Psychosocial outcome in adult men born with hypospadias.

INTRODUCTION: Hypospadias, which is a surgically treated congenital malformation of the male urethra, may have a negative impact on quality of life. This aspect has previously been subject to limited research. This study examined the long-term psychosocial outcome of a large cohort of adult males born with hypospadias. OBJECTIVE: The purpose of this case-control study was to assess a possible negative influence on the psychosocial outcome in adult males with hypospadias. STUDY DESIGN: Males with hypospadias treated in Sweden and aged ≥18 years old participated in this follow-up study. Age-matched men and university students were recruited as controls. The participants answered a questionnaire designed to reflect the subjective quality of life, social factors, need of support and follow-up, and the perceived impact of the disease upon upbringing. It also looked at the validated Psychological General Well-Being (PGWB) questionnaire and Relationship Questionnaire (RQ). RESULTS AND DISCUSSION: A total of 167 patients (median age 34 years, 63% distal, 24% mid, and 13% proximal hypospadias) and 169 controls (median age 33 years) participated in the study. Patients had their first operation at 4 years of age (median) and the median follow-up time was 29 years following the first surgery. Men with hypospadias had a comparable total quality of life level with a mean total PGWB score of 82 (normal range 78-83) compared with 85.6 in controls. Scores on wellbeing and vitality were lower, even if the differences were small. Hypospadias did not affect marital status, presence of children in the family, frequency of employment or experience of bullying. These men more often lived at home with their parents (P=0.001) and had a lower level of education (P=0.004), even if the educational level in both patients and controls was high compared with the general Swedish population. Patients with proximal hypospadias were shorter compared with controls (P=0.003), which was consistent with the prenatal growth restriction associated with hypospadias. The group with proximal hypospadias expressed a greater need for medical (45.5%) follow-up compared with mid (28.2%) and distal (18.1%) cases (P=0.001). Patients with proximal hypospadias tended to avoid close relationships because of fear of being hurt. CONCLUSIONS: The findings suggested that patients treated for hypospadias have a good HRQoL, can be expected to have a normal psychosocial life, and marry and have children. Repeated follow-up and psychological support during childhood/adolescence is however of great importance for patients with more proximal hypospadias.

Sexuality and fertility in men with hypospadias; improved outcome.

The aim of this study was to investigate sexual function and fertility in adult men born with hypospadias. Patients born with hypospadias, age-matched controls, and a group of circumcised men completed a questionnaire constructed to reflect their psychosexual situation and fertility. Core gender identity, sexual orientation, and gender role behavior was also assessed. 167 patients [63% distal, 24% mid shaft and 13% proximal, mean age 34 (19-54) years], 169 controls from the general population [mean age 33 (19-48) years] and 47 controls circumcised because of phimosis (mean age 26 [19-44]) participated and completed the questionnaire. There were no differences in having a partner, reported fertility, age at sexarche (mean age 17.8), number of sex partners or sexual interest between the patients and controls. More patients than controls reported anejaculation. Reported glanular sensitivity was lower in hypospadias patients and circumcised controls compared with non-circumcised controls. The odds of being satisfied with their sexual life increased with a higher penile perception score in patients (OR = 1.54, p = 0.01). There was no association with penile length. Sexual orientation, core gender identity and gender role behavior were sex-typical in both patients and controls. Patients with proximal hypospadias had a lower reported fertility, experienced anejaculation more often, and were less satisfied with their sexual life. Men born with hypospadias have a good long-term outcome concerning sexual function and fertility. Men born with proximal hypospadias have a more impaired outcome concerning both sexual function and fertility. As satisfaction with genital appearance is important for sexual life satisfaction, clinical, and psychological follow-up into adulthood is especially important in boys born with proximal hypospadias.

Suboptimal psychosocial outcomes in patients with congenital adrenal hyperplasia: epidemiological studies in a nonbiased national cohort in Sweden.

CONTEXT: Congenital adrenal hyperplasia (CAH), CYP21A2 deficiency, results in cortisol and aldosterone deficiency and increased production of androgens, with a good genotype phenotype correlation. OBJECTIVE: The objective of the investigation was to study psychosocial outcomes in relation to clinical severity, CYP21A2 genotype, in men and women. DESIGN: This was an epidemiological study with a matched case control design. SETTING: The setting of the study was all known CAH patients in Sweden. PARTICIPANTS: Five hundred eighty-eight patients, more than 80% with known severity of CAH, and 100 controls per patient matched for sex, year, and place of birth participated in the study. MAIN OUTCOME AND MEASURES: Proxies for quality of life were selected: level of education, employment, income, sick leave, disability pension, marriage, and children. RESULTS: Women with salt-wasting (SW) CAH had completed primary education less often [odds ratio (OR) 0.3], not explained by neonatal salt crisis or hypoglycemia because the men did not differ from controls. Men and women in the less severe I172N genotype group were more likely to have an academic education (OR 1.8). SW women were more likely to have an income in the top 20th percentile (OR 2.0). Both men and women had more disability pension (OR 1.5) and sick leave (OR 1.7). The men more often had long-lasting employment (OR 3.1). Men were more often (OR 1.6) and women were less often married (OR 0.7). Patients had children less often (OR 0.3). CONCLUSIONS: This study shows important outcome differences regarding education; employment; marriage and fertility, depending on sex; and severity of CAH. The mechanisms behind this and the increased risk for sick leave or disability pension in both men and women should be identified to improve medical and psychological care.

The KMO allele encoding Arg452 is associated with psychotic features in bipolar disorder type 1, and with increased CSF KYNA level and reduced KMO expression.

The kynurenine pathway metabolite kynurenic acid (KYNA), modulating glutamatergic and cholinergic neurotransmission, is increased in cerebrospinal fluid (CSF) of patients with schizophrenia or bipolar disorder type 1 with psychotic features. KYNA production is critically dependent on kynurenine 3-monooxygenase (KMO). KMO mRNA levels and activity in prefrontal cortex (PFC) are reduced in schizophrenia. We hypothesized that KMO expression in PFC would be reduced in bipolar disorder with psychotic features and that a functional genetic variant of KMO would associate with this disease, CSF KYNA level and KMO expression. KMO mRNA levels were reduced in PFC of bipolar disorder patients with lifetime psychotic features (P=0.005, n=19) or schizophrenia (P=0.02, n=36) compared with nonpsychotic patients and controls. KMO genetic association to psychotic features in bipolar disorder type 1 was studied in 493 patients and 1044 controls from Sweden. The KMO Arg(452) allele was associated with psychotic features during manic episodes (P=0.003). KMO Arg(452) was studied for association to CSF KYNA levels in an independent sample of 55 Swedish patients, and to KMO expression in 717 lymphoblastoid cell lines and 138 hippocampal biopsies. KMO Arg(452) associated with increased levels of CSF KYNA (P=0.03) and reduced lymphoblastoid and hippocampal KMO expression (P≤0.05). Thus, findings from five independent cohorts suggest that genetic variation in KMO influences the risk for psychotic features in mania of bipolar disorder patients. This provides a possible mechanism for the previous findings of elevated CSF KYNA levels in those bipolar patients with lifetime psychotic features and positive association between KYNA levels and number of manic episodes.

Ocular torsions and the subjective visual vertical with central vestibulo-ocular system lesions: independence disproved.

OBJECTIVES: Torsions of the eyes and deviations of the subjective visual vertical in roll occur regularly with disorders of the central vestibulo-ocular system. Although nearly universally coexisting, torsions and deviation have been held to be more or less independent of each other. MATERIALS AND METHODS: Angles of torsion were determined from fundus photographs in 55 subjects representing a variety of acute, focal, brainstem or cerebellar lesions. Measured torsions were contrasted with quantitative measurements of the subjective visual vertical. RESULTS: Torsions and deviations proved to be directly proportional, with a direction coefficient close to unity, and were strongly correlated (r = 0.86). CONCLUSIONS: Torsions and deviations are strongly dependent. This result should allow the generation of a more transparent pathophysiological model. From a practical point of view, measurements of deviation appeared more robust than those of torsion.

Scope of super-resolution in central vision.

BACKGROUND: The term super-resolution refers to computational enhancement of detail in sets of similar images, particularly undersampled images. Undersampling is a key feature of visual disorders associated with neuroretinal matrix damage. It is conceivable that a neurophysiological equivalent of super-resolution might be recruited in these settings. The need for sets of similar images might be satisfied by augmenting retinal image movements. METHODS: Monocular letter acuity thresholds were measured by computer graphics in normal subjects, with and without controlled test target movements. Various degrees of neuroretinal matrix defects were simulated by superposing stationary masks on the test targets. RESULTS: Static acuity thresholds increased monotonically with increased mask densities. The addition of target movement partially counteracted the threshold increment. The effect was barely measurable at small mask densities and increased monotonically to a gain of approximately two lines on a decimal acuity scale with masks simulating loss of 90% of neural matrix elements. Similar results were obtained from a patient with an acquired neuroretinal matrix defect, attesting to the validity of the mask experiments. CONCLUSION: Super-normal retinal image movements have subtle effects on visual resolution in normal eyes, whereas eyes with neuroretinal matrix defects may improve markedly. This finding may have implications for the development of aids for the visually handicapped.

The Amsler grid in modern clothes.

BACKGROUND: The Amsler chart, a printed grid with a central fixation mark, is widely used to test for central/paracentral scotomata and metamorphopsias. Abnormal results are easily recognised but are not directly accessible to quantitative analysis. Negative results may be misleading, because it is never known how good an observer the subject is. METHODS: A new version was created in computer graphics. The grid was made to sweep the tested area in an optic flow manner. The sweeps provided seamless coverage, counteracted the Troxler fade-from-view effect, and encouraged stable fixation. Simulations of scotomata and metamorphopsias allowed quantitative evaluations of subject performance. RESULTS: Normal observers consistently detected absolute paracentral scotomata subtending > or =2 degrees . Grid deformation was consistently detected at 4' near fixation, whereas up to 20' was needed at the grid border. A patient with real metamorphopsia reproducibly nulled the apparent deformation of the grid in a manner closely matching his own renditions. CONCLUSIONS: The classical Amsler grid can be made to meet modern demands of quality control and quantitative measurements. The new "MacuFlow" test is freely accessible on the internet. Test results can easily be transmitted electronically for evaluation at distance.

Fertility and pregnancy outcome in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

BACKGROUND: Low pregnancy rate has been reported in women with congenital adrenal hyperplasia (CAH) and little information on pregnancy and children is known. METHODS: In a Swedish study, 62 adult women with CAH, aged 18-63 years, and 62 age-matched controls were followed-up. Medical records, including those concerning pregnancies and deliveries, were examined and the 21-hydroxylase genotype of patients was noted. All women answered a questionnaire concerning sexual and reproductive health including health of the children. RESULTS: Pregnancy and delivery rates were significantly lower in women with CAH (P < 0.001, P < 0.0056, respectively), and the severity of the 21-hydroxylase-mutation correlated with the reduced number of children born. More women with salt-wasting CAH were single and had not attempted pregnancy. Pregnancies were normal except for a significantly increased incidence of gestational diabetes in CAH patients (P < 0.0024). The children had normal birthweight and no malformations were observed. A later follow-up of the children showed a normal intellectual and social development. The sex ratio of the offspring differed significantly, with 25% boys in the CAH group compared with 56% among controls (P < 0.016). CAH women had more gynaecological morbidity during menopause. CONCLUSIONS: Pregnancy and delivery rates are reduced in women with CAH mainly due to psychosocial reasons. The outcome of children did not differ from controls. The unexpected sex ratio in children born to mothers with CAH warrants further research.

How robust is the optic chiasm? Perimetric and neuro-imaging correlations.

OBJECTIVES: Analysis of form and function relationships with tumour-mediated dislocations and deformations of the optic chiasm. MATERIALS AND METHODS: Results of magnetic resonance tomography and two forms of quantitative, computerized perimetry were contrasted in 31 patients with pituitary adenomata impinging on the chiasm, prior to treatment. RESULTS: Perimetric abnormalities ranged from none to modest. High-pass Resolution Perimetry (HRP) produced abnormal results in 10 cases and RareBit perimetry (RBP) in 15 cases. Overall, field defects and qualitative stages of deformation and dislocation of the chiasm were well correlated. Among quantitative indices, the best correlations were obtained by a measure of the cranio-caudal position of the chiasm. CONCLUSIONS: On average, an elevation of the chiasm by 6 mm will be associated with abnormal visual fields in 50% of the cases. An additional elevation of 5 mm will raise the incidence of field defects to 90%.

Polymorphisms of estrogen receptor beta gene are associated with hypospadias.

INTRODUCTION: Hypospadias is a common male congenital urethral malformation, defined as the displacement of the urethral meatus ventrally from the tip of the glans penis. The importance of androgen receptor in male external genitalia development has been well recognized. Recently, the presence of active estrogen receptors (ER) in the developing male external genitalia has also been demonstrated. There are two isoforms of the human estrogen receptor, ESR1 and ESR2, which occur, with distinct tissue and cell patterns of expression. We hypothesized that modifications in these nuclear receptors' genes could lead to hypospadias. MATERIALS AND METHODS: We screened 60 boys with hypospadias for mutations in the coding regions of ESR1 and ESR2 genes, by denaturing high-performance liquid chromatography and automated sequence analysis. We also genotyped the CA repeat polymorphism in ESR2 and the TA repeat polymorphism in ESR1. RESULTS: The CA repeat polymorphism in ESR2 is prolonged in hypospadias patients compared to controls (p < 0.05). Prolongation of this CA repeat polymorphism has previously been associated with lower levels of testosterone. Six patients presented the genetic variant 2681-4A > G (rs944050) in the heterozygous form in ESR2, which was a significantly higher frequency than in the control population (p < 0.05). One of these patients also presented a 266_267insC in exon 1 of ESR2, which is also a known single nucleotide polymorphism (SNP; rs3832949). In ESR1, no significant gene alteration was found to be associated with hypospadias. CONCLUSIONS: Our results suggest that variations in the ESR2 might influence susceptibility to hypospadias.

Visual field defects after temporal lobectomy -- comparing methods and analysing resection size.

OBJECTIVES: The frequency of visual field defects (VFD) after temporal lobe resections (TLR) was compared for two types of TLR and VFD frequency was correlated to resection size. METHODS: Pre- and post-operative perimetry results were analysed for 50 patients with TLR for medically intractable epilepsy. Thirty-three patients had a classical TLR and 17 had a TLR with less lateral extension. Post-operative MRIs were studied in 34 patients by scoring resection size in 12 compartments in the temporal lobe. RESULTS: Twenty-five patients developed a VFD. In the classical TLR group, 16 of 33 developed a VFD, compared with nine of 17 in the other group. The resection points were higher for the VFD group in the most anterior compartment studied, in the superior temporal gyrus. CONCLUSIONS: There was no clearcut difference in VFD frequency between the surgical methods studied. However, the compartmentalized analysis disclosed a relation between the extent of resection in the anterior part of the superior temporal gyrus and VFD frequency.

Multiple sclerosis siblings with cerebrospinal fluid immunopathy but without any indication of neuronal damage.

OBJECTIVE: In a previous study, we found that nine of the 47 siblings to multiple sclerosis (MS) patients with a normal neurologic examination carry an intrathecal oligoclonal immunopathy with limited specificity, a condition we termed MS immunopathic trait. Here we searched for neurological dysfunction with increased sensitivity. METHOD: We used high-pass resolution perimetry, which reveals visual pathway lesions by their impaired neural effective capacity (EC) in early MS cases even without optic neuritis. RESULTS: These nine individuals with MS immunopathic trait did not differ from nine healthy controls with normal cerebrospinal fluid regarding their EC. CONCLUSION: This is further evidence that a group of MS immunopathic trait individuals, siblings to MS patients, are essentially free from the central nervous system functional loss typically found in MS.

Spatial vision in visually asymptomatic subjects at high risk for multiple sclerosis.

OBJECTIVE: To investigate the state of spatial vision in visually asymptomatic subjects at high risk for multiple sclerosis. METHODS: Fifteen subjects suffering a first neurological episode suggestive of multiple sclerosis in clinical presentation, immunological profile, and magnetic resonance imaging, were examined with a new, sensitive test of spatial vision, rarebit perimetry. None had symptoms or signs of optic neuropathy. RESULTS: Results of rarebit perimetry were significantly worse than those of 15 age matched normal controls (p=0.01); seven patients (47%) were outside normal limits. One patient only obtained abnormal results in high pass resolution perimetry. CONCLUSIONS: Rarebit perimetry may help to close the sensitivity gap between clinical examinations and neuroimaging.

Internal carotid artery aneurysms, cranial nerve dysfunction and headache: the role of deformation and pulsation.

Cranial nerve dysfunction and headache may occur with unruptured aneurysms of the cavernous and supraclinoid portions of the internal carotid artery. Nerve deformation (mass effect) and transmitted pulsations have been suggested as pathogenetic mechanisms. Differentiation may be possible by studying effects of endovascular treatment with Guglielmi detachable coils. Symptoms and signs of cranial neuropathy were retrospectively contrasted with angiographic aneurysm volumes before and after treatment in 10 patients. Mean follow-up was 36 months. Symptoms improved in three of four patients with cranial nerve dysfunction and in all patients with headache. None of the other patients, one with cranial nerve dysfunction, and three who were asymptomatic, developed any new symptoms after treatment. Aneurysm volume ranged from 0.1 to 2.7 cm(3 )before and 0.2 to 5.7 cm(3) after treatment; the size thus increased by 15 to 110%, a change which was statistically significant (P=0.004). The consistent increase in aneurysm volume with treatment is not associated with clinical deterioration, suggesting that deformation and displacement play a minor role in cranial neuropathy and that transmitted pulsations may be more important.

Vigabatrin visual toxicity: evolution and dose dependence.

PURPOSE: To investigate the prevalence and prognosis of visual field defects (VFDs) in epilepsy patients with and without vigabatrin (VGB) treatment; to investigate the possible relationship between VFDs and cumulative VGB dose, and to characterise the evolution of VFDs. METHODS: A cohort of 155 presurgical candidates who had undergone full-field Goldmann perimetry (GP) was studied, 99 (64%) of whom had been treated with VGB. All GPs were reevaluated in 1998 by one experienced examiner, blinded to medication. Duration of treatment and total VGB dose were related to perimetric results. RESULTS: Twenty-five (16%) of the 155 patients had VFDs: Nineteen (19%) of the 99 VGB-treated patients, and six (11%) of the 56 patients unexposed to VGB. VGB-treated patients with VFDs had been treated significantly longer than those without VFDs. Cumulative VGB dose could be calculated for 84 patients. The prevalence of VFDs increased significantly with increasing total VGB-dose, from 4% in the 51 patients who had been exposed to

Asymptomatic visual loss in multiple sclerosis.

Visual disturbances are common in multiple sclerosis (MS) and often a result of acute demyelinating optic neuropathy. Careful examination of MS patients, who have never suffered optic neuritis, may also reveal asymptomatic visual loss. This type of silent disease activity was investigated by computerised resolution perimetry, which has the potential to reflect the percentage of functional retino-cortical neural channels. The time of onset and the evolution of asymptomatic visual loss was investigated. One approach was to retrospectively select patients who never had suffered acute optic neuritis from a closely monitored MS population and re-examine them again. Sixteen patients were identified and vision was evaluated during a period of 5.5-9 years of follow-up and compared with that in 14 healthy controls. The mean channel percentage of the MS group was 89 +/- 19 % (SD) on entry into the study, compared with 110 +/- 15% (SD) of controls (p < 0.003). At termination of the study the mean percentage was essentially unchanged both in MS patients (87 +/- 21%, SD) and controls (110 +/- 19%, SD). The second approach was to test a group of 7 patients with MS or strongly suspected MS, with the same method, in close connection with their first clinical exacerbation. All cases lacked visual symptoms and none had previously had acute visual loss. Again, virtually all performed subnormally in the vision tests, and to the same degree as in the first group of patients. Results were compared with those obtained from 25 MS patients who had experienced one or more attacks of optic neuritis. Compared with controls the loss of functional retino-cortical neural channels was 20% in patients without a previous history of optic neuritis and 30 % in patients who previously had experienced optic neuritis. We conclude that asymptomatic visual loss seems to be a universal feature of MS and has a substantial impact on the visual pathways, that it is present already at the time of clinical onset of the disease, and that any progression thereafter is slow enough to elude detection during several years of follow-up.

Direct puncture and sclerotherapy with sotradecol ((r)) . Orbital lymphatic malformations.

SUMMARY: We evaluated sclerotherapy in the treatment of orbital lymphatic malformations. Six consecutive patients with unilateral orbital cystic masses and recurrent episodes of orbital swelling were included in this retrospective study. All have been treated with percutaneous puncture and injection of Sotradecol (sodium tetredecyl sulphate) under radiographic guidance, on one or more occasions. Reduction of orbital mass volume was documented clinically and radiologically within a few weeks in all cases. There was total regression of proptosis in three instances. There were no immediate complications. One subject suffered a presumably coincidental orbital hemorrhage two weeks after treatment. Follow-up times ranged between six months and four years. Sotradecol sclerotherapy appears to be a useful adjunct to the therapeutic arsenal for orbitallymphatic malformations.

Gabapentin versus vigabatrin as first add-on for patients with partial seizures that failed to respond to monotherapy: a randomized, double-blind, dose titration study. GREAT Study Investigators Group. Gabapentin in Refractory Epilepsy Add-on Treatment.

PURPOSE: Our objective was to compare the efficacy and safety of gabapentin and vigabatrin as first-line add-on treatment in patients with partial epilepsy. METHODS: This was a multicenter, double-blind, randomized dose titration study. After baseline assessment and randomization, the dose could be increased if seizures persisted and reduced if side effects occurred. Health-related quality of life was assessed at baseline and at the end of the study. By a protocol amendment post hoc, all randomized patients were offered a standardized perimetry examination at the end of the study. Improvement rate was the proportion of patients with a reduction of seizure frequency of at least 50% during an 8-week period without any adverse events causing withdrawal. RESULTS: One hundred two patients were randomized and analyzed on an intent-to-treat basis. The improvement rate was 48% in the gabapentin group and 56% in the vigabatrin group. The improvement rate, when per protocol criteria were fulfilled, was 57% in the gabapentin group and 59% in the vigabatrin group. The proportion of seizure-free patients was 31% in the gabapentin group and 39% in the vigabatrin group. There was no difference in quality-of-life scores between the groups. Perimetry after termination of the study on 64 patients showed abnormal results in 3 of 32 patients in the vigabatrin group. CONCLUSION: Approximately one third of the patients in both groups became seizure-free. Although no major differences were seen in terms of the improvement rate between the groups, equivalence between the two drugs was not found.

Surgically created fourth-third cranial nerve communication: temporary success in a child with bilateral third nerve hamartomas. Case report.

Shortly after birth, an otherwise healthy infant developed eye deviation and ptosis due to a hamartomatous lesion of the interpeduncular segment of the right oculomotor nerve. The left nerve became similarly involved when the child was 1.5 years of age. Direct nerve repair was not possible. Instead, the trochlear nerve was divided and its proximal end was attached to the distal end of the third nerve. Elevation of the upper eyelid and partial adduction of the eye developed gradually over the ensuing 3 to 5 months. Both functions were lost after an additional 2 months, presumably as a result of tumor recurrence or neuroma formation. This case report shows that surgically created fourth-third cranial nerve communication is feasible and may merit consideration under similar circumstances.