Low Prevalence of Isolated Growth Hormone Deficiency in Patients After Brain Injury: Results From a Phase II Pilot Study.

Growth hormone deficiency (GHD) results in an impaired health-related quality of life (HrQoL) and cognitive impairment in the attention and memory domain. GHD is assumed to be a frequent finding after brain injury due to traumatic brain injury (TBI), aneurysmal subarachnoid hemorrhage (SAH) or ischemic stroke. Hence, we set out to investigate the effects of growth hormone (GH) replacement therapy in patients with isolated GHD after brain injury on HrQoL, cognition, and abdominal fat composition. In total, 1,408 patients with TBI, SAH or ischemic stroke were screened for inclusion. Of those, 54 patients (age 18-65 years) were eligible, and 51 could be tested for GHD with GHRH-L-arginine. In 6 patients (12%), GHD was detected. All patients with isolated GHD (n = 4 [8%], male, mean age ± SD: 49.0 ± 9.8 years) received GH replacement therapy for 6 months at a daily dose of 0.2-0.5 mg recombinant GH depending on age. Results were compared with an untreated control group of patients without hormonal insufficiencies after brain injury (n = 6, male, mean age ± SD: 49.5 ± 13.6 years). HrQoL as well as mood and sleep quality assessed by self-rating questionnaires (Beck Depression Index, Pittsburgh Sleep Quality Index) did not differ between baseline and 6 months within each group or between the two groups. Similarly, cognitive performance as assessed by standardized memory and attention tests did not show significant differences within or between groups. Body mass index was higher in the control vs. the GH replacement group at baseline (p = 0.038), yet not different at 6 months and within groups. Visceral-fat-by-total-fat-ratio measurements obtained from magnetic resonance imaging in 2 patients and 5 control subjects exhibited no consistent pattern. In conclusion, this single center study revealed a prevalence of GHD of about 12% (8% with isolated GHD) in brain injury patients which was lower compared with most of the previously reported cohorts. As a consequence, the sample size was insufficient to conclude on a benefit or no benefit of GH replacement in patients with isolated GHD after brain injury. A higher number of patients will be necessary to draw conclusions in future studies. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01397500.

Leber's hereditary optic neuropathy with late disease onset: clinical and molecular characteristics of 20 patients.

BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease that typically causes bilateral blindness in young men. Here we describe the clinical and molecular characteristics of 20 patients with disease onset after the age of 50 years (late onset-LHON). METHODS: From a cohort of 251 affected and 277 unaffected LHON carriers, we identified 20 patients with onset of visual loss after the age of 50 years. Using structured questionnaires, data including basic demographic details, age of onset, progression of visual loss and severity as well as exposure to possible environmental triggers including alcohol, smoking and illicit drugs were retrospectively collected. Groups were compared using the Mann-Whitney-U-Test for two independent groups of sampled data. RESULTS: The proportion of late onset-LHON in our cohort was 8% (20 patients, 15 males, 5 females). The mtDNA mutations m.11778G > A and m.3460G > A were found in 16 and 4 patients, respectively. Among 89 asymptomatic carriers above the age of 50 years (28 males, 61 females), the mtDNA mutations m.11778G > A, m.3460G > A and m.14484 T > C were found in 60, 12 and 17 carriers, respectively. Late onset-LHON patients had significantly higher mean cumulative tobacco and alcohol consumption compared with unaffected carriers. However, there was no significant difference between late onset- and typical LHON patients with regard to daily tobacco and weekly alcohol consumption before disease onset. CONCLUSION: As already shown for typical LHON, alcohol consumption and smoking are important trigger factors also for the late manifestation. LHON should be considered in the differential diagnosis of subacute blindness even in older patients.

Gene-environment interactions in Leber hereditary optic neuropathy.

Leber hereditary optic neuropathy (LHON) is a genetic disorder primarily due to mutations of mitochondrial DNA (mtDNA). Environmental factors are thought to precipitate the visual failure and explain the marked incomplete penetrance of LHON, but previous small studies have failed to confirm this to be the case. LHON has no treatment, so identifying environmental triggers is the key to disease prevention, whilst potentially revealing new mechanisms amenable to therapeutic manipulation. To address this issue, we conducted a large, multicentre epidemiological study of 196 affected and 206 unaffected carriers from 125 LHON pedigrees known to harbour one of the three primary pathogenic mtDNA mutations: m.3460G>A, m.11778G>A and m.14484T>C. A comprehensive history of exposure to smoking, alcohol and other putative environmental insults was collected using a structured questionnaire. We identified a strong and consistent association between visual loss and smoking, independent of gender and alcohol intake, leading to a clinical penetrance of 93% in men who smoked. There was a trend towards increased visual failure with alcohol, but only with a heavy intake. Based on these findings, asymptomatic carriers of a LHON mtDNA mutation should be strongly advised not to smoke and to moderate their alcohol intake.

Quality of life in patients with leber hereditary optic neuropathy.

PURPOSE: Leber hereditary optic neuropathy (LHON) is an inherited mitochondrial optic neuropathy characterized by bilateral, severe loss of central vision. In this study, the first formal assessment was conducted of visual disability in affected and unaffected individuals from molecularly confirmed LHON pedigrees. METHODS: Four hundred two LHON carriers--196 affected and 206 unaffected--from 125 genealogically distinct pedigrees were prospectively interviewed using the well-validated visual function index (VF-14) questionnaire: m.3460G>A (n = 71), m.11778G>A (n = 270), and m.14484T>C (n = 61). RESULTS: The mean age of onset of visual loss was 27.9 years (SD, 14.9) and mean disease duration was 15.5 years (SD, 15.4), with 74.5% of the affected subjects being men. The mean VF-14 score was 25.1 (SD, 20.8) in the affected patients, compared with 97.3 (SD, 7.1) in the unaffected carriers. Within the affected group, VF-14 score did not worsen with increasing disease duration and individuals with the m.14484T>C mutation had higher VF-14 scores compared with those in the m.3460G>A and m.11778G>A groups. Reading small print and reading a newspaper or book were the two VF-14 items that presented the greatest difficulty. CONCLUSIONS: LHON has a severe negative impact on quality of life and has the worst VF-14 score when compared with other previously studied ophthalmic disorders. However, affected LHON carriers can be reassured that their level of visual impairment is unlikely to progress with time. The VF-14 questionnaire will be a useful tool for assessing the natural history of LHON and measuring outcome in future treatment trials.