John Elston

Neuropathology of inflicted head injury in children

Geddes et al . have raised several interesting questions about the pathogenesis of non‐accidental head injury. It has been suspected previously that hypoxia secondary to apnoea rather than direct impact is responsible for the diffuse brain damage seen in non‐accidental injury (Johnson et al ., 1995). The authors’ neuro‐pathological findings support this theory and also demonstrate injuries at the cranio‐cervical junction that account for the apnoea and hypoxia in infants with non‐accidental injury (Geddes et al ., 2001 a, b ). Although we accept that it may not be necessary to shake an infant very violently to produce …

Amiloride Clinical Trial In Optic Neuritis (ACTION) protocol: a randomised, double blind, placebo controlled trial.

Introduction Neurodegeneration is a widely accepted contributor to the development of long-term disability in multiple sclerosis (MS). While current therapies in MS predominantly target inflammation and reduce relapse rate they have been less effective at preventing long-term disability. The identification and evaluation of effective neuroprotective therapies within a trial paradigm are key unmet needs. Emerging evidence supports amiloride, a licenced diuretic, as a neuroprotective agent in MS through acid sensing ion channel blockade. Optic neuritis (ON) is a common manifestation of MS with correlates of inflammation and neurodegeneration measurable within the visual pathways. Amiloride Clinical Trial In Optic Neuritis (ACTION) will utilise a multimodal approach to assess the neuroprotective efficacy of amiloride in acute ON. Methods and analysis 46 patients will be recruited within 28 days from onset of ON visual symptoms and randomised on a 1:1 basis to placebo or amiloride 10 mg daily. Double-blinded treatment groups will be balanced for age, sex and visual loss severity by a random-deterministic minimisation algorithm. The primary objective is to demonstrate that amiloride is neuroprotective in ON as assessed by scanning laser polarimetry of the peripapillary retinal nerve fibre layer (RNFL) thickness at 6 months in the affected eye compared to the unaffected eye at baseline. RNFL in combination with further retinal measures will also be assessed by optical coherence tomography. Secondary outcome measures on brain MRI will include cortical volume, diffusion-weighted imaging, resting state functional MRI, MR spectroscopy and magnetisation transfer ratio. In addition, high and low contrast visual acuity, visual fields, colour vision and electrophysiology will be assessed alongside quality of life measures. Ethics and dissemination Ethical approval was given by the south central Oxford B research ethics committee (REC reference: 13/SC/0022). The findings from ACTION will be disseminated through peer-reviewed publications and at scientific conferences. Trial registration number EudraCT2012-004980-39, ClinicalTrials.gov Identifier: NCT01802489.

Amiloride does not protect retinal nerve fibre layer thickness in optic neuritis in a phase 2 randomised controlled trial.

Background: Recent basic and clinical evidence suggests amiloride may be neuroprotective in multiple sclerosis (MS) through the blockade of the acid sensing ion channel (ASIC). Objective: To examine the neuroprotective efficacy of amiloride in acute optic neuritis (ON). Methods: A total of 48 patients were recruited to a phase 2, double blind, single site, randomised controlled trial. Scanning laser polarimetry (GDx) at 6 months was the primary outcome measure and optical coherence tomography (OCT) and visual and electrophysiological measures were secondary outcome measures. Participants aged 18–55 years, ≤28 days of onset of first episode unilateral ON, were randomised to amiloride (10 mg daily for 5 months) or placebo (clinicaltrials.gov, NCT 01802489). Results: Intention-to-treat (ITT) cohort consisted of 43 patients; 23 placebo and 20 amiloride. No significant drug-related adverse events occurred. No significant differences were found in GDx (p = 0.840). Visual evoked potentials (VEP) were significantly prolonged in the amiloride group compared to placebo (p = 0.004). All other secondary outcome measures showed no significant difference. Baseline analysis of OCT data demonstrated a significant pre-randomisation thinning of ganglion cell layer. Conclusion: Amiloride has not demonstrated any neuroprotective benefit within this trial paradigm, but future neuroprotective trials in ON should target the window of opportunity to maximise potential neuroprotective benefit.

Novel Variant of Miller Fisher Syndrome Occurring With Tumor Necrosis Factor α Antagonist Therapy

Novel Variant of Miller Fisher Syndrome Occurring With Tumor Necrosis Factor α Antagonist Therapy Miller Fisher syndrome (MFS) is characterized by the acute onset of external ophthalmoparesis, ataxia, and areflexia,1 and it is highly correlated with the presence of anti-GQ1b antibodies.2 Here we present a case with a limited variant of MFS characterized by mild ophthalmoparesis, pupillary unresponsiveness, lid twitches, and lid hops in the presence of an extremely high anti-GQ1b antibody level differing from the previously described tumor necrosis factor α (TNFα) antagonist–associated MFS cases.3,4 Report of a Case | A 43-year-old woman presented to the acute medical team with a 3-day history of worsening diplopia. She initially noticed blurring of distance vision, which then progressed to horizontal diplopia in primary gaze, worsening on gaze to the left-hand side. She also had a mild, nonspecific bitemporal headache. She denied any other neurological symptoms. The patient provided written informed consent to report her case. Her medical history included mesenteric ischemia thought secondary to factor V Leiden mutation. This required resection of the small bowel and subsequent anticoagulation with long-term warfarin therapy (target therapeutic range of international normalized ratio, 2.0-3.0). She had been diagnosed as having ulcerative colitis 12 years prior to her neurological presentation. This had been treated with azathioprine for 7 years then methotrexate. She had commenced treatment with infliximab 9 weeks prior to presentation owing to a corticosteroid-resistant severe flare-up of her ulcerative colitis. She had received 2 infusions of infliximab and was due to receive a third infusion on the day of her presentation with diplopia. Onpresentation,visualacuitywas20/20inbotheyesbutN14 for near with clear media and healthy optic discs and maculae. Pupils were mid-dilated and unreactive to light and accommodation. There was a mild asymmetric global ophthalmoparesis with both horizontal and vertical separation of images. There was no ptosis but upper eyelid twitches were evident on vertical eye movements with lid hops on horizontal gaze. Orbicularis oculi function was normal (Video and Figure, which demonstrates upper eyelid twitches on vertical eye movements, lid hops on horizontal eye movements, and unreactive pupils). The neurological examination was otherwise normal; in particular, the tendon reflexes were normal and symmetrical, plantar responses were down going, and there was no ataxia. Video at jamaneurology.com

Diagnosis of sporadic neurofibromatosis type 2 in the paediatric population

Objective Onset of symptoms in severe sporadic neurofibromatosis type 2 (NF2) is typically within childhood; however, there is poor awareness of presenting features in young children, potentially resulting in delayed diagnosis and poorer outcome. We have reviewed presentation of sporadic paediatric NF2 to raise awareness of early features, highlighting those requiring further investigation. Design Patients diagnosed with NF2 at age ≤16 and seen between 2012 and 2015 were notified via the British Paediatric Neurology Surveillance Unit or identified through the English NF2 service. Results Epidemiological data estimate that 1 in 110 611 births are affected with childhood-onset NF2. Notes of 32 patients with sporadic NF2 were reviewed. Of those presenting under the age of 5, 89% (17/19) had ocular, 74% (14/19) dermatological and 58% (11/19) neurological signs; in 84% (16/19) features were multisystemic. Sixty-six per cent (21/32) had ≥1 atypical feature, including cerebellar hypoplasia in three cases (9%) and focal cortical dysplasia in five out of seven seizure-related presentations. Five cases presented with a sometimes transient or intermittent cranial nerve mononeuropathy. The mean delay to diagnosis was 3.16 years; in eight cases (25%) this exceeded 6 years. Most significant delay occurred in mononeuropathy, ophthalmological and/or seizure presentations, with a mean delay of 3, 4.5 and 6 years, respectively. Eighty-four per cent (27/32) of cases needed intervention in childhood. Conclusions All non-vestibular schwannoma NF2 presentations in childhood had significant diagnostic delay. We emphasise the importance of detailed assessment of skin and eyes in unusual presentations and propose an aide to prompt timely referral to specialist services.

Opportunistic Infections of the Retina in Patients With Aquaporin-4 Antibody Disease

IMPORTANCE Patients with neuromyelitis optica who have aquaporin-4 antibodies are being identified and receiving immunosuppressant treatment earlier and more aggressively as a result of increasing awareness of the importance of preventing relapses responsible for the high morbidity and mortality associated with the disease. To our knowledge, opportunistic retinal infection in patients with aquaporin-4 antibodies who are receiving immunosuppressants has not been reported to date. OBSERVATIONS We describe 2 patients with aquaporin-4 antibodies who were receiving conventional doses of first-line immunosuppressive therapy. Both patients presented with vision loss that was initially thought to be optic neuritis attacks. The subsequent diagnoses were ocular toxoplasmosis and cytomegalovirus retinitis. CONCLUSIONS AND RELEVANCE Retinal opportunistic infections can occur in patients with aquaporin-4 antibodies who are receiving relatively low levels of immunosuppression, may mimic optic neuritis, and are a potentially reversible cause of vision loss when treated promptly.

Peripheral ulcerative keratitis as a complication of acute myeloid leukaemia

We report a rare presentation of acute bilateral peripheral ulcerative keratitis (PUK) in a patient with a new diagnosis of untreated acute myeloid leukaemia (AML). To the best of our knowledge, this is the first report of PUK associated with untreated AML and we stress the importance of a rapid and thorough testing to exclude other diagnoses. The patient lost his vision within 10 days to counting fingers. Rapid diagnosis allowed a good visual recovery following prompt treatment with oral steroids and systemic chemotherapy treatment for the AML.

133 Aquaporin 4 antibody seropositivity and visual function in a UK cohort

Objectives To identify clinical features of aquaporin 4 (AQP4) antibody positive optic neuritis (ON) in neuromyelitis optica (NMO) and NMO spectrum disorder (NMOSD) in a UK cohort. Methods We performed a retrospective review of case notes of NMO and NMOSD patients referred to the joint UK National NMO service (based at Liverpool and Oxford) positive for AQP4 antibody by cell based assay between 2006 and 2011. The clinical features, visual acuity, visual perimetry, optical coherence tomography results and visual evoked responses were analysed. Results 50 AQP4 antibody positive patients were identified. The optic neuronopathy was associated with severe sight impairment. However some NMO patients had a mild ON indistinguishable clinically from MS. Patients with isolated longitudinally extensive myelitis (LETM) and AQP4 antibodies did not show subclinical optic nerve abnormalities. Conclusions AQP4 antibody optic neuritis is clinically expressed and generally causes severe optic nerve damage. In those without clinical features the antibodies do not cause asymptomatic evidence of damage unlike in Multiple sclerosis which is commonly associated with subclinical involvement. The factors that influence whether AQP4 antibodies cause ON require elucidating. DoH National Specialised Commissioning Team joint UK Neuromyelitis Optica Service.

The evidence base for retinal haemorrhages in shaken baby syndrome

‘The evidence base for retinal haemorrhages in shaken baby syndrome’ SIR–Dr Squier’s review analyses the evidence base for subdural haemorrhages which we agree is an important finding in ‘shaken baby syndrome’ (non-accidental head injury [NAHI]). However, it provides a skewed perspective on the subject by focusing on subdural haemorrhages in isolation. It ignores another important finding – the presence of retinal haemorrhages which, along with the history, clinical examination, radiology, and pathology findings help arrive at the diagnosis. The severity of retinal haemorrhages in NAHI closely parallels the degree of brain injury, and the neurological outcome. There is ample evidence that the same mechanism is responsible for the eye and brain findings. Of the theories that have been proposed for the mechanism of retinal haemorrhages in NAHI, rotational and shearing traction between the vitreous gel and the retina is the likeliest mechanism. The infant eye has strong adhesions between the vitreous gel and the internal limiting membrane of the retina, especially around the optic disc and in the retinal periphery. The differential movement at the interface between the vitreous and retina due to acceleration-deceleration forces is believed to result in shearing of retinal vessels, which may be dilated as a result of increased intracranial venous pressures secondary to raised intrathoracic pressure. Moreover, macular retinoschisis and retinal folds, characteristic but not invariable findings in NAHI, result from mechanical separation of the retinal layers. This cannot occur without repeated traction between the retina and the vitreous gel, lending further support to this theory. Dr Squier has suggested that the subdural haemorrhages in NAHI may occur from vessels damaged by hypoxia and haemodynamic disturbances, rather than from traumatic rupture of bridging vessels. The author refers to Larroche et al 8 who reported the association of findings of venous congestion and hypoxic–ischaemic injury with the presence of subdural haemorrhages in a study of 700 autopsies of perinatal deaths, not cases of head injury. The author has interpreted this association to imply causation. This theory, previously proposed by Geddes (referred to as Geddes III, an autopsy study of deaths from various causes including but not restricted to head injury) and later retracted in the UK Court of Appeal, provides no explanation for the characteristic retinal haemorrhages of NAHI. The abnormal haemodynamic forces referred to by the author include venous hypertension, systemic arterial hypertension, and episodic surges in blood pressure. The retinal haemorrhages in NAHI are large, extend throughout the retinal layers, and into the periphery. In contrast, the retinal haemorrhages in hypoxia and haemodynamic instability, when present, are flame shaped, superficial, and do not extend to the peripheral retina. This difference may be explained by the direct transmission of the abnormal haemodynamic forces to the posterior retinal vesels, and the greater density of vessels at the posterior pole. For example, the combination of severe hypoxia, and a sustained, severe rise in venous pressure is seen after strangulation or hanging. Reports of fundus examinations in survivors or autopsy findings do not show haemorrhages of the same severity as NAHI. Macular retinoschisis and retinal folds are never seen in cases of hanging or strangulation. Similarly, conditions like phaeochromocytoma that can produce a sudden rise in systemic arterial pressure are not associated with the retinal findings seen in NAHI. Also, vigorous cardio-pulmonary resuscitation, which is necessarily associated with hypoxia and raised venous pressure, is almost never associated with retinal haemorrhages. Haemodynamic changes may thus contribute, but cannot be the sole mechanism for the retinal changes seen in NAHI. There has to be another mechanism to account for the ophthalmological findings seen in these cases. Anterior tracking of sub-arachnoid haemorrhage was proposed as a possible mechanism, but this theory has been disproved by clinico-pathological studies. The most likely mechanism that would explain all these findings is the tractional forces generated by repeated abusive handling. The author quotes Ommaya’s study of adult primates, and the conclusion that manual shaking of a child cannot generate the same magnitude of forces as single high impact trauma as in a motor vehicle accident. There is good evidence that high speed single impact head trauma of sufficient severity to produce serious brain injury or even death, is only rarely associated with retinal haemorrhages. The ALSPAC study confirmed that falls from beds and settees in young infants did not result in skull fractures, and serious injury was the result of complex accidents. From consideration of the likely mechanism of retinal haemorrhages in NAHI and the rare description of the trauma by perpetrators, it is evident that sufficient shearing forces can be generated by abusive handling. The author suggests that in contrast to diffuse axonal injury which produces immediate brain swelling, hypoxic– ischaemic damage produces slower onset of brain swelling, with resultant damage to the intracranial vessels and subdural bleeding. This slower onset of brain swelling has been proposed as an explanation for a lucid interval in such cases. However, the characteristic history given by the carers admitting to NAHI is that the infant collapsed immediately. The lucid interval suggested by the author is not seen in clinical practice, undermining the validity of her hypothesis. Furthermore, the author suggests that awake apnoea may be caused by aspiration of feed ⁄ vomit, or even nappy changing. She proposes that the apnoea may produce hypoxia and increased blood flow to the brain, which in turn may result in dural haemorrhages. However, we know that severe hypoxia from acute life-threatening events in infants is not associated with retinal haemorrhages. This theory therefore cannot explain the eye findings in NAHI. In conclusion, the hypotheses advanced in this review for the causation of subdural haemorrhages cannot explain the retinal haemorrhages in NAHI. This could have serious implications, both scientific and legal on the mechanism of non-accidental shaking injuries.

Mystery Case: Terson syndrome on CT head

A 36-year-old woman presented with acute severe headache and generalized tonic-clonic seizures. CT head scan revealed a tentorial acute subdural hemorrhage (ASDH) and posterior globe hyperdensities suggestive of intraocular blood with a right posterior communicating artery aneurysm on cerebral angiography (figure 1). Ophthalmologic assessment confirmed Terson syndrome (figure 2).