Microvascular perfusion abnormalities of the Thalamus in painful but not painless diabetic polyneuropathy: a clue to the pathogenesis of pain in type 1 diabetes.
ABSTRACT The pathogenesis of painful diabetic neuropathy (DN) remains undetermined, with both central and peripheral mechanisms implicated. This study investigates whether thalamic perfusion abnormalities occur in painful DN.
Eighteen subjects with type 1 diabetes (no DN = 6, painful DN = 5, painless DN = 7) and six healthy volunteers (HV) were recruited. Microvascular perfusion characteristics (relative cerebral blood volume [rCBV], flow [rCBF], and transit time [tt(FM)]) of the thalamus and caudate nucleus were assessed using magnetic resonance perfusion imaging. The caudate nucleus was chosen to serve as an in vivo control region.
Subjects with painful DN had significantly greater thalamic rCBV (means [SD]; painful DN, 228.7 [19.5]; no DN, 202.3 [25.8]; painless DN, 216.5 [65.5]; HV, 181.9 [51.7]; P = 0.04) and the longest tt(FM)(s) (painful DN, 38.4 [3.6]; no DN, 35.3 [13.2]; painless DN, 35.9 [13.7]; HV, 33.7 [14.9]; P = 0.07). There was no significant difference in markers of caudate nucleus perfusion.
Painful DN is associated with increased thalamic vascularity. This may provide an important clue to the pathogenesis of pain in DN.
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ABSTRACT: The diagnosis of autonomic neuropathy frequently depends on results of tests which elicit reflex changes in heart rate. Few well-documented normal ranges are available for these tests. The present study was designed to investigate the effect of age upon heart rate variability at rest and in response to a single deep breath, the Valsalva manoeuvre, and standing. A computerised method of measurement of R-R interval variation was used to study heart rate responses in 310 healthy subjects aged 18-85 years. Heart rate variation during each procedure showed a skewed distribution and a statistically significant negative correlation with age. Normal ranges (90% and 95% confidence limits) for subjects aged 20-75 years were calculated for heart rate difference (max-min) and ratio (max/min) and standard deviation (SD). Heart rate responses were less than the 95th centile in at least one of the four procedures in 39 (12.6%) out of the 310 subjects, and were below this limit in two or more tests in five (1.6%) subjects. In view of the decline in heart rate variation with increasing age, normal ranges for tests of autonomic function must be related to the age of the subject.Heart 05/1986; 55(4):348-54.
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ABSTRACT: At least one of four diabetic patients is affected by distal symmetric polyneuropathy, which represents a major health problem, since it may present with partly excruciating neuropathic pain and is responsible for substantial morbidity, increased mortality, and impaired quality of life. Treatment is based on four cornerstones: 1) causal treatment aimed at (near)-normoglycemia, 2) treatment based on pathogenetic mechanisms, 3) symptomatic treatment, and 4) avoidance of risk factors and complications. Recent experimental studies suggest a multifactorial pathogenesis of diabetic neuropathy. From the clinical point of view, it is important to note that, based on these pathogenetic mechanisms, therapeutic approaches could be derived, some of which are currently being evaluated in clinical trials. Among these agents, only alpha-lipoic acid is available for treatment in several countries and epalrestat in Japan. Although several novel analgesic drugs such as duloxetine and pregabalin have recently been introduced into clinical practice, the pharmacologic treatment of chronic painful diabetic neuropathy remains a challenge for the physician. Individual tolerability remains a major aspect in any treatment decision. Epidemiological data indicate that not only increased alcohol consumption but also the traditional cardiovascular risk factors such as hypertension, smoking, and cholesterol play a role in development and progression of diabetic neuropathy and hence need to be prevented or treated.Diabetes care 03/2008; 31 Suppl 2:S255-61. · 8.09 Impact Factor
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ABSTRACT: Quantitative morphological data are presented from a series of studies assessing both nerve fiber and capillary pathology in 30 diabetic patients with varying stages and symptoms of neuropathy. There is a significant relationship between clinical measures of neuropathic severity and myelinated fiber loss. However, unmyelinated fibers continue to regenerate even in patients with established neuropathy. Microvascular abnormalities, particularly basement membrane thickening and endothelial cell hyperplasia, are an early feature of diabetic microangiopathy and relate to neuropathic severity. There are no neurophysiological or morphological differences between patients with type 1 and type 2 diabetes nor between diabetic patients with and without painful neuropathy.Diabetes 10/1997; 46 Suppl 2:S50-3. · 7.90 Impact Factor
Microvascular Perfusion Abnormalities
of the Thalamus in Painful but Not
Painless Diabetic Polyneuropathy
A clue to the pathogenesis of pain in type 1 diabetes
DINESH SELVARAJAH, MBCHB, MRCP1
IAIN D. WILKINSON, PHD2
RAJIV GANDHI, MBCHB, MRCP1
PAUL D. GRIFFITHS, FRCR, PHD2
SOLOMON TESFAYE, MD, FRCP1
OBJECTIVE—The pathogenesis of painful diabetic neuropathy (DN) remains undetermined,
with both central and peripheral mechanisms implicated. This study investigates whether tha-
lamic perfusion abnormalities occur in painful DN.
RESEARCH DESIGN AND METHODS—Eighteen subjects with type 1 diabetes
(no DN = 6, painful DN = 5, painless DN = 7) and six healthy volunteers (HV) were recruited.
Microvascular perfusion characteristics (relative cerebral blood volume [rCBV], flow [rCBF],
and transit time [ttFM]) of the thalamus and caudate nucleus were assessed using magnetic
resonance perfusion imaging. The caudate nucleus was chosen to serve as an in vivo control
RESULTS—Subjects with painful DN had significantly greater thalamic rCBV (means [SD];
painful DN, 228.7 [19.5]; no DN, 202.3 [25.8]; painless DN, 216.5 [65.5]; HV, 181.9 [51.7];
P = 0.04) and the longest ttFM(s) (painful DN, 38.4 [3.6]; no DN, 35.3 [13.2]; painless DN, 35.9
[13.7]; HV, 33.7 [14.9]; P = 0.07). There was no significant difference in markers of caudate
CONCLUSIONS—Painful DN is associated with increased thalamic vascularity. This may
provide an important clue to the pathogenesis of pain in DN.
Diabetes Care 34:718–720, 2011
We previously reported thalamic neuro-
nal dysfunction in subjects with painless
DN but not painful DN (2). The aim of
this study was to assess thalamic micro-
vascular perfusion characteristics in DN.
iabetic neuropathy (DN) results in
chronic painful symptoms that can
affect quality of life immensely (1).
RESEARCH DESIGN AND
men with type 1 diabetes were recruited.
Exclusion criteria were as follows: clini-
consumption (.20 units/day), neuropa-
thies other than DN, hypoglycemia in the
that could alter cerebrovascular perfusion
were omitted. Subjects with painful DN
toms for at least 6 months and were on
stable pain medications. Six age- and sex-
matched nondiabetic healthy volunteers
(HV) were also recruited. All subjects gave
written informed consent, and the study
had ethical approval.
Assessment of neuropathy
Clinical and neurophysiological assess-
a neuropathy composite score (NCS)
based on the neuropathy impairment
score of the lower limbs plus seven tests
(NIS[LL]+7) as described previously (7).
Subjects were divided into the following
groups: 1) noDN(asymptomaticsubjects
with normal NCS, 2) painless DN (pain-
two abnormalities of neurophysiologic
assessment), and 3) painful DN (painful
symptoms together with clinical and neu-
MR perfusion protocol
Examinations were performed on a 1.5-T
system (Eclipse, Philips Medical Sys-
tems). Cerebral perfusion was assessed
using a multitime point, single shot T2*
weighted echo-planar imaging (EPI) se-
quence (TEeff= 60 ms; TR = 1.4 s; acqui-
sition matrix = 192 3 188, zero-filled
before Fourier transformation to 256 3
256; field of view (FOV) = 25 cm). Exog-
enous perfusion contrast was provided
by a 20-mL bolus of gadolinium diethy-
lenetriamine pentaacetic acid (Gd-DTPA;
Magnevist, Schering AG, Germany),
which was followed by a 20-mL saline
flush, administered intravenously at a
rate of 5 mL/s.
The microvascular perfusion charac-
in modulating/processing nociceptive in-
formation) (8) and the caudate nucleus
were assessed. The caudate nucleus was
chosen as a control region since it is not
involved in somotosensory perception (9).
of cerebral perfusion were calculated: 1)
relative cerebral blood volume (rCBV),
thevolume of blood perunittime passing
through a region of brain tissue relative
proximal internal carotid artery flow; 2)
first moment transit time (TTFM, in sec-
onds), the average time for contrast bolus
to pass through a region of brain tissue;
and 3) relative cerebral blood flow
(rCBF), the average volume of blood per
unit time (rCBV:TTFM) (10).
Analyses were performed using SPSS
14.0. Appropriate tests for normality were
conducted to guide subsequent analysis.
Subgroup demographics were compared
using one-way ANOVA and perfusion
markers using nonparametric tests.
c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c
of Magnetic Resonance Imaging, University of Sheffield, Sheffield, U.K.
Corresponding author: Dinesh Selvarajah, firstname.lastname@example.org.
Received 11 August 2010 and accepted 5 December 2010.
© 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly
licenses/by-nc-nd/3.0/ for details.
DIABETES CARE, VOLUME 34, MARCH 2011 care.diabetesjournals.org
P a t h o p h y s i o l o g y / C o m p l i c a t i o n s
B R I E FR E P O R T
RESULTS—Subjects with painful DN
(62.0 [3.9]) were significantly older than
those with no DN (44.9 [7.1]) and HV
(45.8 [14.7]; P = 0.03; painful DN vs. no
DN, P = 0.005, 95% CI 5.7–28.5; painful
DN vs. HV, P = 0.01, 95% CI 3.8–28.5).
Subjects were matched for BMI (HV 26.7
[2.3], painful DN 31.1 [5.1]; P = 0.08)
and HbA1c(no DN 8.4 [0.2]), painless
DN 8.9 [0.9], and painful DN 7.7 [0.9];
P = 0.71). Subjects with painful DN (NCS
31.0 [9.5]) and painless DN (21.8 [15.5])
had comparable severity of neuropathy,
which were greater than those with no
DN (1.0 [1.1]). There was no difference
in the presence of microvascular compli-
cations (diabetic retinopathy data from
retinal screening database; painful DN
[n = 3], painless DN [n = 2], no DN
[n = 2], and diabetic nephropathy based
on albumin:creatinine ratio; painful DN
Figure1 isa composite time profile of
thalamic perfusion of the study groups.
The bolus arrival time (in seconds) was
delayed in both neuropathy subgroups
(painful DN 28.6 [1.6] and painless DN
27.3 [2.4]) compared with HV 23.6 (6.3)
and no DN 24.2 (5.9), P = 0.7, x2= 1.3.
Overall group comparison showed that
subjects with painful DN (rCBV 228.7
[19.5]) have the tallest peak concentra-
tion of Gd-DTPA and significantly greater
mean thalamic rCBV compared with HV
(181.9 [51.7]), no DN (202.3 [25.8]),
and painless DN (216.5 [65.5]); P = 0.04,
x2= 8.3). Subjects with painful DN
(TTFM 38.4 [3.6]) had the longest tha-
lamic TTFM (in seconds) compared with
the other study groups (HV 33.7 [14.9]),
no DN 35.3 [13.2], painless DN 35.9
[13.7]; P = 0.07, x2= 6.9). Caudate nu-
cleus perfusion markers were not signifi-
cantly different between groups.
CONCLUSIONS—Painful DN is the
most distressing complication of diabetes
(11), but unfortunately current treat-
ments are often ineffective (12). This
ing of the pathophysiological processes
involved (13). Using established MR per-
fusion techniques, we demonstrated in-
creased thalamic vascularity (increased
rCBV) with sluggish flow (prolonged
TTFM) in painful DN, possibly reflecting
underlying vasodilatation. Delay in bolus
arrival time in both neuropathy sub-
groups reflects the burden of underlying
vascular disease. Similar perfusion abnor-
malities have been described in the sural
nerve (14). Despite this, there remains
clear difference in the perfusion profiles
of both painful and painless DN. There
were no significant differences in the mi-
crovascular perfusion characteristics of
the caudate nucleus. Unlike the caudate,
the thalamus plays a central role in modu-
lating/processing somatosensory informa-
We have previously reported that
preservation of thalamic neuronal func-
tion may be a prerequisite for the percep-
tion of pain in DN (2). Hyperexcitable
thalamic neurons have since been re-
ported to contribute to neuropathic pain
in experimental diabetes (15). Thus tha-
lamic neurons can act as central genera-
tors or amplifiers of pain in diabetes. Our
finding of elevated thalamic perfusion
may be related to increased neuronal ac-
Limitations of the current study in-
clude an age spread of several years
between cohorts, and age is a factor in
cerebral hypoperfusion. Paradoxically,
however, subjects with painful DN com-
greatest thalamic rCBV. This would sug-
gest comparative hyperperfusion rather
than hypoperfusion. Interestingly, the
difference in thalamic microvascular per-
not reflected by microvascular disease
burden elsewhere with comparable prev-
alence of minimal retinopathy and ne-
phropathy in both groups.
Our goal was to assess whether tha-
lamic perfusion abnormalities are present
in DN. The data presented here at least
preliminarily support this view. A larger
the four groups would achieve 91%
power to detect significant differences
among the groups. Future MR perfusion
studies may lead to identification of ob-
DN enabling the targeting of specific
components of the pain matrix pharma-
cologically, hopefully resulting in the de-
velopment of more effective and better
Acknowledgments—This research was sup-
ported by a Diabetes UK grant.
No potential conflicts of interest relevant to
this article were reported.
D.S. researched data and wrote the article.
I.D.W. researched data, contributed to dis-
cussion, and reviewed and edited the article.
R.G. researched data and contributed to dis-
researched data, contributed to discussion,
and reviewed and edited the article.
form at the American Diabetes Association
69th Scientific Sessions, New Orleans, Loui-
siana, 5–9 June 2009.
The authors would like to acknowledge the
invaluable contributions of the radiographers
in this study.
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Figure 1—Composite concentration time profiles of the bolus passage of exogenous contrast
agent (Gd-DTPA) though the thalamus in each subgroup: HV, no DN, painless DN, and painful
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Perfusion abnormalities in diabetic neuropathy