Journal of Neurology, Neurosurgery, and Psychiatry 1984;47:686-691

Diabetic gastroparesis from autonomic neuropathy:

surgical considerations and changes in vagus nerve
morphology
RJC GUY,* JL DAWSON,t JR GARRETT,: JW LAWS,§ PK THOMAS,|| AK SHARMA,¶
PJ WATKINS*
From the Diabetic Department, * Departments of Surgery, t Oral Pathology and Oral Medicine, Dental
School, t and Diagnostic Radiology, § King's College Hospital, London, Department of Neurological Science,
Royal Free Hospital, London|| and the Department of Anatomy, University of Aberdeen,¶ UK

SUMMARY Two cases with intractable vomiting due to gastroparesis, a rare feature of diabetic
autonomic neuropathy, are described. Both required surgical treatment. In the first a gastroen-
terostomy was complicated by reflux gastritis requiring a revision operation; in the second a
gastrojejunostomy was successful. Electron microscopic studies of the vagus nerve in one of the
cases showed a severe reduction in the density of unmyelinated axons, the surviving axons
tending to be of small calibre. The severity of the abnormalities supports the view that diabetic
gastroparesis is related to vagal denervation.
Gastroparesis is an uncommon complication of dia- ulceration of both hands and feet, bilateral Charcot
betes mellitus. Recurrent and debilitating vomiting changes in the ankle joints, and a painless fracture of his
from this cause is extremely rare. In exceptional right fifth metacarpal bone. Symptoms of an autonomic
cases where intractable vomiting cannot be control- neuropathy were also present. Impotent by the age of 23,
over the next six years he developed diabetic diarrhoea,
led by simple measures, surgery may be needed. We symptomatic postural hypotension and retention of urine.
describe two cases in which conservative measures Recurrent vomiting was, however, his most debilitating
failed and report the results of surgery, together problem. It gradually progressed until he was vomiting two
with morphometric observations on the abdominal or three times each week by the age of 23. Daily vomiting,
vagus nerve, obtained at the time of operation. often lasting twelve hours and sometimes persisting for five
days was present at the age of 27. Frequent admission in
CASE HISTORIES ketoacidosis followed this vomiting. In the year 1975-
Only two patients from the Diabetic Department, King's 1976, after fifteen years of diabetes, he had seven admis-
College Hospital, have undergone elective surgery for per- sions in ketoacidosis. During this same period he lost
sistent vomiting due to gastroparesis in the last ten years. weight from 72 to 60 kg. Barium meal studies were
Both had severe autonomic neuropathy. abnormal from the age of 23. Residual food and fluid from
the previous day were present at the start of the test,
Case I barium was still present in the stomach after 23/4 hours, and
A male, born in 1947, developed insulin dependent dia- there was delayed passage of barium into the duodenum
betes in 1960 when aged 12 years. He had seven admis- despite intravenous metoclopramide. When aged 28, after
sions in the next 7 years either for stabilisation or because 15 years of diabetes, a barium meal, recorded on videotape
of ketoacidosis. At the age of 22 years he had his first for later analysis, showed no effective peristaltic contrac-
episode of iritis which recurred over the next two years. tions in oesophagus or stomach, the latter emptying very
After 11 years of diabetes he developed peripheral slowly by gravity. The pylorus, duodenal cap and small
neuropathy which over two years became exceptionally bowel appeared normal and once barium had entered the
severe. By the time he was 25 years old he had painless small bowel its transit to the terminal ileum was not
delayed.
Treatment with antiemetics was ineffective. Although
some symptomatic benefit was initially produced by meto-
Address for reprint requests: Dr R Guy, Diabetic Department, clopramide at night, this did not last. Combinations of
Kings College Hospital, Denmark Hill, London SE5 9RS, UK. metoclopramide, chlorpromazine and prochlorperazine
Received 6 October 1983 and in revised form 25 January 1984. failed to alleviate his vomiting, which could persist, despite
Accepted 30 January 1984 intravenous fluids, for up to five days. Elective surgery was
686
Diabetic gastroparesis from autonomic neuropathy 687
therefore undertaken for intractable symptoms in 1976 ketoacidosis followed, secondary to vomiting with no relief
when he was aged 29 years. A gastroenterostomy was per- from metoclopramide or pizotifen. She was then vomiting
formed, anastomosing the greater curvature to the first up to five times a day and food ingested over 12 hours
part of the jejunum with a two finger stoma. Postopera- beforehand was sometimes observed. A barium meal and
tively he was troubled by bilious vomiting, which resulted video showed a fluid and food residue with poor peristalsis
in six admissions in the next year. Gastroscopy one year in oesphagus and stomach and delayed emptying.
postoperatively showed a normal stoma although a consid- A trial of domperidone,2 a dopamine antagonist, was
erable excess of bile was present in the stomach, refluxing started and although initially this gave some symptomatic
from the afferent loop, with an associated gastritis. A relief with weight gain (54 to 59 kg) over two months,
barium meal and video again showed virtually no peristal- there was no improvement in peristalsis as seen on video
sis of the stomach, with emptying of the barium into the films. She then had three further admissions with
jejunum via the gastroenterostomy under gravity. Because ketoacidosis after vomiting in the next two months. The
the gastroenterostomy was complicated by reflux gastritis, vomiting might last up to five days, while still on intraven-
a revision operation was done when he was aged 30. An ous fluids. Because of continuing weight loss, (minimum
antrectomy with a Roux-en-Y gastrojejunostomy and an weight was 49 kg), severe symptoms, recurrent
anterior and posterior vagotomy were performed. This ketoacidosis and loss of morale, surgery was performed. A
relieved his biliary reflux and improved his overall state. truncal vagotomy, an antrectomy and Roux-en-Y gastroje-
He only had two admissions with vomiting over the next junostomy were performed in February 1982 when she
five months. was 28 after 12 years of diabetes. A 45 cm retrocolic roux
Later that year, he died suddenly at home at night, aged loop to the gastric remnant, without a valve, was made.
30 after 17 years of diabetes mellitus. Post mortem exami- Postoperatively she has felt better, and she has had only
nation, full details of which have been reported previ- two admissions in seventeen months with vomiting. On
ously,' showed no obvious cause of death. neither occasion has she been ketoacidotic and has been
managed on oral fluids, intramuscular metoclopramide and
Case 2 elevation of the head of the bed. Three weeks postopera-
A female born in 1954 was found to be an insulin- tively, a barium meal and video showed poor peristalsis as
dependent diabetic in 1969 when aged 15 years. By the age before with negligible emptying of the stomach via the
of 17 she had bilateral cataracts requiring lens extraction in gastrojejunostomy in the supine position, but free empty-
the following year. The first episode of vomiting occurred ing in the semierect position.
when aged 23 and during this year she developed symp-
toms of postural hypotension, diabetic diarrhoea and lost Summary of case histories (see Table 1)
both knee and ankle jerks. Over the next three years she Both patients were young insulin-dependent diabetics with
had three admissions in ketoacidosis secondary to vomit- a severe symptomatic diabetic autonomic neuropathy.
ing. Between these episodes she was asymptomatic. Table 2 summarises their grossly abnormal autonomic
A gastroscopy during this time showed oesophagitis function tests. In additional both had a pronounced sen-
but a barium meal in 1979 was reported as normal. sorimotor neuropathy and bilateral cataracts. Neither had
In 1981 when aged 27 years, after 11 years of diabetes any evidence of nephropathy and only Case 1 had minor
she became pregnant. Intractable vomiting started at the background retinopathy. Surgery was performed for
eighth week of gestation and continued over the next nine intractable vomiting and while not wholly satisfactory in
weeks despite intravenous fluids and antiemetics. The Case 1, resulted in symptomatic relief and definite
pregnancy was terminated. Monthly admission in improvement in gastric emptying by gravity in Case 2.

Table 1 Summary of case histories

Case 1 Case 2
Duration of diabetes Age (yr) Age (yr) Duration of diabetes
(years) (years)
12 Diabetes mellitus 15
10 23 Bilateral cataracts 17 2
10 23 Episodic vomiting 23 7
10 23 Impotence - -
11 24 Diabetic diarrhoea 23 7
12 25 Charcot joints - -
13 26 Background retinopathy - -
14 27 Postural hypotension 23 7
14 27 Severe vomiting 27 11
16 29 Bladder dysfunction - -
16 29 1st operation 28 12
17 30 2nd operation - -
17 30 Death
688
Table 2 A utonomic function tests
Case I
120/85 mm Hg
80/60 mm Hg
2
102 bpm
4
Supine blood pressure
Standing blood pressure
Heart rate variability
Resting heart rate
Heart rate increase
on standing

The anterior and posterior abdominal vagus nerves

Case 2
115/80 mm Hg
80/70 mm Hg
3*
110 bpm
5t

*Normal over 12. tNormal increase over 15 beats/min.

Abdominal vagus biopsy findings

were removed at the time of gastrectomy in Case 2.

They were fixed in 3 % glutaraldehyde in PIPES buf-
fer for 3 h with 2 % sucrose and, after washing in
buffer, postfixed with 1 % osmium tetroxide in buf-
fer containing 1-5% potassium ferricyanide.3 The
specimens were dehydrated in increasing concentra-
tions of ethanol and embedded in Araldite via 1, 2
epoxypropane. Ultrathin sections were stained with
4.. ,$;,
:._' i,
Guy, Dawson, Garrett, Laws, Thomas, Sharma, Watkins

...s
...

^S'iNk
::

..R ...
...
.::

lead citrate and uranyl acetate and examined in an Fig 2 Electron micrograph of transverse section through
Elmiskop 101 electron microscope. The quantitative abdominal vagus nerve of a control subject aged 24,
morphometric studies were performed on nonover- showing a dense population of unmyelinated axons (ax) and
lapping photographs at a magnification of x 17 000. associated Schwann cell processes. Bar = 1 ,tm.
The total area examined was 3000 ,.m2. The
findings were compared with the control values undergoing vagotomy for the treatment of peptic
obtained by Sharma and Thomas4 from patients ulceration. This nerve normally contains very few
i
myelinated axons.
:...:.

.:e,..X.'., x<'. ....

The specimens from the patient showed a severe

..
..

::

reduction in the density of unmyelinated axons. This

was 49 000/mm2 as compared with the control value
of 209 000 ± 66/mm2 (mean + SD). Those that
remained were generally of small diameter.
Representative areas from the patient and a control
subject aged 24 years are shown in figs 1 and 2.
Numerous Schwann cell subunits unassociated with
axons were present in the patient. The basal lamina
surrounding the Schwann cells was thickened in the
'..
nerve from the patient. This was assessed quantita-
tively. Its thickness was measured at 5-16 equidis-
V tant points around the perimeter of 30 Schwann cell
subunits, the number of measurements depending
upon the size of the subunit. Only regions in true
transverse section were assessed, tangentially-cut
areas being avoided. A value of 293 5 + 12 nm
(mean + SE) was obtained. Similar observations on
a control subject aged 24 yielded a value of 72 5 +
11 nm. This difference is significant (p < 0-01). Case
2 also showed multiple portions of basal lamina
unassociated with Schwann cell processes (fig 1).
Fig Electron micrograph of transversesection through
abdominal vagus nerve from Case 2, showing considerable
Not infrequently they enclosed dense collections of
loss in density of unmyelinated axons (ax). Groups of
collagen fibrils, the appearance resembling "col-
Schwann cell processes (Sp) are present, unassociated with
lagen pockets" from which the surrounding
axons, and portions of basal lamina (bl) are seen, Schwann cell processes had disappeared (fig 3). The
unassociated with Schwann cell -m.
processes.Bar
=
1 amount of endoneurial collagen was increased. The
Diabetic gastroparesis from autonomic neuropathy 689
Discussion
.

Gastric retention with delayed stomach emptying

was described over 40 years ago5 and linked with
diabetic autonomic nerve dysfunction by Rundles in
1943.6 The term gastroparesis diabeticorum was
used by Kassander to describe asymptomatic gastric
retention.'
Gastroparesis is a feature of autonomic
neuropathy6-'0 but it is an uncommon complica-
tion.8 Vomiting is generally intermittent, while
debilitating symptoms from intractable vomiting are
rare. Mild nonspecific symptoms such as nausea,
v14 \ - ^ epigastric discomfort, anorexia, bloated feelings,
and borborygmi have been rather dubiously attri-
buted to gastroparesis. Delayed emptying,7 residual
food and absent or ineffective peristalsis9 may be
discovered at barium meal examination. A Crosby
4.
-g,i capsule often fails to pass through the duodenum
because of poor peristalsis.
Gastric vagal denervation has long been consi-
dered to cause gastroparesis, although surgical
Fig 3 Electron micrograph of tra)nsverse section through denervation causes abnormalities of gastric motility
abdominal vagus of Case 2 showinIg portions of Schwann which are not identical to those in diabetic
cell basal lamina (bl) enclosing po,ckets of collagen fibnls.
ax, axons; fb, fibroblast process. B tar = 1 L&m. neuropathy. The present study demonstrates for the
first time that there are severe structural abnor-
malities in the vagus nerve (from Case 2), support-
ing the view that vagal denervation may be respon-
sible for gastroparesis. Gastric smooth muscle
abnormalities have also been observed in both these
cases, and consist of very striking hyaline bodies of
unknown origin interspersed amongst the smooth
muscle cells. They were also demonstrated in
smooth muscle from other organs.'
Observations on the pathological changes in
M X Odiabetic gastroenteropathy have not so far been
extensive. Smith'2 found abnormalities in the inner-
vation of the oesophagus in 18 out of 20 unselected
cases of diabetes. None had clinical dysphagia or
neuropathy. Kristensson et al'3 reported loss of
myelinated fibres in the vagus nerve of three necrop-
sied cases of diabetic neuropathy, one of whom had
diabetic diarrhoea and radiologically demonstrated
gastric atony. Duchen et al,' reported necropsy
~-**
^<- X findings in five insulin-dependent diabetics with sen-
No sorimotor and autonomic neuropathy. Severe loss of
myelinated fibres was found in the vagus nerves. A
Ai conspicuous feature was the presence of inflammat-
Fig 4 Electron micrograph of encdoneurialcapillaryfrom ory changes in the autonomic ganglia and in and
abdominal vagus nerve of Case 2, .surrounded by thickened around bundles of axons in the walls of viscera, but
zone composed of reduplicated basgal lamina (bl) and not in nerve trunks.
associated collagen fibrils. Bar = 22 ,um. The abdominal vagus in Case 2 from the present
study showed a severe loss of unmyelinated axons.
endoneurial capillaries were abnormal, being sur-
-
The surviving axons tended to be of small calibre.
rounded by a thick zone comlposed of reduplicated This suggests either a preferential loss of axons of
basal laminae with associated 4collagen fibrils (fig 4). larger size or a diffuse involvement with the pres-
690 Guy, Dawson, Garrett, Laws, Thomas, Sharma, Watkins
ence of small regenerating axons. These findings the problem. Nonetheless, when intractable vomit-
support the idea that diabetic gastroparesis is related ing from gastroparesis does occur, surgery may be
to vagal denervation. the only appropriate treatment.
The substantial thickening of the Schwann cell
basal lamina is of interest. It has been commented We thank Dr DA Pyke for his helpful advice and
upon by Bischoff'4 in sural nerve biopsies from encouragement, and Dr RHM King and Miss JM
patients with diabetic neuropathy, although it is not Workman for collaboration in the electron micro-
a regular feature. The vascular changes observed in scope studies. RJCG is supported by a research
the present case, are also not consistently present in grant from Pfizer Ltd.
diabetic neuropathy. No inflammatory infiltration
was observed. References
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