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.

Debate--does a reversible penumbra exist in intracerebral haemorrhage?

Intracerebral haemorrhage is a devastating condition lacking effective therapies, with an uncertain role for surgery in many. Early research described an ischaemic penumbra around the haematoma, representing an area of potential therapeutic intervention. This article discusses the evidence for and against the existence of an ischaemic penumbra in ICH, with particular reference to recent imaging studies.

Difficulties with recruiting into neurosurgical clinical trials: the Surgical Trial in IntraCerebral Haemorrhage II as an example.

BACKGROUND: Spontaneous supratentorial intracerebral haemorrhage (ICH) is a devastating condition with a high morbidity and mortality, and uncertainty remains regarding the role of surgery in many cases. The Surgical Trial in IntraCerebral Haemorrhage II (STICH II) was initiated to look at subjects with superficial lobar ICH, as the initial STICH trial showed the greatest benefit from early surgery in this subgroup. Our aim was to estimate how many patients with ICH referred to the Greater Manchester Neurosciences Centre (GMNC) met the inclusion and exclusion criteria of the STICH II trial. METHODS: The number of patients eligible for STICH II was determined from the GMNC referral database and admissions to the stroke unit over 1 year (2008). Eligibility was determined by predefined criteria, and equipoise was agreed by two consultant neurosurgeons. RESULTS: One hundred and sixty-eight (38.7%) of 434 ICH referrals were lobar ICH; 53 (31.5% of lobar ICH) of these met the radiological and Glasgow Coma Scale (GCS) criteria for STICH II, but only 16 (9.5% of lobar ICH; 3.7% of all ICH) had equipoise agreed on by two neurosurgeons. Thirty-five ICH patients were admitted to the stroke unit, and 12 (34.3%) of these had lobar ICH; none were eligible for STICH II. CONCLUSIONS: The number of patients eligible for recruitment into STICH II is small, necessitating an aggressive recruitment approach. Recruitment should focus on neuroscience centres with neurosurgical units as opposed to stroke units.

Posterior listhesis of a lumbar vertebra in spinal tuberculosis.

The management of spinal tuberculosis, especially in children, is controversial. In children, vertebral destruction is more severe than adults because of the cartilaginous nature of their bone. Modern chemotherapy has significantly decreased mortality in spinal tuberculosis, but morbidity remains high. Without early surgery, patients can develop severe kyphosis leading to respiratory insufficiency, painful costopelvic impingement and paraplegia. Lumbar kyphosis results in early degenerative lumbar canal stenosis and is cosmetically unacceptable. We report a paediatric case of atypical spinal tuberculosis demonstrating the need for early surgical intervention to prevent significant spinal instability and neurologic deficit. A 12-year-old girl presented with increasing ambulatory difficulty and double incontinence 4 months after initiating treatment for pulmonary tuberculosis. There was no history of traumatic injury. Examination revealed severe lower limb neurologic deficit, with hypotonia, areflexia, marked sensory loss, and grade 0/5 power in both lower limbs. Plain radiographs and magnetic resonance imaging (MRI) demonstrated grade IV posterior listhesis of the L2 vertebral body over L3, cauda equina compression and bilateral psoas abscesses. Erosion of both the body and pedicle of L2 was observed. Both serology and pus drained from the psoas abscesses were negative for microorganisms. The patient underwent an L2 vertebrectomy via a left retroperitoneal approach. A titanium cage packed with autologous bone graft was inserted, and the spine was stabilized by fixation with screw and rods. Histopathology confirmed a diagnosis of tuberculosis. Eighteen months following the procedure, the patient has regained some power in her right leg and has completed her course of anti-tuberculous chemotherapy, but remains wheelchair-bound. To our knowledge, this is the first reported case of posterior listhesis secondary to spinal tuberculosis. Here, we discuss the possible management options in such a case, and the indications for surgery. As the global HIV/AIDS epidemic causes a resurgence in tuberculosis, increased awareness among the medical community regarding the atypical presentations of spinal tuberculosis is necessitated; both in the developing world where advanced clinical presentations are common, and in the developed world where spinal tuberculosis is an often-neglected diagnosis.

The accuracy of hospital discharge coding for hemorrhagic stroke.

BACKGROUND: Hospital discharge data is used in monitoring stroke epidemiology, and ensuring adequate resource allocation to treatment programs. Previous studies have reported variable accuracy levels for such data. We present the first study assessing the accuracy of International Classification of Diseases 10th Edition (ICD-10) discharge coding for hemorrhagic stroke in England. METHODS: We identified all patients with a primary diagnosis of intracerebral hemorrhage (ICH; ICD-10 code: I61.x) and subarachnoid hemorrhage (SAH; I60.x) admitted to the Newcastle upon Tyne Hospitals from 2002-2007. Positive predictive values (PPV) were calculated through validation with patient notes. RESULTS: Hospital discharge coding identified 978 ICH and 1169 SAH admissions over the six years. The number of diagnoses verified by patient notes was excellent for both ICH (n = 938) and SAH (n = 1123), with a PPV of 95.9% for ICH (95% confidence interval, CI = 94.5-97.0%) and 96.1%for SAH (95% CI = 94.8-97.0%). The coding errors observed were largely expected, with different types of stroke miscoded as ICH and SAH. CONCLUSIONS: The accuracy of ICD-10 hospital discharge coding for hemorrhagic stroke was excellent. However further research is needed to find ways to further improve its accuracy.

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.