Pathology of Autonomic Neuropathy in Diabetes Mellitus
L W. DUCHEN, M.D.; A. ANJORIN, M.B.; P. J. WATKINS, M.D.; and J. D. MACKAY, M.B., B.Chir.;
London, England
Pathologic changes in the autonomic nervous system
were studied postmortem in five cases of insulin-
dependent diabetes of early onset. All had had clinical
evidence of peripheral sensorimotor neuropathy and
developed disturbances of autonomic function that
included postural hypotension, diarrhoea, bladder
dysfunction, impotence (in the men), and signs of cardiac
denervation. In coeliac and other sympathetic ganglia
there were many distended ('giant') or vacuolated
neurons as well as enlarged club-shaped neural
processes. The vagus nerve and sympathetic trunks
showed severe loss of myelinated fibres. Smooth muscle
in many viscera showed a hitherto undescribed focal
hyaline degeneration. There were inflammatory changes
in the autonomic ganglia in all cases and in or around
bundles of unmyelinated nerve fibres in many. These
findings suggest that there may be several different
pathogenetic mechanisms involved in the development of
autonomic neuropathy in diabetes.
O V E R T H E past few years pathologic changes in the ner-
vous systems of five patients who had been treated in the
Diabetic Unit of Kings College Hospital, London, have
been studied postmortem. These studies are still not com-
plete, and the present report is a preliminary summary of
the findings.
Patients included four men whose ages at death ranged
from 30 to 52 years, and one 47-year-old woman. Ages at
the time of diagnosis of diabetes mellitus ranged from 11
to 24 years, and the duration of diabetes until death was
18 to 34 years. All patients had evidence of peripheral
neuropathy varying in severity, with wasting and weak-
ness of muscles, absent reflexes, and sensory distur-
bances. They also had evidence of nephropathy, and
renal insufficiency associated with fluid retention was
present in one patient. Other diabetic complications in-
cluded proliferative retinopathy in all and ischaemic
heart disease in three.
All five patients had symptoms indicative of autonomic
neuropathy. These included postural hypotension; diar-
rhoea of a characteristic pattern, with nocturnal bouts
and episodes of faecal incontinence; gastric atony, shown
radiologically, with frequent episodes of vomiting; gusta-
tory sweating; bladder atony manifest by gross painless
• From the Department of Neuropathology, The National Hospital for Nervous
Diseases and Institute of Neurology; and the Diabetic Unit, Kings College Hospi-
tal; London, England.
Annals of Internal Medicine. 1980;92 (Part 2):301-303.
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bladder distension; and impotence in all four men. The
immediate cause of death was massive intragastric hae-
morrhage in one patient, renal failure in one, congestive
cardiac failure in two patients, and the cause was not
clear in one patient.
General Pathologic Findings
Postmortem examination was done at various times af-
ter death, the interval being as much as 3 days in some
cases. Sampling of viscera muscles and nerves was exten-
sive and included cervical, lumbar, and coeliac sympa-
thetic ganglia, the vagus nerve in the neck and the brain,
and spinal cord with nerve roots and sensory ganglia.
Histologic abnormalities seen in all five cases included
extensive microangiopathy affecting vessels at many sites
and, in particular, the kidney where glomerulosclerosis
was present. In four of the five cases (the exception being
the 30-year-old man), there was evidence of myocardial
ischaemia ranging from frank old infarction to increased
interstitial fibrosis. Skeletal muscles, in particular those
from the lower limbs, showed evidence of neurogenic at-
rophy. We have not done quantitative or single fibre stud-
ies of myelinated peripheral nerves, as such pathology
has been extensively reported in the literature (1).
Pathology of the Autonomic Nervous System
The changes described here were found in all cases but
the degree of severity varied considerably from case to
case and at different sites. The principal findings were in
the major autonomic ganglia, visceral unmyelinated
nerves, the vagus nerve, and smooth muscle.
S Y M P A T H E T I C G A N G L I O N CELLS
Ganglia studied histologically or with electron micros-
copy included the superior cervical and coeliac in all cas-
es, and the thoracic and lumbar paravertebral chain in
only some instances. Scattered through the ganglia were
many abnormal nerve cells that were considerably larger
than normal with a rounded outline and usually periph-
eral nucleus. Some of these large rounded cells contained
evenly distributed granules that stained intensely with
luxol-fast blue, suggesting a lipid or phospholipid compo-
sition, whereas other cells were somewhat foamy in ap-
©1980 American College of Physicians 301
 Figure 1A. Section of superior cervical sympathetic ganglion. Many lymphocytes lie scattered in the connective tissue between nerve cells
but are particularly aggregated around a small vessel. (Haematoxylin and eosin; original magnification, x 1 5 0 . ) B. Longitudinal section of
muscle of pyloric region of stomach. Rounded hyaline bodies (arrows) lie among or replace smooth muscle cells. (Haematoxylin and eosin,
original magnification, x 2 7 5 . )

pearance and distended with vacuoles. Many "empty
spaces" were seen in the ganglia and seemed to represent
the end stage of cellular distension by vacuoles. Electron
microscopy of the formalin-fixed postmortem tissue was
not very satisfactory but showed that some ganglion cells
were filled with aggregations of membranous material,
probably membrane bound, or with multilamellar bodies.
The vacuoles in nerve cells were seen with electron mi-
croscopy to be rounded distensions of endoplasmic retic-
ulum around which ribosomes could still be identified. In
some cells the vacuoles appeared to be coalescent where-
as in others there remained only a ring of satellite cells
around the remnants of the vacuolated material. It was
also apparent that vacuolation was present not only in
the perikaryon but also extended into axonal or dendritic
processes. Silver impregnation of paraffin sections
showed many rounded or club-shaped argyrophilic mass-
es lying in close apposition to ganglion cells, in many
instances in continuity with lengths of an axonal or den-
dritic process. It is not clear whether these densely silver-
stained bodies were degenerating axonal terminals or
whether they were distended initial segments of ganglion
cell processes.
I N F L A M M A T O R Y C E L L U L A R INFILTRATIONS
Infiltrations by lymphocytes, macrophages or occa-
sional plasma cells were widely distributed in all cases
and seemed to be particularly related to autonomic nerve
3 0 2 February 1980 • Annals of Internal Medicine • Volume 92 • Number 2 (Part 2)
bundles and ganglia. The variation in appearance ranged
from a scattering throughout ganglionic tissue of isolated
lymphocytes; clusters of lymphocytes or macrophages
around individual nerve cells; lymphocytes and plasma
cells lying in or around bundles of unmyelinated nerve
fibres in the wall of oesophagus, intestine, and bladder; or
large perivascular aggregations of lymphocytes in the
ganglia in one case (Figure 1A). In none of the cases was
cellular infiltration seen in interstitial connective tissues
of muscles or nerves, spinal cord, or brain.
" N E U R O M A T A " IN U N M Y E L I N A T E D N E R V E S
Nodules consisting of tangles of unmyelinated axons
and Schwann cells were seen in the pancreas, in the inter-
stitial tissues close to ducts and vessels. These nodules lay
in continuity with nerve bundles that were numerous and
unusually large and fibrotic in the pancreas in all the
cases. These little "neuromatous" lesions were reminis-
cent of those commonly seen in and around the spinal
cord and which consist of peripheral nerve neurofibromas
probably originating from aberrant regeneration of axons
in nerve roots after minor traumas. It seems likely that in
the autonomic nerves of the pancreas these lesions have
been due to recurrent injury leading to aberrant regenera-
tion of axons.
CELL N U M B E R S IN I N T E R M E D I O L A T E R A L C O L U M N S
The total number of nerve cells in the intermediolater-

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 al columns of the spinal cord were counted in 20 consecu-
tive 10-jam paraffin sections at levels T2-3, T5-6, T10-11
in a normal person and in the five diabetic patients.
The preliminary findings were that in four cases there
was a considerable reduction in cell numbers at all levels
but in one case the numbers were higher than in controls.
Because there is considerable variation in the numbers of
cells of the intermediolateral columns at different levels,
the present quantitative studies need further amplifica-
tion.
SMOOTH MUSCLE
A unique change has been found in smooth muscle of
viscera, such as in the wall of the oesophagus, stomach,
small and large intestine, bladder, and prostate. The ab-
normality consists of eosinophilic rounded or club-
shaped bodies lying in or replacing smooth muscle cells
and having a hyaline, structureless appearance (Figure 1
B). These bodies also stain weakly with periodic acid-
Schiff and resemble the material deposited in vessel walls
and renal glomeruli. They were present in all five of our
diabetic patients. We have never seen them in smooth
muscle in other cases.
THE VAGUS NERVE
Samples of vagus nerve were taken from the neck,
where there should normally be an even distribution of
small and large myelinated axons as well as unmyelinated
fibres. In the five diabetics studied there was a very severe
loss of myelinated axons and a marked excess of collagen.
Only occasional small fascicles, usually at the periphery
of the nerve, contained myelinated fibres in any quantity.
Discussion
Distended ganglion cells have been described in diabet-
ic and alcoholic autonomic neuropathy (2, 3), and the
term "giant sympathetic neurons" has been applied to
them. In the present studies there appear to be two types
of cellular enlargement: one is due to generalized dilata-
tions in endoplasmic reticulum leading eventually to cel-
lular disintegration; other cells are distended by the accu-
mulation of membranous lipid-rich bodies giving the neu-
ron an appearance similar to that seen in neuronal stor-
age diseases. Olsson and Sourander (4) saw vacuolation
of neurons and club-shaped enlargement of cell processes
similar to those described in the present cases. Demyeli-
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nation of preganglionic sympathetic fibres has been seen
in some studies (4, 5) and in the vagus nerve (6). The loss
of myelinated fibres in the vagus nerve and the evidence
for peripheral sensorimotor neuropathy in the present
cases point towards a common demyelinating cause, as
demonstrated previously (1). The vagal nuclei did not
show significant changes in our cases.
N o report of inflammatory changes in autonomic gan-
glia or nerve in diabetes has been found in the literature.
It was a feature of all our cases and a very striking abnor-
mality in one case. The inflammation seems unlikely to
be a reaction to degenerating neurons since it was also
seen in bundles of unmyelinated fibres and in perivascular
areas. The changes observed by Appenzeller and associ-
ates (7) in rabbits in which an experimental autonomic
neuropathy was induced by injection, with Freund's ad-
juvants, of autonomic tissue suggest that there could be
an immunological disturbance, possibly of an autoim-
mune type, in these cases. The changes in smooth muscle
also seem to be hitherto unrecorded, and their nature is
not clearly understood. We have considered the possibili-
ty of artefact but this interpretation is not tenable. What-
ever its nature, the extensive distribution of smooth mus-
cle lesions may contribute to the intestinal or bladder
dysfunction.
It is likely that there are several quite different causes
of the different types of abnormalities seen in the auto-
nomic system. In addition to the factors considered etio-
logically important in diabetic peripheral neuropathy we
may also have to look for toxic as well as immunologic
pathogenetic mechanisms as causes of autonomic neuro-
pathy.
References
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4. OLSSON Y, SOURANDER P. Changes in the sympathetic nervous system
in diabetes mellitus: a preliminary report. J Neurovis Rel. 1968;31:86-95.
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Duchen eta/. • Pathology of Diabetic Neuropathy 303