Cerebrovasc Dis 2012;34:406–410

Ischemic Vagus Nuclei Lesions and Hyperglycemia: A Study in 26 Patients with Lateral Medullary Infarction and Matched Controls

Ruano L.a · Alves I.a · Barreto R.a · Araújo I.b · Veira C.a · Cruz V.T.a, b
aNeurology Department, Hospital São Sebastião, Centro Hospitalar Entre Douro e Vouga, Santa Maria da Feira, and bSecção Autónoma de Ciências da Saúde, Universidade de Aveiro, Campus Universitário de Santiago, Aveiro, Portugal
email Corresponding Author


 goto top of outline Key Words

  • Hyperglycemia
  • Acute ischemic stroke
  • Brainstem stroke
  • Lateral medullary infarction
  • Wallenberg syndrome
  • Autonomic dysfunction

 goto top of outline Abstract

Background: Hyperglycemia is common after stroke in diabetic and nondiabetic patients. Furthermore, it has been associated with infarct expansion, worse functional outcomes and higher mortality. In a previous study, infarction of the insular region was related to higher poststroke glucose levels than infarcts in other cortical areas. Experimental studies in animal models suggested that the lower brainstem nuclei of the vagus nerve modulate insulin secretion. These nuclei are usually affected in lateral medullary infarction (LMI). We evaluated whether patients with lateral medullary stroke have worse poststroke glycemic control than other stroke patients. Methods: A hospital-based stroke registry was used to identify 26 patients from the years 2000 to 2010 who fulfilled the following inclusion criteria: (1) a first-ever stroke; (2) neurological deficits compatible with LMI; (3) MRI confirmation of an ischemic lesion of the lateral medulla involving the vagus nerve nuclei, and (4) no simultaneous infarcts. Patients were excluded if they were admitted to the hospital more than 24 h after stroke onset or died in the first 24 h after hospital admission. A control group of other stroke patients was randomly selected from the same stroke registry and over the same time period, matching for the age and gender of the LMI group. The average glycemia was compared between the two groups using a linear regression model adjusted for confounders. Glycated hemoglobin at admission was used to estimate prestroke glycemic control. Prestroke glycemic averages were then compared with poststroke glycemia for the two groups using the Wilcoxon signed test for related samples. Results: The average glycemia of the LMI patients in the first 24 h after stroke was 9.4 mmol/l (SD 3.2), and from 24 to 72 h it was 7.6 mmol/l (SD 2.8). In the comparison group, these values were 7.7 (SD 2.8) and 7.1 mmol/l (SD 2.7), respectively. As expected, diabetic patients had a significantly higher glycemia than nondiabetic patients (p < 0.0001). The adjusted linear regression model showed the average glycemia differences to be significant for the first 24 h (p = 0.001; R2 = 55.6%) but not for the 24– 72 h period. The frequency of previous diabetes mellitus was similar in both groups. As compared to prestroke glycemic estimates, glycemia in lateral medullary stroke patients increased significantly more than in controls during the first 24 h after stroke (p = 0.01), but again there were no significant differences for the 24–72 h period. Conclusions: This study suggests that ischemic lesions of the vagus nerve nuclei are associated with worse early poststroke glycemic control than stroke in other locations. Confirmation of this hypothesis and the long-term implications of glucose control impairment warrant further prospective studies.

Copyright © 2012 S. Karger AG, Basel

goto top of outline Introduction

Poststroke hyperglycemia is common in diabetic and nondiabetic patients [1]. Furthermore, there is strong and consistent evidence that hyperglycemia is an independent determinant of infarct expansion [2,3], worse functional outcome and mortality [4,5,6,7].

A study found that infarct of the insular region was associated with higher poststroke glucose levels than infarct in other cortical areas [8]. The acute hyperglycemic effects of vascular lesions in other cerebral areas involved in parasympathetic control, namely in the brainstem, are not established.

The regulation of glucose homeostasis depends on the central integration, probably in the insula, of afferent stimuli generated by specialized receptor cells in the bowels and blood vessels. Efferent signaling is generated towards the liver, muscles, blood vessels and pancreas. The vagus nerve tract seems to have a major role in both pathways of this complex metabolic reflex [9]. Experimental models in mice suggest that the nucleus ambiguus is a source of vagal motoneurons that facilitate insulin secretion by the pancreas [10] and that the dorsal nucleus of the vagus nerve is the source of excitatory and inhibitory inputs that modulate insulin secretion [11]. The extent of the role of vagus nerve nuclei in the modulation of insulin secretion in humans is not well known. The study of patients with ischemic infarction of the medulla, classically associated with Wallenberg syndrome, may represent a good opportunity to evaluate this subject. Lateral medullary infarcts (LMI) are very diverse and show multiple patterns of medullary involvement [12]. Nevertheless, the vagus nerve nuclei are usually damaged in large LMI [13]. These are commonly caused by posterior inferior cerebellar artery (PICA) or vertebral artery infarctions.

The aim of this study was to assess whether patients with LMI have worse poststroke glycemic control than patients with stroke in other locations.


goto top of outline Patients and Methods

goto top of outline Study Design and Setting

This was an observational study performed in a group of patients with LMI and a comparison group of other ischemic stroke patients. A prospective stroke registry from a 300-bed hospital with a reference population of 350,000 was used to identify LMI patients admitted from 2000 to 2010. They were compared with a control group of other stroke patients. This comparison group was randomly selected from the same stroke registry, matching for gender and age group (5 years) of the LMI patients, over the equivalent time period.

LMI Patients Selection Criteria. Patients were included if they were admitted with (1) a first-ever stroke, (2) neurological deficits compatible with LMI (dysarthria, dysphagia, vertigo, sensibility loss, ataxia) and (3) MRI confirmation of LMI with involvement of the vagus nerve nuclei. Patients were excluded if they (1) died in the first 24 h of their hospital stay, (2) had simultaneous infarct of another cerebral region or (3) were admitted to hospital more than 24 h after stroke onset.

MRI Analysis. We used the definitions and schematic drawing of the medullar structures by Kim [13] to identify patients with ‘typical’ and ‘large’ LMI demonstrated on fluid-attenuated inversion recovery, diffusion-weighted and T2-weighted MRI. Therefore, we selected patients with topographical lesions of the vagus nerve nuclei in the territory of both the medial and the lateral branch of the PICA.

Control Group Selection Criteria. The control group consisted of patients admitted with a first-ever ischemic stroke, except those with ischemic involvement of the insular region or any of the exclusion criteria listed above.

goto top of outline Glycemic Control Markers

Poststroke glycemic measurements were performed at regular periods and registered by clinical protocol in the first 72 h after admission, disregarding the patient’s previous diabetic state. Short-acting insulin was given when glycemia was higher than 8.3 mmol/l. Patients were on the same dietary protocol. High-calorie supplements were not given to patients in the period of the study. Since 2008, glycated hemoglobin (HbA1c) has been routinely assessed at admission.

goto top of outline Clinical Data

Baseline clinical data [gender, age, National Institutes of Health Stroke Scale (NIHSS) score at admission, HbA1c on the day of admission and previous diabetic status] and potential confounders (infection, steroid therapy) were collected from the stroke registry database and clinical records.

goto top of outline Statistics

We compared the average glucose levels between LMI patients and controls, in the 0–24 h and 24–72 h periods, using a linear regression model adjusted for confounding factors. These two periods were selected according to previous studies that showed biphasic hyperglycemic peaks [14]. Confounding was tested for previous diabetic state, infection and NIHSS score at admission. Interaction was also tested for age. The average glycemia of the previous 1–3 months (AG1–3 months) is linearly correlated with HbA1c by the following equation: AG1–3 months (mg/dl) = (HbA1c × 35.6) – 77.3 [15].

In the subgroups of LMI patients (n = 11) and controls (n = 19) admitted after 2008, the HbA1c at admission was used to estimate average prestroke glucose levels. The differences between individual average pre- and poststroke glycemia were compared using the Wilcoxon signed test for related samples. The statistical package used was IBM SPSS Statistics 20.0.


goto top of outline Results

Of 36 patients admitted with LMI, 33 were first-ever strokes and 26 complied with the selection criteria. The main cause of exclusion was hospital admission more than 24 h after stroke onset (n = 5). There was also 1 death in the first 24 h and 1 patient with simultaneous insular involvement, both of whom were excluded. The 7 excluded patients had an average age of 59.0 years (SD 17.4) and were predominantly males (85.7%); none had diabetes.

The distribution of ischemic lesions in the 26 patients from the comparison group was as follows: 56.5% in the anterior circulation, 26.1% in the posterior cerebral artery and 17.4% in the superior cerebellar artery.

The number of patients with previous diabetes and HbA1c values at admission was similar between LMI patients and the comparison group (table 1). Pulmonary infection developed in the first 72 h after stroke in 11.5% of LMI patients and in none of the patients in the comparison group. The average number of glycemic measurements used in the study was 8.9 for the patients in the comparison group and 9.3 for LMI patients, with a minimum of 6 for both groups.

Table 1. Patients’ clinical data at baseline

The serum glucose of LMI patients showed a biphasic curve over time, with peaks in the 6–12 h (10.3 mmol/l) and 60–66 h (8.6 mmol/l) intervals after stroke. The comparison group patients followed a similar pattern, but with lower glucose levels (fig. 1).

Fig. 1. Average poststroke glycemia in patients with LMI and other ischemic stroke patients (Controls).

As expected, diabetic patients had significantly higher glycemia than the nondiabetic patients (p < 0.0001). Patients’ age, gender, stroke side, NIHSS score and infection were not associated with glycemic control for either the 0–24 h or 24–72 h poststroke periods. In the first 24 h after stroke, the average glycemia of LMI patients was 9.4 mmol/l (SD 3.2); for the patients in the comparison group, it was 7.4 mmol/l (SD 2.3). In a linear regression model adjusted for previous diabetic state, this difference was found to be significant (p = 0.002; R2 = 46.5%). In the 24–72 h period, the LMI patients had an average glycemia of 7.6 mmol/l (SD 2.8), and for the comparison group patients, it was 7.1 mmol/l (SD 1.8). This difference was not significant (p = 0.29).

In the subgroup analysis of patients with HbA1c assessed at admission (admitted after 2008), the LMI patients had higher median poststroke glycemia than the estimate for the past 3 months (fig. 2). This difference was found to be significant only for the first 24 h after stroke (p = 0.01). There were no significant differences between pre- and poststroke glycemia in the control group (p = 0.53).

Fig. 2. Comparison between prestroke glycemic values (estimated by HbA1c at admission) and poststroke glycemia in patients with LMI and in other ischemic stroke patients (Controls).


goto top of outline Discussion

The average glycemia levels in the poststroke period in our patients are in line with other studies [1,8,14]. The biphasic glycemic curve observed has already been described [14], though its cause remains uncertain. LMI patients had significantly higher glycemic values than patients with other stroke locations in the first 24 h after stroke. In the 24–72 h period, this was not evident. When compared to prestroke values, glycemic control worsened in LMI patients. Again, this difference was only significant for the first 24 h. The control group patients had glycemic values comparable to those of the prestroke period.

The observed differences were not significant in the 24–72 h period. The reason could be a low statistical power or that the time frame chosen did not fully capture the second glycemic peak.

This study has some important limitations. It has a relatively small number of cases and may be underpowered. This number reflects the strict inclusion criteria regarding the extent of the PICA infarction, with demonstrable involvement of the vagus nerve nuclei. Patients who arrived late at the hospital or died early, and therefore did not have a reasonable number of poststroke glycemic values, were excluded. This was the main reason behind the exclusion of 21% of eligible patients. Furthermore, glycemic values were routinely registered by clinical protocol, but not for the purpose of this study. The 0–72 h observation window was selected because after this period, glycemic measurements are ceased in patients without hyperglycemia. Since the role of the insular region was previously established, we excluded patients with possible insular ischemic lesions. So, the comparable effects of complete and inferior branch middle cerebral artery infarcts were not assessed.

The use of a control group allowed correction for stress-induced hyperglycemia and other stroke-related factors. Confounding by age or gender was addressed by matching the controls. The random selection process resulted in two groups with very similar patterns of diabetes. The patients underwent the same protocols of glycemic control, insulin administration and feeding. None of the patients involved in this study was given corticosteroids or high-calorie nutritional supplements. The infection rate was higher in the LMI patients; however, this did not seem to be associated with higher glycemic values.


goto top of outline Conclusion

This study seems to support the hypothesis that vascular lesions of the vagus nerve nuclei worsen poststroke glycemic control. Additionally, it supports the proposed role of the vagus nerve as an important relay for brain modulation of pancreatic insulin secretion. Nevertheless, the results may not be definitive, and further clinical research is required to confirm these statements. As with previous studies addressing insular infarction, our results reinforce the hypothesis that poststroke hyperglycemia may be associated with particular stroke locations. This possibility should encourage a closer look at the impact of hyperglycemia and tight glycemic control in these subgroups. Furthermore, the assessment of other possible manifestations of autonomic dysfunction should also be carried out in future studies of patients with LMI.


goto top of outline Acknowledgments

We would like to thank Prof. Carolina Silva for her critical review of the study methods and statistics.


goto top of outline Disclosure Statement


 goto top of outline References
  1. Scott JF, Robinson GM, French JM, O’Connell JE, Alberti KG, Gray CS: Prevalence of admission hyperglycaemia across clinical subtypes of acute stroke. Lancet 1999;353:376–377.
  2. Baird TA, Parsons MW, Phanh T, Butcher KS, Desmond PM, Tress BM, Colman PG, Chambers BR, Davis SM: Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome. Stroke 2003;34:2208–2214.
  3. Els T, Klisch J, Orszagh M, Hetzel A, Schulte-Monting J, Schumacher M, Lucking CH: Hyperglycemia in patients with focal cerebral ischemia after intravenous thrombolysis: influence on clinical outcome and infarct size. Cerebrovasc Dis 2002;13:89–94.
  4. Hu GC, Hsieh SF, Chen YM, Hsu HH, Hu YN, Chien KL: Relationship of initial glucose level and all-cause death in patients with ischaemic stroke: the roles of diabetes mellitus and glycated hemoglobin level. Eur J Neurol 2012;19:884–891.
  5. Yong M, Kaste M: Dynamic of hyperglycemia as a predictor of stroke outcome in the ECASS-II trial. Stroke 2008;39:2749–2755.
  6. Putaala J, Sairanen T, Meretoja A, Lindsberg PJ, Tiainen M, Liebkind R, Strbian D, Atula S, Artto V, Rantanen K, et al: Post-thrombolytic hyperglycemia and 3-month outcome in acute ischemic stroke. Cerebrovasc Dis 2011;31:83–92.
  7. De Silva DA, Ebinger M, Christensen S, Parsons MW, Levi C, Butcher K, Barber PA, Bladin C, Donnan GA, Davis SM: Baseline diabetic status and admission blood glucose were poor prognostic factors in the EPITHET trial. Cerebrovasc Dis 2010;29:14–21.
  8. Allport LE, Butcher KS, Baird TA, MacGregor L, Desmond PM, Tress BM, Colman P, Davis SM: Insular cortical ischemia is independently associated with acute stress hyperglycemia. Stroke 2004;35:1886–1891.
  9. Burcelin R: The gut-brain axis: a major glucoregulatory player. Diabetes Metab 2010;36(suppl 3):S54–S58.
  10. Bereiter DA, Berthoud HR, Brunsmann M, Jeanrenaud B: Nucleus ambiguus stimulation increases plasma insulin levels in the rat. Am J Physiol 1981;241:E22–E27.
  11. Mussa BM, Sartor DM, Rantzau C, Verberne AJ: Effects of nitric oxide synthase blockade on dorsal vagal stimulation-induced pancreatic insulin secretion. Brain Res 2011;1394:62–70.
  12. Kumral E, Kisabay A, Atac C, Calli C, Yunten N: Spectrum of the posterior inferior cerebellar artery territory infarcts. Clinical-diffusion-weighted imaging correlates. Cerebrovasc Dis 2005;20:370–380.
  13. Kim JS: Pure lateral medullary infarction: clinical-radiological correlation of 130 acute, consecutive patients. Brain 2003;126:1864–1872.
  14. Allport L, Baird T, Butcher K, Macgregor L, Prosser J, Colman P, Davis S: Frequency and temporal profile of poststroke hyperglycemia using continuous glucose monitoring. Diabetes Care 2006;29:1839–1844.
  15. Rohlfing CL, Wiedmeyer HM, Little RR, England JD, Tennill A, Goldstein DE: Defining the relationship between plasma glucose and HbA(1c): analysis of glucose profiles and HbA(1c) in the Diabetes Control and Complications Trial. Diabetes Care 2002;25:275–278.

 goto top of outline Author Contacts

Luis Ruano, MD
Neurology Department, Hospital de São Sebastião, CHEDV
Rua Dr Cândido de Pinho
PT–4520-211 Santa Maria da Feira (Portugal)
E-Mail lmruano@gmail.com

 goto top of outline Article Information

Received: July 12, 2012
Accepted: September 14, 2012
Published online: December 4, 2012
Number of Print Pages : 5
Number of Figures : 2, Number of Tables : 1, Number of References : 15

 goto top of outline Publication Details

Cerebrovascular Diseases

Vol. 34, No. 5-6, Year 2012 (Cover Date: December 2012)

Journal Editor: Hennerici M.G. (Mannheim)
ISSN: 1015-9770 (Print), eISSN: 1421-9786 (Online)

For additional information: http://www.karger.com/CED

Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.