Gordon Smith

Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments

Preceding the joint meeting of the 19th annual Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) and the 8th International Symposium on Diabetic Neuropathy in Toronto, Canada, 13–18 October 2009, expert panels were convened to provide updates on classification, definitions, diagnostic criteria, and treatments of diabetic peripheral neuropathies (DPNs), autonomic neuropathy, painful DPNs, and structural alterations in DPNs.

Small fibre neuropathy: role in the diagnosis of diabetic sensorimotor polyneuropathy

Small fibres constitute 70–90% of peripheral nerve fibres and regulate several key functions such as tissue blood flow, temperature and pain perception as well as sweating, all of which are highly relevant to the clinical presentation and adverse outcomes associated with foot ulcerations in patients with diabetes. Recent studies demonstrated significant abnormalities in the small fibres in subjects with impaired glucose tolerance and diabetes, despite normal electrophysiology, suggesting that the earliest nerve fibre damage is to the small fibres. Unfortunately, guidelines and consensus statements focus on large fibres and continue to advocate electrophysiology as a diagnostic modality and as a primary end point for the assessment of therapeutic benefit. (In part, this reflects the difficulties in quantifying small fibre dysfunction and damage.) We have therefore critically assessed currently available techniques that measure small fibre dysfunction in diabetic neuropathy, using quantitative sensory and sudomotor testing. We have assessed the role of identifying structural damage by quantifying intraepidermal nerve fibre density in skin biopsies and corneal nerve morphology using corneal confocal microscopy. Finally, we propose a definition for diabetic neuropathy that incorporates small fibre damage. Copyright

Normative Values for Corneal Nerve Morphology Assessed Using Corneal Confocal Microscopy: A Multinational Normative Data Set

OBJECTIVE Corneal confocal microscopy is a novel diagnostic technique for the detection of nerve damage and repair in a range of peripheral neuropathies, in particular diabetic neuropathy. Normative reference values are required to enable clinical translation and wider use of this technique. We have therefore undertaken a multicenter collaboration to provide worldwide age-adjusted normative values of corneal nerve fiber parameters. RESEARCH DESIGN AND METHODS A total of 1,965 corneal nerve images from 343 healthy volunteers were pooled from six clinical academic centers. All subjects underwent examination with the Heidelberg Retina Tomograph corneal confocal microscope. Images of the central corneal subbasal nerve plexus were acquired by each center using a standard protocol and analyzed by three trained examiners using manual tracing and semiautomated software (CCMetrics). Age trends were established using simple linear regression, and normative corneal nerve fiber density (CNFD), corneal nerve fiber branch density (CNBD), corneal nerve fiber length (CNFL), and corneal nerve fiber tortuosity (CNFT) reference values were calculated using quantile regression analysis. RESULTS There was a significant linear age-dependent decrease in CNFD (−0.164 no./mm2 per year for men, P < 0.01, and −0.161 no./mm2 per year for women, P < 0.01). There was no change with age in CNBD (0.192 no./mm2 per year for men, P = 0.26, and −0.050 no./mm2 per year for women, P = 0.78). CNFL decreased in men (−0.045 mm/mm2 per year, P = 0.07) and women (−0.060 mm/mm2 per year, P = 0.02). CNFT increased with age in men (0.044 per year, P < 0.01) and women (0.046 per year, P < 0.01). Height, weight, and BMI did not influence the 5th percentile normative values for any corneal nerve parameter. CONCLUSIONS This study provides robust worldwide normative reference values for corneal nerve parameters to be used in research and clinical practice in the study of diabetic and other peripheral neuropathies.

Defects of mutant DNMT1 are linked to a spectrum of neurological disorders

We report a broader than previously appreciated clinical spectrum for hereditary sensory and autonomic neuropathy type 1E (HSAN1E) and a potential pathogenic mechanism for DNA methyltransferase (DNMT1) mutations. The clinical presentations and genetic characteristics of nine newly identified HSAN1E kinships (45 affected subjects) were investigated. Five novel mutations of DNMT1 were discovered; p.C353F, p.T481P, p.P491L, p.Y524D and p.I531N, all within the target-sequence domain, and two mutations (p.T481P, p.P491L) arising de novo. Recently, HSAN1E has been suggested as an allelic disorder of autosomal dominant cerebellar ataxia, deafness and narcolepsy. Our results indicate that all the mutations causal for HSAN1E are located in the middle part or N-terminus end of the TS domain, whereas all the mutations causal for autosomal dominant cerebellar ataxia, deafness and narcolepsy are located in the C-terminus end of the TS domain. The impact of the seven causal mutations in this cohort was studied by cellular localization experiments. The binding efficiency of the mutant DNMT proteins at the replication foci and heterochromatin were evaluated. Phenotypic characterizations included electromyography, brain magnetic resonance and nuclear imaging, electroencephalography, sural nerve biopsies, sleep evaluation and neuropsychometric testing. The average survival of HSAN1E was 53.6 years. [standard deviation = 7.7, range 43-75 years], and mean onset age was 37.7 years. (standard deviation = 8.6, range 18-51 years). Expanded phenotypes include myoclonic seizures, auditory or visual hallucinations, and renal failure. Hypersomnia, rapid eye movement sleep disorder and/or narcolepsy were identified in 11 subjects. Global brain atrophy was found in 12 of 14 who had brain MRI. EEGs showed low frequency (delta waves) frontal-predominant abnormality in five of six patients. Marked variability in cognitive deficits was observed, but the majority of patients (89%) developed significant cognitive deficit by the age of 45 years. Cognitive function decline often started with personality changes and psychiatric manifestations. A triad of hearing loss, sensory neuropathy and cognitive decline remains as the stereotypic presentation of HSAN1E. Moreover, we show that mutant DNMT1 proteins translocate to the cytoplasm and are prone to form aggresomes while losing their binding ability to heterochromatin during the G2 cell cycle. Our results suggest mutations in DNMT1 result in imbalanced protein homeostasis through aggresome-induced autophagy. This mechanism may explain why mutations in the sole DNA maintenance methyltransferase lead to selective central and peripheral neurodegeneration.

Electromyography of sternocleidomastoid muscle in ALS: A prospective study

Needle electromyography (EMG) of the tongue is difficult to perform because of frequent uncontrollable movement. We chose the sternocleidomastoid (SCM) muscle as a possible alternative for assessing the involvement of the rostral neuraxis in amyotrophic lateral sclerosis (ALS). We prospectively studied 21 ALS patients during our initial diagnostic evaluation. EMG parameters that we recorded included the presence of abnormal spontaneous activity, pattern of motor unit potential recruitment, and configuration of motor unit action potentials. For the six patients with bulbar‐onset ALS, three had abnormalities in the SCM and three had abnormalities in the tongue. In contrast, for the 15 patients with limb‐onset ALS, 9 had abnormalities in the SCM, and only 3 had abnormalities in the tongue. Our results demonstrate the utility of needle EMG of the SCM in the evaluation of ALS. EMG of the SCM carries a similar sensitivity as the tongue in ALS patients with bulbar symptoms, but is more sensitive than the tongue in patients without bulbar symptoms. SCM innervation includes the rostral cervical cord and brainstem, and EMG abnormalities in this muscle support a diffuse involvement, which is unique to ALS.

Association of Collateral Blood Vessels Detected by Arterial Spin Labeling Magnetic Resonance Imaging With Neurological Outcome After Ischemic Stroke

Importance Robust collateral blood vessels have been associated with better neurologic outcome following acute ischemic stroke (AIS). The most commonly used methods for identifying collaterals are contrast-based angiographic imaging techniques, which are not possible in all patients after AIS. Objective To assess the association between the presence of collateral vessels identified using arterial spin labeling (ASL) magnetic resonance imaging, a technique that does not require exogenous administration of contrast, and neurologic outcome in patients after AIS. Design, Setting, and Participants This retrospective cohort study examined 38 patients after AIS admitted to a tertiary academic medical center between 2012 and 2014 who underwent MRI with ASL. Main Outcomes and Measures According to a prespecified hypothesis, ASL images were graded for the presence of collaterals by 2 neuroradiologists. Modified Rankin Scale (mRS) scores at discharge and other composite data were abstracted from the medical record by a neurologist blinded to radiologic data. Results Of the 38 patients, 19 (50.0%) were male, and the mean (SD) age was 61 (20) years. In 25 of 38 patients (65.8%), collaterals were detected using ASL, which were significantly associated with both a good outcome (mRS score of 0-2 at discharge; P = .02) and a 1-point decrease in mRS score at discharge (odds ratio, 6.4; 95% CI, 1.7-23.4; P = .005). In a multivariable ordinal logistic regression model, controlling for admission National Institutes of Health Stroke Scale score, history of atrial fibrillation, premorbid mRS score, and stroke parent artery status, there was a strong association between the presence of ASL collaterals and a 1-point decrease in the mRS score at discharge (odds ratio, 5.1; 95% CI, 1.2-22.1; P = .03). Conclusions and Relevance Following AIS, the presence of ASL collaterals is strongly associated with better neurological outcome at hospital discharge. This novel association between ASL collaterals and improved neurologic outcome may help guide prognosis and management, particularly in patients who are unable to undergo contrast-based radiological studies.

Determinants of the impact of blood pressure variability on neurological outcome after acute ischaemic stroke

Introduction Increased blood pressure variability (BPV) is detrimental after acute ischaemic stroke, but the interaction between BPV and neuroimaging factors that directly influence stroke outcome has not been explored. Methods We retrospectively reviewed inpatients from 2007 to 2014 with acute anterior circulation ischaemic stroke, CT perfusion and angiography at hospital admission, and a modified Rankin Scale (mRS) 30–365 days after stroke onset. BPV indices included SD, coefficient of variation and successive variation of the systolic blood pressure between 0 and 120 hours after admission. Ordinal logistic regression models were fitted to mRS with predictor variables of BPV indices. Models were further stratified by CT perfusion volumetric measurements, proximal vessel occlusion and collateral score. Results 110 patients met the inclusion criteria. The likelihood of a 1-point rise in the mRS increased with every 10 mm Hg increase in BPV (OR for the 3 BPV indices ranged from 2.27 to 5.54), which was more pronounced in patients with larger ischaemic core volumes (OR 8.37 to 18.0) and larger hypoperfused volumes (OR 6.02 to 15.4). This association also held true for patients with larger mismatch volume, proximal vessel occlusion and good collateral vessels. Conclusions These results indicate that increased BPV is associated with worse neurological outcome after stroke, particularly in patients with a large lesion core volume, concurrent viable ischaemic penumbra, proximal vessel occlusion and good collaterals. This subset of patients, who are often not candidates for or fail acute stroke therapies such as intravenous tissue plasminogen activator or endovascular thrombectomy, may benefit from interventions aimed at reducing BPV.

Increased Blood Pressure Variability Is Associated with Worse Neurologic Outcome in Acute Anterior Circulation Ischemic Stroke

Background. Although research suggests that blood pressure variability (BPV) is detrimental in the weeks to months after acute ischemic stroke, it has not been adequately studied in the acute setting. Methods. We reviewed acute ischemic stroke patients from 2007 to 2014 with anterior circulation stroke. Mean blood pressure and three BPV indices (standard deviation, coefficient of variation, and successive variation) for the intervals 0–24, 0–72, and 0–120 hours after admission were correlated with follow-up modified Rankin Scale (mRS) in ordinal logistic regression models. The correlation between BPV and mRS was further analyzed by terciles of clinically informative stratifications. Results. Two hundred and fifteen patients met inclusion criteria. At all time intervals, increased systolic BPV was associated with higher mRS, but the relationship was not significant for diastolic BPV or mean blood pressure. This association was strongest in patients with proximal stroke parent artery vessel occlusion and lower mean blood pressure. Conclusion. Increased early systolic BPV is associated with worse neurologic outcome after ischemic stroke. This association is strongest in patients with lower mean blood pressure and proximal vessel occlusion, often despite endovascular or thrombolytic therapy. This hypothesis-generating dataset suggests potential benefit for interventions aimed at reducing BPV in this patient population.

Rapidly Progressive Quadriplegia and Encephalopathy

A woman aged 77 years was transferred to our neurocritical care unit for evaluation and treatment of rapidly progressive motor weakness and encephalopathy. Examination revealed an ability to follow simple commands only and abnormal movements, including myoclonus, tongue and orofacial dyskinesias, and opsoclonus. Imaging study findings were initially unremarkable, but when repeated, they demonstrated enhancement of the cauda equina nerve roots, trigeminal nerve, and pachymeninges. Cerebrospinal fluid examination revealed mildly elevated white blood cell count and protein levels. Serial electrodiagnostic testing demonstrated a rapidly progressive diffuse sensory motor axonopathy, and electroencephalogram findings progressed from generalized slowing to bilateral periodic lateralized epileptiform discharges. Critical details of her recent history prompted a diagnostic biopsy. Over time, the patient became completely unresponsive with no further abnormal movements and ultimately died. The differential diagnosis, pathological findings, and diagnosis are discussed with a brief review of a well-known yet rare diagnosis.