ORI GI NAL ARTI CLE

Ophthalmoplegia in diabetes mellitus: a retrospective study

Domenico Greco Francesco Gambina
Filippo Maggio
Received: 14 January 2008 / Accepted: 21 July 2008 / Published online: 29 August 2008
Springer-Verlag 2008
Abstract Ophthalmoplegia, despite being a rare entity in
diabetes mellitus, is associated with great anxiety for the
patients and often appears to be a serious problem from a
diagnostic and therapeutic point of view. There have been
few studies primarily concerned with the relative fre-
quencies and clinical characteristics of oculomotor
neuropathies in diabetic subjects. Those published have
emanated largely from neurological and/or ophthalmolog-
ical referral centres rather than metabolic departments.
Objective of this study was to determine the incidence, the
clinical characteristics and risk factors for developing
ophthalmoplegia among persons with diabetes mellitus.
We have performed a retrospective study of all diabetic
patients with ophthalmoplegia who were seen in the Met-
abolic Division at S. Biagio Hospital, Marsala, over the
10 year period from 1998 to 2007. A detailed history and
blood laboratory prole were obtained for each patient.
During the period of the survey a total of 6,765 diabetic
subjects were hospitalised and ophthalmoplegia was iden-
tied in 27 patients (0.40%). Isolated III nerve palsies
accounted for the majority of patients (59.3%), with VI
nerve palsies (29.6%) occurring more frequently than
multiple palsies (11.1%). These patients had a marked
comorbidity and were found to have a poorly controlled
diabetes. The patients with VI nerve palsies showed a
tendency toward a higher coexistence of diabetic retinop-
athy and cardiovascular risk factors than those with III
cranial nerve palsies. Ophthalmoplegia is a serious and not
common problem among patients with diabetes mellitus;
the oculomotor nerve was most frequently affected in our
case-report. The fact that the coexistence of diabetic
complications and cardiovascular risk factors was slightly
higher in patients with VI nerve palsy is compatible with
the hypothesis that this ischemic event might be more
closely related to diabetes and metabolic syndrome in its
pathogenesis.
Keywords Cranial neuropathies Diabetes mellitus
Ophthalmoplegia
Introduction
Diabetic mononeuropathy is one of the not so common
forms of neuropathy, which often appears to be a serious
problem from a diagnostic and therapeutic point of view.
Cranial neuropathies in diabetic patients are extremely rare
and occur in older individuals with a long duration of
diabetes [1, 2]. In particular, ocular neuropathies usually
causes considerable diplopia, which can be debilitating and
signicantly impair the everyday and professional activity
of aficted individuals. Patients with diabetes mellitus may
develop diplopia from isolated oculomotor (third), troch-
lear (fourth), or abducens (sixth) nerve palsies, or from
combined ocular nerve palsies (mononeuropathia multi-
plex) [35]. Although different incidences of cranial
nerve palsies in diabetic patients have been reported, such
abnormalities are seen relatively rarely in the general
population. Patients with diabetes have a 10-fold increase
in the incidence of cranial nerve palsies, with an incidence
of 1% among diabetics compared with an incidence of
0.1% for the nondiabetic population [2].
D. Greco F. Gambina F. Maggio
Division of Diabetology, S. Biagio Hospital,
Marsala (TP), Italy
D. Greco (&)
Via Cosenza, 155, 91016 Erice (TP), Italy
e-mail: drgreco@alice.it
1 3
Acta Diabetol (2009) 46:2326
DOI 10.1007/s00592-008-0053-8
There have been few studies primarily concerned with
the relative frequencies and clinical characteristics of
oculomotor neuropathies in diabetic subjects. Those pub-
lished have emanated largely from neurological and/or
ophthalmological referral centres rather than metabolic
departments. Objective of this study was to determine the
incidence, the clinical characteristics and risk factors for
developing ophthalmoplegia among persons with diabetes
mellitus. Moreover, we sought to determine if the type,
duration, or severity of diabetes was associated with paresis
of third, fourth and/or sixth cranial nerves. An additional
purpose of this study was to evaluate the prevalence
of metabolic syndrome in patients with diabetic
ophthalmoplegia.
Methods
We have performed a retrospective study of all diabetic
patients with ophthalmoplegia who were seen in a meta-
bolic department. In the present study all episodes of ocular
nerve palsies were documented among the diabetic patients
who attended the Division of Diabetology of the S. Biagio
HospitalMarsala (Italy), between 1 January 1998 and
31 December 2007.
A detailed history and blood laboratory prole were
obtained for each patient. Information was collected con-
cerning age, sex, time of onset of diabetes, type of treatment
for diabetes (oral hypoglycemic agents or insulin), presence
of chronic complications of diabetes, history of other
underlying medical conditions and medication history of
subjects considered. The ophthalmoscopic examination was
available for all the patients and was done by one expert
ophthalmologist; if diabetic retinopathy was diagnosed, it
was recorded as non-proliferative or proliferative.
In order to set proper diagnosis of diabetic mononeu-
ropathy and to exclude other possible causes for the
impairment of these nerves, all the patients were referred to
a neurologist; MRI and/or CT were performed when con-
sidered necessary.
Data were expressed as mean standard deviation (SD)
and/or as percentage. Students t-test was used for statis-
tical evaluation of the data. Statistical signicance was
posted at level P\0.05.
Results
During the period of the survey a total of 6,765 diabetic
subjects were hospitalised and ophthalmoplegia was
identied in 27 patients (0.40%). Of these 27 diabetic
patients, 14 were men and 13 were women; the mean age
was 65 10 years and the known duration of diabetes
was 16 10 years. Only one of the patients was with
type 1 diabetes mellitus and 26 with type 2 diabetes
(12 of them were on oral antidiabetic treatment and 14
on insulin therapy). In addition to the antidiabetic agents,
these patients were taking mainly cardiovascular prepa-
rations; it is noteworthy that about an half of them
were taking an antiplatelet agent (acetylsalicilic acid or
ticlopidine).
Isolated third nerve palsies accounted for the majority of
patients (59.3%), with isolated sixth nerve palsies (29.6%)
occurring more frequently than mononeuropathia multiplex
(11.1%). No fourth nerve palsy was identied in the con-
sidered period.
The onset of palsy was abrupt in all the cases and all the
patients presented with clinical signs of the affected cranial
ocular nerves (double vision, loss of or impaired motility of
the eyeball, deviation of the eyeball, ptosis of the upper
eyelid). The pupil was affected only in 3 (19%) of the
patients with oculomotor paresis (mild paretic mydriasis
was found).
These patients were found to have a poorly controlled
diabetes (their HbA1c, at the onset of diabetic mononeu-
ropathy, was 8.8 2.5%) and had a marked comorbidity.
Hypertension was present in 74% of the patients, diabetic
retinopathy in 37% (in 2 cases proliferative and in 8 non-
proliferative) while peripheral diabetic neuropathy was
present only in 22% of them.
According to NCEP (ATP III) criteria [6], 59% of these
patient were affected by metabolic syndrome.
No specic treatment of nerve palsy-induced diplopia
was performed in our diabetic patients.
Finally, we divided the diabetics with cranial nerve
palsy into three groups (III, VI and III + VI) and intended
to characterize their clinical features. The results showed
no remarkable differences with regards to age, known
duration of the diabetes and state of diabetic metabolism;
however, the patients with sixth nerve palsies showed a
tendency toward a higher coexistence of cardiovascular
risk factors and diabetic retinopathy than those with third
cranial nerve palsies (Table 1).
Discussion
Diabetic mononeuropathy of the cranial nerves has been
reported to affect about 1% of diabetic patients [2]; oph-
thalmoplegia, despite being a rare entity in diabetes
mellitus, is associated with great anxiety for the patients
and often appears to be a serious problem from a diagnostic
and therapeutic point of view.
Diabetic mononeuropathy should be considered in the
presence of signs and symptoms of cranial nerve distur-
bances in diabetic patients when other causes are excluded.
24 Acta Diabetol (2009) 46:2326
1 3
Paralysis of the sixth cranial nerve is recognized as the
most common type in most of the series throughout the
literature [4, 7, 8] even though in some series, the third
cranial nerve was the most affected [911].
In our patients, the oculomotor nerve was the most
frequently involved (59%); the abducent nerve palsies
accounted for 30% of all patients; mononeuropathia mul-
tiplex was present in 11%. These data are similar to the
data reported by others: this distribution of the cranial
nerve palsies is in accordance with that reported by
Watanabe and by Naghmi [2, 12]. No palsy of trochlear
nerve was reported in the considered period; this nding
conrms that the trochlear nerve is the least often involved
in diabetic ophthalmoplegia.
The majority of our subjects were type 2 diabetic
patients (96%) compared to type 1 patients (4%).
The classical presentation of oculomotor nerve palsy in
diabetes is that of an acute-onset diplopia with ptosis and
pupillary sparing associated with ipsilateral headache.
While pupillary sparing is often quoted as a means of
differentiating diabetic from other structural ophthalmo-
plegias (aneurysm, tumor or mass), 1418% of diabetic
patients do develop pupillary dysfunction [13].
Of the 16 patients with diabetic oculomotor paralysis,
only 3 patients (19%) had dilated unreactive pupil sug-
gestive of pupillomotor involvement. These data conrm
that in diabetic oculomotor involvement, the pupil is usu-
ally undisturbed.
Only one of the patients who presented with an acute
pupil-involving third nerve palsy, was found to have a
pituitary adenoma with parasellar extension on neuroim-
aging. We suggest that for diabetic patients with
neurologically isolated sixth and pupil sparing third nerve
palsies, close observation alone is initially appropriate.
However, progressions of the palsy, new neurological signs
or symptoms, or failure to resolve by 3 months are all
indications for more extensive investigation including
neuroimaging.
The data from the present study clearly demonstrate that
peripheral neuropathy was not present in all patients with
diabetic mononeuropathy, but just in only 22% of them;
these data are similar to those reported in other studies
[14, 15]. Therefore, diabetic mononeuropathy should be
looked for and should be considered even in the absence of
other more commonly seen forms of diabetic neuropathy.
Although the precise etiological role of diabetes in
ocular nerve palsy is uncertain, ischemia of the peripheral
nerve may be important [16]. Previous reports demon-
strated focal ischemic nerve infarction in diabetic
oculomotor nerve palsy patients, suggesting that distur-
bances in microcirculation contribute to the cause of
diabetic mononeuropathy [17].
Dysfunction of the ocular motor nerves in patients with
systemic vascular disease, such as diabetes mellitus or
hypertension, is a common cause of acquired diplopia.
The study of Patel and coll [18], conrms the widely
accepted belief that diabetes is a risk factor for sixth nerve
palsy but, contrary to popular belief, the same study reports
that hypertension may not be considered an independent
risk factor; however, the combination of diabetes and
hypertension was associated with an eightfold increased
risk of sixth nerve palsy. This study suggests the possibility
that hypertension may worsen the effect of diabetes in
ischemic nerve palsies.
Because both diabetes and hypertension are present in
metabolic syndrome, intuition suggests that the prevalence
of metabolic syndrome should be increased among dia-
betic subjects with ophthalmoplegia. However, to our
knowledge there are no large studies directly evaluating
this relationship.
Metabolic syndrome was present in 59% of our diabetic
subjects and considering only the patients with sixth nerve
palsy, in 87.5% of them.
Therefore, in our case-report, the patients with VI nerve
palsies showed an higher prevalence of metabolic syn-
drome and a tendency toward an higher coexistence of
cardiovascular risk factors (e.g., hypertension and dyslipi-
demia) than those with III cranial nerve palsies.
No specic treatment of nerve palsy-induced diplopia in
diabetic patients has been established; management is
expectant with strong reassurance to the patient for
recovery. Maintaining optimal glycemic control as well as
minimizing the other stronger risk factors for ischemia,
Table 1 Characteristics of groups of diabetic subjects with different
cranial nerve palsy
Cranial nerve III VI III + VI
Number 16 8 3
Sex (M/F) 10/6 3/5 1/2
DM type 2/type 1 15/1 7/0 3/0
Age (years) 65 9.9 63.3 6 75.3 17.6
BMI (kg/m
2
) 28.5 4.6 31.7 5.4 25.6 2.8
Duration of diabetes (years) 18.3 11.7 11.2 5.9 15.3 8.9
HbA1c (%) 9 2.3 8.45 3.2 7.9 0.2
Creatinine (mg/dl) 1.1 0.4 0.92 0.6 0.93 0.2
Cholesterol (mg/dl) 185 27 258 76* 196 12
Triglycerides (mg/dl) 175 90 227 167 158 71
Fibrinogen (mg/dl) 293 57 331 112 204 14
Metabolic syndrome 9 (56%) 7 (88%) 0 (0%)
Hypertension 10 (62%) 8 (100%) 2 (66%)
Retinopathy 5 (31%) 5 (63%) 0 (0%)
Peripheral neuropathy 5 (31%) 1 (13%) 0 (0%)
Smokers 5 (31%) 2 (25%) 1 (33%)
Antiplatelet drugs use 7 (44%) 4 (50%) 1 (33%)
* P\0.05 vs. III
Acta Diabetol (2009) 46:2326 25
1 3
including hypertension and hyperlipidemia, may aid
recovery.
The retrospective nature of this study did not allow us to
evaluate in detail the percentage and the time of recovery
from palsy but it is well known that in most cases, nerve
function restores itself, although it usually takes several
months or even over a year for the symptoms to resolve.
Finally, our data conrm that aspirin may be ineffective
in preventing ischemic third and sixth cranial nerve palsies
[19].
In conclusion, ophthalmoplegia is a serious and not
common problem among patients with diabetes mellitus;
the oculomotor nerve was most frequently affected in our
case-report.
The evaluation and management of cranial nerve palsies
in diabetic subjects is controversial, but we believe most of
these patients can be observed with sequential examina-
tions; nevertheless, if new neurologic signs or symptoms
appear, or the nerve palsy progresses, repeat neurologic
evaluation with neuroimaging is warranted.
The fact that the coexistence of diabetic retinopathy and
cardiovascular risk factors was slightly higher in patients
with sixth nerve palsy is compatible with the hypothesis
that this ischemic event might be more closely related to
diabetes and metabolic syndrome in its pathogenesis; on
the other hand, considering the rarity of the condition
investigated and the fact that this study was carried out in a
highly selected population, is possible that the association
between ophthalmoplegia and cardiovascular risk factors
might be due to pure chance.
Finally, we are aware of the small number of patients
evaluated in the present paper; however, these ndings
represent preliminary data that require further prospective
study with larger cohorts.
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