hemorrhage (10% [n = 3]). Subdural hematomas were detected in 21 patients (70%). Twenty children (67%) had seizures and 16 (53%) required ventilatory support; bruises and long bone fractures were seen in 14 (47%) and 4 (13%) children, respectively. Eight patients died. All patients with nonreactive pupils on presentation died, while all patients with a pupillary light reaction lived (P<.001). Six (86%) of 7 patients with midline shift died, whereas 21 (91%) of 23 with no midline shift lived (P<.001). At follow-up, retinal hemorrhages had resolved in nearly all children by 4 months, and 16 children (73%) had at least fix-and-follow vision. Ventilatory requirement was associated with poorer vision (P<.01). CONCLUSIONS: Nonreactive pupils and midline shift of the brain structures correlate highly with mortality. Ventilatory requirement, but not visual acuity on presentation, predicts visual outcome.