Indran Davagnanam

Cerebral artery dilatation maintains cerebral oxygenation at extreme altitude and in acute hypoxia—an ultrasound and MRI study

Transcranial Doppler is a widely used noninvasive technique for assessing cerebral artery blood flow. All previous high altitude studies assessing cerebral blood flow (CBF) in the field that have used Doppler to measure arterial blood velocity have assumed vessel diameter to not alter. Here, we report two studies that demonstrate this is not the case. First, we report the highest recorded study of CBF (7,950 m on Everest) and demonstrate that above 5,300 m, middle cerebral artery (MCA) diameter increases (n = 24 at 5,300 m, 14 at 6,400 m, and 5 at 7,950 m). Mean MCA diameter at sea level was 5.30 mm, at 5,300 m was 5.23 mm, at 6,400 m was 6.66 mm, and at 7,950 m was 9.34 mm (P<0.001 for change between 5,300 and 7,950 m). The dilatation at 7,950 m reversed with oxygen. Second, we confirm this dilatation by demonstrating the same effect (and correlating it with ultrasound) during hypoxia (FiO2 = 12% for 3 hours) in a 3-T magnetic resonance imaging study at sea level (n = 7). From these results, we conclude that it cannot be assumed that cerebral artery diameter is constant, especially during alterations of inspired oxygen partial pressure, and that transcranial 2D ultrasound is a technique that can be used at the bedside or in the remote setting to assess MCA caliber.

Cerebral venous system and anatomical predisposition to high-altitude headache

As inspired oxygen availability falls with ascent to altitude, some individuals develop high‐altitude headache (HAH). We postulated that HAH results when hypoxia‐associated increases in cerebral blood flow occur in the context of restricted venous drainage, and is worsened when cerebral compliance is reduced. We explored this hypothesis in 3 studies.

Distinguishing optic neuritis in neuromyelitis optica spectrum disease from multiple sclerosis: a novel magnetic resonance imaging scoring system.

Background: The management of acute optic neuritis differs according to the underlying etiology and techniques which may help with early differential diagnosis are therefore of considerable value. Objective: We wanted to determine if multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) could be differentiated on the basis of neuroimaging abnormalities of the anterior visual pathways following an episode of optic neuritis. Methods: Magnetic resonance imaging (MRI) findings of 27 patients diagnosed with MS (n = 15) or NMOSD (n = 12), who presented with acute isolated optic neuritis over a 3-year period, were reviewed retrospectively. The extent and location of inflammation along the anterior visual pathways were analyzed. A novel scoring system was devised, based upon the number of anatomical segments involved. Results: Patients with NMOSD had a relative risk of 7.5 (confidence interval: 0.3–17.3) of having a score of 4 or more. Only NMOSD patients were found to have a score of 6 or higher. A trend for more posterior involvement of the anterior visual pathways was noted in the NMOSD group. Conclusion: This pilot study suggests that the MRI-based scoring system described here may aid in distinguishing patients with optic neuritis who have MS vs NMOSD. Visual pathway inflammation in NMOSD patients appears to be more extensive than in MS, mirroring the longitudinally extensive spinal cord lesions found in neuromyelitis optica.

Effect of white-matter lesions on the risk of periprocedural stroke after carotid artery stenting versus endarterectomy in the International Carotid Stenting Study (ICSS): a prespecified analysis of data from a randomised trial

Summary Background Findings from randomised trials have shown a higher early risk of stroke after carotid artery stenting than after carotid endarterectomy. We assessed whether white-matter lesions affect the perioperative risk of stroke in patients treated with carotid artery stenting versus carotid endarterectomy. Methods Patients with symptomatic carotid artery stenosis included in the International Carotid Stenting Study (ICSS) were randomly allocated to receive carotid artery stenting or carotid endarterectomy. Copies of baseline brain imaging were analysed by two investigators, who were masked to treatment, for the severity of white-matter lesions using the age-related white-matter changes (ARWMC) score. Randomisation was done with a computer-generated sequence (1:1). Patients were divided into two groups using the median ARWMC. We analysed the risk of stroke within 30 days of revascularisation using a per-protocol analysis. ICSS is registered with controlled-trials.com, number ISRCTN 25337470. Findings 1036 patients (536 randomly allocated to carotid artery stenting, 500 to carotid endarterectomy) had baseline imaging available. Median ARWMC score was 7, and patients were dichotomised into those with a score of 7 or more and those with a score of less than 7. In patients treated with carotid artery stenting, those with an ARWMC score of 7 or more had an increased risk of stroke compared with those with a score of less than 7 (HR for any stroke 2·76, 95% CI 1·17–6·51; p=0·021; HR for non-disabling stroke 3·00, 1·10–8·36; p=0·031), but we did not see a similar association in patients treated with carotid endarterectomy (HR for any stroke 1·18, 0·40–3·55; p=0·76; HR for disabling or fatal stroke 1·41, 0·38–5·26; p=0·607). Carotid artery stenting was associated with a higher risk of stroke compared with carotid endarterectomy in patients with an ARWMC score of 7 or more (HR for any stroke 2·98, 1·29–6·93; p=0·011; HR for non-disabling stroke 6·34, 1·45–27·71; p=0·014), but there was no risk difference in patients with an ARWMC score of less than 7. Interpretation The presence of white-matter lesions on brain imaging should be taken into account when selecting patients for carotid revascularisation. Carotid artery stenting should be avoided in patients with more extensive white-matter lesions, but might be an acceptable alternative to carotid endarterectomy in patients with less extensive lesions. Funding Medical Research Council, the Stroke Association, Sanofi-Synthélabo, the European Union Research Framework Programme 5.

Adult Horner's syndrome: a combined clinical, pharmacological, and imaging algorithm.

The diagnosis of Horner’s syndrome (HS) can be difficult, as patients rarely present with the classic triad of ptosis, miosis, and anhydrosis. Frequently, there are no associated symptoms to help determine or localise the underlying pathology. The onset of anisocoria may also be uncertain, with many cases referred after incidental discovery on routine optometric assessment. Although the textbooks discuss the use of cocaine, apraclonidine, and hydroxyamphetamine to diagnose and localise HS, in addition to reported false positive and negative results, these pharmacological agents are rarely available during acute assessment or in general ophthalmic departments. Typically, a week is required between using cocaine or apraclonidine for diagnosis and localisation of HS with hydroxyamphetamine, leaving the clinician with the decision of which investigations to request and with what urgency. Modern imaging modalities have advanced significantly and become more readily available since many of the established management algorithms were written. We thus propose a practical and safe combined clinical and radiological diagnostic protocol for HS that can be applied in most clinical settings.

Skeletal muscle MRI magnetisation transfer ratio reflects clinical severity in peripheral neuropathies

MRI may provide treatment outcome measures in neuromuscular conditions. The authors assessed MRI magnetisation transfer ratios (MTRs) in lower-limb musculature as markers of pathology in peripheral neuropathies and compared the findings with associated clinical data. Ten patients with Charcot–Marie–Tooth disease type 1A (CMT1A) and nine patients with chronic inflammatory demyelinating polyneuropathy (CIDP) were compared with 10 healthy subjects. The MTR in the calf muscles was significantly lower than controls in the two patient groups (both p<0.001). The median MTRs (IQR) were 50.5(1.6) percentage units (p.u.) (control), 41.5(10.6) p.u. (CMT1A) and 39.3(8.7) p.u. (CIDP). Moreover, anterior lower leg MTR correlated strongly with strength of ankle dorsiflexion, measured with the Medical Research Council scale, in CIDP (ρ=0.88, p<0.001) and also in CMT1A (ρ=0.50, p<0.05), where MTR also showed an association with disease duration (ρ=−0.86, p<0.001). Short tau inversion recovery MRI of the same muscles showed abnormalities associated with regions of reduced MTR (p<0.001), and MTR was also reduced in other muscles otherwise deemed normal appearing (p<0.001), indicating that MTR may be more sensitive to muscle damaged by denervation than conventional MRI. The significant reductions in muscle MTR in peripheral neuropathies and the associated correlations with clinical measures indicate that MTR has potential as an imaging outcome measure in future therapeutic trials.

Soluble CD40L in peripheral artery disease Relationship with disease severity, platelet markers and the effects of angioplasty

Although soluble CD40L (sCD40L, possibly derived from platelets and pro-inflammatory in vitro) may be implicated in thrombosis and haemostasis, there are little data in peripheral artery disease (PAD). We hypothesised the following: (a) that sCD40L relates to the clinical severity of PAD; and (b) that peripheral artery angioplasty acutely raises sCD40L levels. sCD40L was compared to established platelet markers soluble P selectin, platelet microparticles and platelet surface expression of CD62 and CD63. We recruited 36 healthy controls, 33 patients with intermittent claudication (IC), and 33 with symptomatically more severe critical limb ischaemia (CLI), measuring plasma markers by ELISA and membrane markers by flow cytometry. Eleven patients with CLI subsequently underwent peripheral artery angioplasty: blood was taken before and 10 minutes after the intervention. Results show that sCD40L was raised in IC at median 68 (IQR 28-333) pg/ml and in CLI at 64 (34-282) pg/mL compared to 35 (IQR 28-55) pg/ml in the healthy controls (p=0.009). Levels were no different between IC and CLI. The same distribution pattern was present for soluble P selectin, %platelets CD62+ve and CD63+ve. sCD40L failed to correlate significantly with ABPI (p=0.264), unlike %platelets CD62+ve (p=0.0032) and CD63+ve (p=0.009). Pre-angioplasty sCD40L level of 72 (35-610) ng/ml rose to 100 ng/ml (IQR=60-237)(p=0.018) post-angioplasty. Plasma sCD40L, in addition to other platelet indices, is raised in peripheral atherosclerosis and is increased by peripheral artery angioplasty, although levels seem unrelated to clinical severity. Failure to correlate with other markers suggest the platelet may not be the sole source of sCD40L, and that other cells may contribute to plasma levels.

MRI shows increased sciatic nerve cross sectional area in inherited and inflammatory neuropathies

Measurements of the cross sectional area of the sciatic nerve are described in a group of 10 patients with genetically confirmed Charcot–Marie–Tooth disease type 1A (CMT1A), nine patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and 10 healthy controls using MRI. One mid-thigh of each individual was imaged using a short tau inversion recovery sequence and the nerve appearance evaluated radiologically with respect to the signal intensity and visibility of the internal neural structure. The cross sectional area of the sciatic nerve of each individual was measured by defining irregular enclosing regions of interest on the MRI images. The sciatic nerve area was enlarged in both CMT1A (p<0.001) and CIDP (p=0.008) compared with controls and in CMT1A compared with CIDP (p<0.001). Median (interquartile range) areas were 67.6 (16.2) mm2 for the CIDP group, 135.9 (46.5) mm2 for the CMT1A group and 43.3 (19.9) mm2 for the control group. The critical upper value for discriminating pathologically enlarged nerves from normal controls with p<0.05 was 64.4 mm2. Quantification of sciatic nerve hypertrophy on MRI may be of assistance in cases where the diagnosis is still in doubt, providing an objective pathological marker complimenting other clinical investigations.

Identification of the Normal Jugular Foramen and Lower Cranial Nerve Anatomy: Contrast-Enhanced 3D Fast Imaging Employing Steady-State Acquisition MR Imaging

SUMMARY: Conventional imaging protocols are unable to visualize the intraforaminal/canalicular segments of the lower cranial nerves (IX–XII). On the basis of previous successful demonstration of individual cranial nerves within the cavernous sinus by constructive interference in steady-state MR imaging, we describe the use of contrast-enhanced 3D fast imaging employing steady-state acquisition MR imaging to demonstrate normal in vivo intraforaminal and canalicular segments of cranial nerves IX–XII in 10 patients by using a standardized imaging protocol.

Analysis of Mutations in AARS2 in a Series of CSF1R-Negative Patients With Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia

Importance Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a frequent cause of adult-onset leukodystrophy known to be caused by autosomal dominant mutations in the CSF1R (colony-stimulating factor 1) gene. The discovery that CSF1R mutations cause ALSP led to more accurate prognosis and genetic counseling for these patients in addition to increased interest in microglia as a target in neurodegeneration. However, it has been known since the discovery of the CSF1R gene that there are patients with typical clinical and radiologic evidence of ALSP who do not carry pathogenic CSF1R mutations. These patients include those in whom the pathognomonic features of axonal spheroids and pigmented microglia have been found. Achieving a genetic diagnosis in these patients is important to our understanding of this disorder. Objective To genetically characterize a group of patients with typical features of ALSP who do not carry CSF1R mutations. Design, Settings, and Participants In this case series study, 5 patients from 4 families were identified with clinical, radiologic, or pathologic features of ALSP in whom CSF1R mutations had been excluded previously by sequencing. Data were collected between May 2014 and September 2015 and analyzed between September 2015 and February 2016. Main Outcomes and Measures Focused exome sequencing was used to identify candidate variants. Family studies, long-range polymerase chain reaction with cloning, and complementary DNA sequencing were used to confirm pathogenicity. Results Of these 5 patients, 4 were men (80%); mean age at onset of ALSP was 29 years (range, 15-44 years). Biallelic mutations in the alanyl-transfer (t)RNA synthetase 2 (AARS2) gene were found in all 5 patients. Frameshifting and splice site mutations were common, found in 4 of 5 patients, and sequencing of complementary DNA from affected patients confirmed that the variants were loss of function. All patients presented in adulthood with prominent cognitive, neuropsychiatric, and upper motor neuron signs. Magnetic resonance imaging in all patients demonstrated a symmetric leukoencephalopathy with punctate regions of restricted diffusion, typical of ALSP. In 1 patient, brain biopsy demonstrated axonal spheroids and pigmented microglia, which are the pathognomonic signs of ALSP. Conclusions and Relevance This work indicates that mutations in the tRNA synthetase AARS2 gene cause a recessive form of ALSP. The CSF1R and AARS2 proteins have different cellular functions but overlap in a final common pathway of neurodegeneration. This work points to novel targets for research and will lead to improved diagnostic rates in patients with adult-onset leukoencephalopathy.