Neuropathology 2001; 21, 241–244
Case Report
Hemorrhage in the oculomotor nerve as a
complication of leukemia
Kenji Jinnai1* and Yoshitake Hayashi2
1
Third Department of Internal Medicine and 2First Department of Pathology, Kobe University School of Medicine,
Kobe, Japan
Oculomotor paralysis of a patient with leukemia was
revealed at autopsy to be caused by a hemorrhage in the
oculomotor nerve. In a 63-year-old woman with pre-B-cell
acute lymphatic leukemia, leukemic invasions occurred
in her spinal cord and right oculomotor nerve during a
hematological remission state. The oculomotor palsy was
aggravated to complete paralysis during a leukemic
relapse, which lasted until her death. An autopsy revealed
a hemorrhage along with leukemic cells in the right
oculomotor nerve at the segment in the upper orbital
fissure. Although hemorrhagic oculomotor paralysis is a
very rare complication, reports of its occurrence will likely
increase with improved survival times of leukemia patients
due to advances in chemotherapy.
Key words: autopsy, cranial nerve, hemorrhage, leukemia,
leukemic infiltration, peripheral nervous system.
INTRODUCTION
Most nervous system complications with leukemia are due
to leukemic infiltration and hemorrhage in the CNS,1 while
the peripheral nervous system is only rarely involved. The
cranial nerves, especially the facial nerve and nerves con-
trolling the eye muscles (third, fourth, and sixth nerves),
are also known to be affected by leukemic infiltration.2
Further, hemorrhages in the peripheral nerves have seldom
been reported, in contrast to the CNS, where they occasion-
ally occur during courses of leukemia or lymphoma.1
However, the incidence of leukemic nervous involvement
Correspondence: Kenji Jinnai, MD, Department of Neurology,
National Sanatorium Hyogo-Chuo Hospital, 1314 Ohara, Sanda,
669–1592 Japan. Email: jinnaike@hyougotyu.hosp.go.jp
*Present address: Department of, Neurology, National Sanatorium
Hyogo-Chuo Hospital, Sanda, Japan.
Received 30 January 2001; revised and accepted 28 May 2001.
has been increasing along with advances in effective anti-
leukemic therapy.1
Neurological symptoms have been known to occur
in the hematological remission period after a success-
ful chemotherapy series because of the presence of the
blood–nerve barrier, which is capable of protecting
infiltrated leukemic cells from cytotoxic drugs.3
Herein we report a hemorrhage in the right oculomotor
nerve and spinal cord in an autopsied case of relapsed
acute lymphatic leukemia. To our knowledge, a hemor-
rhage in the oculomotor nerve has never been reported as a
complication of leukemia.
CLINICAL SUMMARY
A 63-year-old woman complaining of fatigue was diag-
nosed with acute pre-B-cell lymphatic leukemia at another
hospital in July 1991. She received a series of induction
chemotherapy and consolidation therapy from July to
September 1991. Although the patient was free from any
neurological disorders or abnormalities in the CSF, she
received intrathecal injections of anticancer agents once
in August and once in October 1991 to prevent leukemic
nervous involvement.
After discharge and several months of comfortable
remission she began to notice stiffness and sensory loss in
her legs in February 1992. On MRI a solid intramedullary
tumor extending from C7 to Th1 was found in her spinal
cord. She was subsequently referred to a neurosurgeon,
who noticed an incomplete right oculomotor palsy, with
pupillomotor involvement, in addition to the spinal tumor.
No obvious lesion was found in and around the right oculo-
motor nerve on MRI.
The tumor was partially resected and diagnosed as a
massive aggregation of B lymphocytes on 19 March 1992.
Just after the operation a leukemic relapse occurred and
the patient’s general condition became worse. The patient
was immediately transferred to the Department of Internal
242
Medicine at Kobe University Hospital for chemotherapy
treatment. Her condition had worsened to a semicomatose
state, with tetraparalysis and a complete loss of sensation
below the C5 spinal segment. The right oculomotor nerve
had been completely damaged, causing a loss of direct and
indirect light reflexes, impairment of both voluntary and
involuntary inward movements, and ptosis but no other
cranial nerves were involved. A large number of petechiae
in the area of her shoulder and back indicated fatal dissem-
inated intravascular coagulation. Futher MRI study for the
oculomotor paralysis was not performed because of her
serious condition.
Hematological examination of peripheral blood showed
leukocytosis at 13.3 ! 103/mm3 including 2% lymphoblasts,
anemia at 2.9 ! 106/mm3 RBC, and thrombocytopenia at
45.0 ! 103/mm3. Bone marrow smears disclosed a marked
increase of lymphoblasts to 46.4% in 560 ! 103/mm3 of
nucleated cells. Other significant findings in the serum were
a high level of lactic dehydrogenase to 2800 IU/L originat-
ing from the leukemic cells, and findings of disseminated
intravascular coagulation including decreased fibrinogen
to 113 mg/dL, increased fibrinogen degradation product to
11.0 units, and an elongated prothrombin time of 12.0 s.
Although an intravenous administration of anti-leukemic
agents followed by an intrathecal administration of
methotrexate were immediately given on her arrival, the
patient failed to respond to the therapy and died 1 week
later.
PATHOLOGICAL FINDINGS
Autopsy was performed on 5 April 1992, 2 h after death.
The tissues were fixed in buffered formalin and embedded
in paraffin. The sections were stained with HE and im-
munostaining. Immunohistochemistry was performed with
the monoclonal antibody specific to the human leukocyte
common antigen (Dako, Denmark) at a 1 : 50 dilution
using the biotin–streptavidin–peroxidase method (Dako,
Carpinteria, CA, USA).
The hypoplastic bone marrow contained a small quanti-
ty of B-cell-type lymphocytic leukemic cells, some of which
appeared to be ghost cells due to the last chemotherapy
series. Other reticulo-endotherial tissues, including the
liver and spleen, had no leukemic cells. The enlarged spinal
segments from C7 to Th1 contained an intramedullary
hematoma and residual leukemic cells stained with the
anti-leukocyte common antigen antibody. In the cerebrum,
cerebellum and brainstem no leukemic invasion was
detected, though a few leukemic cells were found around
the pia mater.
The right oculomotor nerve was partially enlarged and
the segment in the upper orbital fissure was colored brown
(Fig. 1). A microscopic examination of the nerve revealed
K Jinnai and Y Hayashi
Fig. 1 Macroscopic appearance of the right oculomotor
nerve. After fixation, the nerve was removed from the upper
orbital fissure, which had been cut from the orbital bone
during the autopsy. Arrowhead indicates an intraneural
hemorrhage under the epineurium at the orbital fissure
segment. The longer white segment was from the cavernous
sinus. Total length of the nerve in the picture is 3 cm.
that a massive hematoma had replaced the endoneurial
parenchyma and a large amount of leukocytes had infiltrat-
ed the nerve fibers. Although most of the leukocytes found
in the nerve had lost their nuclei, the cell membranes were
stained by an anti-leukocyte common antigen antibody
(Fig. 2). The leukemic cells were not found in the epineuri-
um or around the nerve trunk.
DISCUSSION
Acute oculomotor nerve palsy is often attributed to occlu-
sion of the vessels in the nerve or compression of the nerve
by a tumor and an aneurysm. The former mononeuropathy
is known as an ischemic oculomotor nerve palsy, the cause
of which is mainly diabetes mellitus.4,5 The other important
vascular risk factor is arteriosclerosis5 and vasculitis by
autoimmune mechanism6 or, rarely, ophthalmic herpes
zoster infection.7 In contrast, the oculomotor palsy from
intraneural bleeding is a rare event and, to our knowledge,
there is no report of such cases with leukemia.
In the present patient incomplete oculomotor distur-
bance suddenly deteriorated to complete paralysis on dis-
seminated intravascular coagulation 1 month after the
detection of the nerve palsy. Anti-leukemic agents, the neu-
ropathy by which is usually chronic and symmetric, are
not plausible as the cause of this acute mononeuropathy.
Moreover, pathological examination found that a hema-
toma had coexisted with an accumulation of exhausted
leukocytes in the nerve. These findings indicate that the
intraneural bleeding aggravated the neuropathy after an
intraneural infiltration of leukemic cells, and the dissemi-
nated intravascular coagulation was its risk factor.
Leukemic cells can infiltrate the nerves by passing
through the vessel or the subarachnoidal space.8,9 In the
present case the leukocytes in the nerve must have accumu-
Hemorrhage in the third nerve
Fig. 2 Microscopic appearance of the intraneural hemorr-
hage (a) and leukemic infiltration (b) in a longitudinal section
of the oculomotor nerve. (a) Hemorrhaging (arrow) spread
among the nerve fibers and beneath the epineurium (HE).
(b) Leukocytes accumulated in the nerve trunk and coe-
xisted with the hemorrhage (1eukocyte common antigen
immunostaining).
lated after passing through the perforating arteriolae,
because no evidence of leptomeningeal invasion was found
around the oculomotor nerve. A case report of B-cell pro-
lymphocytic invasion into the perineurial and endoneurial
spaces postulated that the invasion to the peripheral nerves
had occurred by way of the blood stream through the per-
ineurial and rich endoneurial vascular network.10
A lymphocyte marker analysis of leukemic cells
invading the PNS mostly demonstrates B cells,10–12 as in
the present case or, rarely, T cells.13 Moreover, other types
of leukemia can also invade the peripheral nervous
system.3,9,14
Because oculomotor paralysis in the present patient
occurred suddenly, and extraocular movements and the
pupillary sphincter muscle were disturbed, it was thought
that the nerve had been transectionally damaged by mas-
sive intraneural bleeding. No obvious lesions, however,
appeared in and around the oculomotor nerve in the skull
243
base at the autopsy.Therefore we further examined the dis-
tal part of the nerve in the superior orbital fissure, where an
intraneural hematoma was found. The nerve fibers situated
at the center of the nerve trunk, which control extraocular
movements, can be easily injured by ischemia, as in diabet-
ic oculomotor palsy,5 or by bleeding in the nerve trunk, as
shown in the present patient. Although the pupillomotor
fibers, which lie along the superior surface of the oculomo-
tor nerve, are usually spared in vascular accidents that
occur in the nerve trunk, the nerve segment in the narrow
space may be prone to be totally damaged to both extra-
ocular and intraocular palsy by an intraneural massive
hematoma. A detailed inspection in the canals or fissures
during autopsy is essential in the case of severely damaged
cranial nerve paralysis.
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