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Cerebral and retinal vascular complications of inflammatory bowel disease.

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Cerebral and Retinal Vascular Complications
of Inflammatory Bowel Disease
Jacob H. Schneiderman, MD, James A. S h a r p e , MD, and David M. C. Sutton, MD
Recurrent retinal branch artery occlusions, carotid thromboembolism, cerebral venous thrombosis, transient brainstem ischemia, a n d massive brainstem a n d cerebral infarction complicated the course of inflammatory bowel disease
i n 5 patients. Three patients h a d ulcerative colitis and 2 had regional enteritis. The usual risk factors for stroke were
absent. Neuropathological examination i n 1 patient showed i n situ thrombosis of small cerebral and brainstem
arteries a n d veins. Coagulation studies showed thrombocytosis, short partial thromboplastin times, and elevation of
fibrinogen and Factor VIII levels. Platelet counts and coagulation factors returned toward normal after control of
intestinal inflammation in each of the 4 surviving patients. Inflammatory bowel disease can b e accompanied by a
hypercoagulable state t h a t predisposes to stroke.
Schneiderman J H , Sharpe JA, Sutton DMC: Cerebral and retinal vascular complications of inflammatory
bowel disease. Ann Neurol 5:331-337, 1979
Peripheral v e n o u s and arterial thrombosis is a recognized complication of ulcerative colitis and regional
enteritis [4, 19, 3 11. Cerebrovascular disease, h o w e v e r , is rarely described in these conditions [3, 7, 14,
16, 23, 27-29]. Although an a b n o r m a l coagulation
state exists i n inflammatory b o w e l disease ( I B D ) [ 19,
21, 24, 31, 321, it has not been correlated with
s t r o k e in this disease. I n this paper we r e p o r t cerebral
a n d retinal vascular involvement in 5 patients w i t h
IBD. The results of coagulation studies in each patient a n d neuropathological examination i n l patient
are correlated with t h e s e neurological manifestations
of intestinal disease.
Hematological investigations included platelet counts;
prothrombin, partial thromboplastin, and thrombin times;
and assays of fibrinogen, Factor V, Factor VIII, fibrin degradation products, cryofibrinogen, and antithrombin Ill.
Commercially available reagents and substrate plasmas
were used for screening tests of coagulation and individual
factor assays. Platelet counts were performed by the
method of Brecher et a1 [ 6 ] .Fibrin degradation products
were assayed by the Thrombowellcotest [ l l ] , and antithrombin 111 was measured by the method reported by
Lane et al[20]. In Patient 1, platelet survival time was studied by chromium labeling [2].
Methods
A 34-year-old man noted a defect in the upper field of the
left eye, and an inferior temporal retinal infarct (Fig 1B)
was observed. Four months later he complained of blurring
in the upper nasal field of the right eye. Crohn's disease
involving the jejunum, ileum, and colon had been diagnosed eight months prior to the initial visual complaint,
after an eight-year history of abdominal symptoms. At the
time of the retinal infarcts the patient was taking Prednisonc, 15 mg per day, and his bowel symptoms were mild.
The physical examination showed a blood pressure of
110/70, and the pulse was regular at 80 per minute. There
were no murmurs o r bruits. Thickened and tender loops of
bowel were palpated in the right lower quadrant. A superficial hemorrhage and infarct (cotton-wool spot) was evident
in the inferior temporal nerve fiber layer of the right fundus (Fig 1 0 . The left fundus showed loss of the inferior
arcuate nerve fiber bundle and ascending atrophy of the
Five patients who had I B D with cerebral or retinal vascular
occlusions were seen by the neurology service between
August, 1975, and August, 1977. Two patients had regional enteritis (Crohn's disease) and 3 had ulcerative colitis,
each diagnosed by small and large bowel contrast roentgenograms, sigmoidoscopy, and intestinal biopsy. No patient had hypertension or a family history of premature
atherosclerosis. Concentrations of serum triglyceride,
cholestcrol, and fasting and 2 hour posrprandial blood glucose were normal. None of the patients had valvular heart
disease. Echocardiography (Patients 1, 2, 4 , and 5) and
electrocardiography were normal. The bowel biopsies
showed n o evidence of vasculitis. Antinuclear factor and
serum VDRL tests were negative. Cerebral angiography,
performed in all patients, showed no atherosclerosis o r vasculitis.
From the NeuroophthalmoloRy Unit, Division nf NeuroloRy, and
the Division of Hematology, Toronto Western Hospital. and the
Department of Medicine. University of Toronto Faculty of Medicine. Toronto. Ont. Canada.
Description of Cases
Patient I: Bilateral Retinal Branch Artery Occhsions
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lower optic disc (Fig 1D)as a result of the previous infarct.
Fluorescein angiography showed no evidence of intrinsic
retinal vascular disease. T h e remainder of the neurological
examination was normal. Aortic arch and bilateral selective
internal carotid angiograrns with magnified and subtracted
views o f carotid siphons and ophthalmic arteries were normal. Cardiological investigations. including echocardiography, were normal.
Patient 2: lnternal Carotid Artery Thrombosis
A 34-year-old man developed an acute right hemiplegia
and nonfluent aphasia while being treated in hospital for
ulcerative colitis. His blood pressure and pulse were normal. The left lower abdominal quadrant was tender.
Carotid angiography performed within 6 hours of che onset
332
Annals of Neurology
Vol 5
No 4 April 1979
FiK 1. (Patient 1 . I ( A . B ) Fundids photographs at initial exumination show left retinal infarct (6).
lC, D ) Fozrr month
later, infarct and hemorrhage in the right retina (C) and usrending atrophy of the inferior nenvJ5her layer and lower optic
disc nf the left eye (D) ure erident.
of his neurological deficit demonstrated an elongated filling
defect extending upward from the origin of the left internal
carotid artery. At surgery, a 5 cm long clot was removed
from the internal carotid artery; no atherosclerotic plaques
were seen in the carotid wall. The hemiplegia and aphasia
were permanent. T h e patient was given anticoagulants, first
heparin and then sodium warfarin (Coumadin), but antico-
agulant therapy was discontinued two months later because
of intestinal bleeding.
Patient 3: Hemorrhagic Infarction from Presumed
Cortical Venous Thrombosis
A 56-year-old woman suddenly developed difficulty naming objects and complained of left occipital headache. Her
speech worsened over a period of four days before
her admission to the hospital. She had first complained
of diarrhea three months previously. In hospital, Crohn’s
disease involving the rectum was detected.
The patient was afebrile. The blood pressure was 130180;
the pulse was 110 per minute and regular. Abdominal examination showed no abnormality, but there was fresh
blood on rectal examination. She had severe fluent aphasia.
The neurological examination was otherwise normal. After
three days the patient’s spontaneous speech returned to
normal, but defective repetition and dyslexia persisted. A
carotid angiogram showed a mass in the left temporoparietal region. The venous phase showed nonfilling of the
inferior anastomotic vein of Labbi, but the sagittal and
lateral sinuses were patent. Computerized axial tomography showed the temporoparietal mass to be an intracerebral hematoma, which became smaller two weeks later and
resolved completely in four months.
Patient 4: Transient Brainstem Ischemia and Axillary
Artery Occlusion
A 52-year-old woman awoke with vertigo, vomiting, diplopia, tinnitus, and frontal headache. H e r left arm was cold,
numb, and weak. O n e month previously she had had
bloody diarrhea caused by ulcerative colitis extending to
the rectosigmoid junction. The colitis improved on treatment with cortisone enemas and sulfasalazine, 3 gm per
day. She had been taking Ortho-Novum, 2 mg tablets, for
ten years.
The blood pressure was lGOll00 in the right arm; the left
arm was white, pulseless, and paralyzed. The heart rate was
100 per minute and regular, and there were n o murmurs.
The abdomen was tender. Blood and mucus were found on
rectal examination. The patient had dysarthria, left internuclear ophthalmoplegia, and gaze-evoked vertical nystagmus. T h e brainstem signs cleared within 24 hours, hut the
left arm remained ischemic. An aortic arch angiogram
demonstrated proximal occlusion of the left axillary artery.
Cardiac angiography was normal. At surgery, fresh clot was
removed from the left axillary artery, but gangrene developed and amputation of the hand was necessary.
Patient 5: Brainstem and Cerebral Infarctionfrom Small
Arterial and Venous 0cclu.rions
A 12-year-old girl was awakened by headache and complained of transient diplopia. A physician found no neurological deficit. Four days later she had a generalized seizure
and was admitted to the hospital with severe left-sided
headache and vomiting. Ulcerative colitis, diagnosed one
year earlier, was being treated with cortisone and sulfasalazine.
The patient was afebrile and normotensive. The pulse
rate was 120 per minute and regular. A right homonymous
hemianopia, which cleared within 24 hours, was the only
neurological sign. Sigmoidoscopic examination showed active colitis. Left carotid and vertebral angography demonstrated a filling defect in the distal basilar artery extending
into the left posterior cerebral artery. She was treated with
sulfasalazine and more frequent steroid enemas but received no anticoagulant or antiplatelet therapy. A second
sigmoidoscopic examination ten days after admission
showed improvement in the bowel inflammation, and she
was discharged from hospital. The next day the patient
awoke with severe frontal headache and had a grand ma1
seizure. I n the emergency department she had a cardiorespiratory arrest. Although resuscitated immediately, the
child had no brainstem reflexes and died 48 hours later.
POSTMORTEM EXAMINATION. The general autopsy
showed active inflammation of the descending colon. There
was no vasculitis in intestinal or other blood vessels.
Platelet thrombi were found in some pulmonary vessels.
Gross examination of the brain showed massive brainstem infarction (Fig 2). Multiple white thrombi occluded
small vessels over the surface of the cerebral hemispheres,
and small areas of leptomeningeal hemorrhage were evident. Many thrombi were present in the paramedian arteries, short circumferential arteries, and veins o n the anterior surface of the brainstem. The dural sinuses, the
carotid, vertebral, and basilar arteries, and the major
branches of the circle of Willis were patent. The cerebellum was normal apart from tonsillar herniation. T h e cerebral hemispheres showed uncal herniation. Coronal sections showed many areas of hemorrhagic softening of the
cerebral cortex and basal ganglia.
Microscopic examination showed recent infarction
throughout the cerebral hemispheres and extensive infarction of the brainstem with almost total transverse necrosis
of the midbrain and pons. Small arteries and veins (100 to
300 /.L) were occluded by platelet and fibrin thrombi (Fig 3).
The vessel walls showed n o inflammatory changes.
Results of Coagulation Studies
The results of abnormal coagulation studies are
summarized in Table 1. All patients were studied at
the time of hospital admission for their neurological
symptoms. In Patient 1, an elevated platelet count
was identified one weekprior to retinal infarction. In
Patient 2, early treatment with heparin precluded
complete coagulation testing at the time of the
stroke. Platelet counts ranged from 264 to 950 x loy
per liter (mean, 578 x lo9 per liter). T h e platelet
survival time in Patient 1 was normal (half-life, 4.2
days) three months after the second retinal infarction, when the patient still had thrombocytosis. Fibrinogen was elevated in 2 patients, and Factor VIII
was elevated in the 3 patients in whom it was assayed
at the acute phase of stroke. Partial thromboplastin
time was in the low-normal range in 2 patients and
decreased in a third. Levels of antithrombin 111 (Patients l, 3 , and 5 ) and Factor V (all patients) were
normal. Erythrocyte sedimentation rates were as
Schneiderman et al: Stroke with Inflammatory Bowel Disease
333
F i g 2 . (Patient 5 . ) Hemorrhagic infarction of midbrain tegmentidm a n d pedrrncles (left)a n d pons (right).
F i g 3. (Patient 5 . ) Thrornhrrs in the cerebral I erns. w i t h rnfurctron a n d hemorrhage o/ the cortex. Ves.rel icwllr ujere normal. I P T A H . X 100.)
334
Annals of Neurology
Vol 5
No 4
April 1979
Table 1 . Abnormal Coagulation Studies
Patient 1
Patient 3
Patient 2
Patient 5
Platelet Count and
Clotting Factors
Acute
lescent
Acute
Convalescent
Acute
Convalescent
Acute
Convalescent
Acute
Platelets
615
470
545
401
514
254
950
303
264
540
22 5
29
322
95
...
...
...
3 18
275
245
29
400
165
29
440
390
88
33
2 90
(X
Conva-
Patient 4
10YL)”
Fibrinogen (mg/dl)b
Factor VIll ( V y
Partial
thromboplastin
time (sec)d
33
127
35
...
28
320
26
Convalescent values obtained 1 1 months (Patient l), 8 months (Patient 2), 12 months (Patient 3), and 2 3 months (Patient 4 ) after stroke. In
Patient 2 early treatment with heparin invalidated initial coagulation studies; in Patient 5, death occurred within one week.
Normal values: “150-400 x lO!’/L; h200-400 mddl; ‘50-200%,; ‘229-40 sec.
follows: Patient 1 , 6 to 2 0 mm per hour; Patient 2, 16
to 20 mm per hour; Patient 3, 30 mm per hour;
Patient 4 , 34 to 76 mm per hour; and Patient 5, 9 to
38 mm per hour. All other hematological tests were
normal. Elevated fibrinogen and Factor VIII values
returned to normal after convalescence when intestinal symptoms were quiescent (see Table 1).
Discussion
T h e association of cerebrovascular disease and I B D is
infrequently recognized. A relationship between intestinal disease and stroke was not considered initially by the attending physicians in any of our patients. Enteritis was not diagnosed until after stroke
in Patient 3 . T h e patients described in this series and
12 patients from previous reports are listed in Table
2. The young ages of these patients (mean, 3 1 years)
distinguish them from the general stroke population
(mean age, 6 0 years) [lo]. T h e frequency of thromboembolic events in ulcerative colitis varies from approximately 1g)to 7 9 >in clinical series and from 7%
to 3757, in necropsy studies [19]. While venous
thrombosis may be secondary to immobility, severe
dehydration, or infection [4],none of these conditions was present in our patients. T h e absence of
other accepted causes of cerebrovascular occlusion
implicates the underlying bowel disease as the cause
of their strokes.
Recurrent retinal infarction occurred in Patient 1
without evidence of intrinsic vascular disease or embolic source from the heart or carotid arteries. In
Patient 2, cerebral infarction from internal carotid
artery thrombosis occurred without atheroma being
visible o n direct surgical inspection of the carotid
artery wall. Similarly, no evidence of primary arterial
disease, either vasculitis or atherosclerosis, was found
to explain the vertebrobasilar ischemia and axillary
artery occlusion in Patient 4. As in 3 of our other
patients, Patient 4 had thrombocytosis. Although the
oral contraceptive pills she was taking could predispose to arterial occlusion [8],these agents do not
cause thrombocytosis [l]. In Patient 3, the parietotemporal hemorrhage together with nonfilling
of the inferior anastomotic vein of LabbC was attributed to cortical venous thrombosis. In Patient 5,
multiple cerebral arterial and venous occlusions were
explained by local thrombosis, since no source of
embolism was found at autopsy. These clinical and
pathological observations suggest that in situ thrombosis of arteries and veins is responsible for cerebrovascular occlusion in Crohn’s disease and ulcerative colitis.
A hypercoagulable state could predispose to focal
intravascular thrombosis. Coagulation abnormalities
reported in I B D include accelerated thromboplastin
generation and increased levels of Factor V, Factor
VIII, and fibrinogen [17, 21, 311; low antithrombin
I11 concentrations [ 191; and thrombocytosis [ 19, 24,
321. Elevation of Factor V, Factor VIII, or fibrinogen
in other conditions may predispose to thrombosis
[12, 15, 261. In IBD, elevated fibrinogen and Factor
VIII have been correlated with thrombosis of the
limbs [31]. T h e abnormalities of fibrinogen, Factor
VIII, and thromboplastin generation identified in our
patients were associated with arterial and venous
thrombosis of the brain.
Thrombocytosis was present in 4 of the 5 patients
(see Table 1). Platelet counts of these magnitudes are
associated with transient ischemic attacks [5, 22, 25,
30, 331 or completed strokes in the retinal and cerebral circulations [5, 17, 181, but it is not certain that
the thrombocytosis can by itself cause thrombosis
[33]. Although platelet survival time was normal
in the single patient in whom it was measured (Patient l ) , platelet consumption by multiple cerebral
thrombi might explain the normal platelet count in
Patient 5. Tests of platelet activation were not performed. Transient platelet hyperaggregability occurs
Schneiderman et al: Stroke with Inflammatory Bowel Disease 335
Table 2. Occurrence of
Stroke in lnflurnmatory
T y p e of Stroke
Present series
Retinal branch
artery occlusions
Internal carotid
artery occlusion
Cerebral venous
thrombosis
Vertebrobasilar
ischemia
Multiple small
vessel occlusions
with brain s t e m
and cerebral
infarction
Previous reports
Central retinal
artery occlusion
Bowel Dixase
Type of
Bowel Disease
Patient's
Region a1
enteritis
Ulcerative
colitis
Regional
enteritis
Ulcerative
colitis
34
Ulcerative
colitis
12
Ulcerative
colitis
20
Ulcerative
colitis
54
Ulcerative
colitis
Regonal
enteritis
34
Regional
enteritis
44
Ulcerative
colitis
Ulcerative
colitis
Ulcerative
colitis
Regional
enteritis
23
Age (yr)
34
56
52
mi
Cerebral venous
thrombosis [ I 4 1
Cerebral venous
thrombosis 1141
Internal carotid
artery occlusion
[291
Middle cerebral
artery occlusion
[291
Cerebral venous
thrombosis [7 I
Cerebral venous
thrombosis 1271
Cerebral venous
thrombosis [3]
Superior sagittal
sinus thrombosis
[281
Cerebral arterial
occlusion [23]
Central retinal
and cerebral
arterial occlusion
[231
Cerebral arterial
occlusion [23]
Ulcerative
colitis
Ulcerative
colitis
counts in our series is unclear. The platelet count was
elevated before steroid therapy in Patient 3 . The
mechanism of thrombocytosis and hypercoagulability
in ulcerative colitis and Crohn disease is unknown.
The clinical, pathological, and hematological
findings presented here demonstrate that IBD can be
accompanied by a hypercoagulable state that predisposes to stroke. The occurrence of cerebrovascular
disease does not correlate well with the duration, the
activity, or the extent of intestinal inflammation.
Anticoagulation is hazardous because of hemorrhagic
cerebral infarction (Patients 3 and 5) and the risk of
intestinal hemorrhage (Patient 2). The use of drugs
that alter platelet activity would be rational if platelet
hyperagregability [33] were identified in patients
with IBD complicated by cerebral ischemia. In o u r
patients, platelet counts and coagulation factors returned toward normal after the intestinal symptoms
improved. Therapy must be directed at control of the
underlying bowel disease.
~
37
This paper was presented in part at the Canadian Congress of
Neurological Sciences, Quebec City, Quebec, Canada, June 17,
1977.
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1. Ambrus JL, Mink IB, Courey NG, et al: Progestational agents
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2.
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3.
17
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Ulcerative
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Dr J. F. Ross Fleming and Dr William J. Mcllroy kindly provided
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26
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336 Annals of Neurology Vol 5 N o 4 April 1979
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