BLINDNESS CAUSED BY P H O T O R E C E P T O R
D E G E N E R A T I O N AS A R E M O T E E F F E C T O F CANCER
R A L P H A. S A W Y E R ,
Bethesda,
J O H N B. S E L H O R S T ,
San Francisco,
L O R E N Z E. ZIMMERMAN,
Washington,
AND
W I L L I A M F. H O Y T ,
San Francisco,
Visual disturbances associated with
cancer are ordinarily caused by metastasis
to the brain, méninges, optic nerve, orbit,
choroid, or retina. 1 - 6 This report docu­
ments blindness caused by retinal degen­
eration of obscure pathogenesis in three
patients with cancer.
CASE REPORTS
Case 1—A 65-year-old woman complained of
hoarseness and episodic dimming of vision in May
1973. These obscurations were sudden in onset and
involved both eyes simultaneously. She described
these sensations as if "I were living in a grey world,"
or "lights were turned down low." They persisted
for minutes, hours, or days and occurred several
times weekly. Recovery of vision was abrupt al­
though often incomplete. She also complained of
"seeing only parts of things," as numbers on a clock
or portions of a picture. Later she described bizarre
images in her field that resembled "floating spaghet­
ti or tissue paper." She denied previous visual
difficulties and night blindness.
From the Department of Ophthalmology, Nation­
al Naval Medical Center, Bethesda, Maryland (Dr.
Sawyer); Neuro-Ophthalmology Unit, Departments
of Ophthalmology, Neurology, and Neurological
Surgery, University of California, San Francisco,
California (Drs. Selhorst and Hoyt); and Registry of
Ophthalmic Pathology, Armed Forces Institute of
Pathology, Washington, D.C. (Dr. Zimmerman).
This study was supported in part by National Insti­
tute of Health grants EY-00061-01, EY-00083-01,
and EY-00032-13, National Eye Institute.
The opinions or assertions contained herein are
the private views of the authors and are not to be
construed as official or reflecting the views of the
Department of the Army, of the Navy, or of Defense.
Reprint requests to Lorenz Ε. Zimmerman, M.D.,
Armed Forces Institute of Pathology, Washington,
DC 20306.
606
M.D.
Maryland
M.D.
California
M.D.
D.C.
M.D.
California
Ophthalmologic examination in June 1973
showed corrected visual acuity of 20/25 in each eye.
Color vision discrimination tested by pseudoiso-
chromatic plates was moderately impaired in each
eye. Pupillary light responses were brisk. Bilateral
modified ring scotomas at 15 degrees were detected
by tangent screen examination. The visual field
defect of the right eye was only inferior, while that
of the left eye was open nasally. Intraocular pres­
sures by applanation tonometry were 16 mm Hg
bilaterally. The fundi showed scattered macular
drusen.
In July 1973, she was admitted for evaluation of
her hoarseness. She had a 30-year history of heavy
smoking and chronic lung disease. Her medications
had included digoxin, 0.25 mg daily, since 1972. She
had received tetracycline and aminophylline for
pulmonary infections and occasional chlordiazepox-
ide hydrochloride (Librium) and methylphenidate
hydrochloride (Ritalin). There was no family history
of retinal or neurologic disease. General physical
and neurologic examinations disclosed only paraly­
sis of the left vocal cord. Radiography of the chest,
direct laryngoscopy, esophagoscopy, and bronchos-
copy revealed no abnormalities.
By mid-August, visual acuity was hand motions in
all quadrants, and there were large central scotomas
bilaterally. An infiltrate in the left upper lobe was
identified radiographically, but repeat bronchosco-
py with multiple biopsies showed no abnormalities.
Four lumbar punctures demonstrated opening cere-
brospinal fluid pressures of less than 120 mm H 2 0 ,
protein less than 45 mg/100 ml, normal glucose,
nonreactive sérologie tests, and negative cultures.
No abnormal cells were detected by Millipore cytol­
ogy on three occasions. Roentgenograms of the skull
and tomograms of the sella and optic canal revealed
no abnormalities. An electroencephalogram and a
radioisotope brain scan with flow studies were with­
in normal limits. Detailed hématologie and blood
chemistry examinations were repeatedly normal.
The erythrocyte sedimentation rate was always less
than 16 mm/hr. Skin tests showed a positive re­
sponse to streptococcal antigen.
In September 1973, visual acuity was light per-
VOL'. 81, NO. 5 CANCER AND PHOTORECEPTOR DEGENERATION 607

ception. Perimetric visual fields demonstrated a pre­

served ring of vision at 40 degrees in the right eye
and spared islands of vision in the left eye temporal­
ly (Goldmann V4e). Mildly narrowed retinal arteri­
oles and several peripheral flecks of pigment were
seen in her retinas. Bilateral ophthalmodynamo-
metry and ocular plethysmography revealed pres­
sures within normal limits. Tomograms of the left
lung demonstrated a mass beneath the aortic arch.
Bronchoscopy, mediastinoscopy, and biopsies of
periaortic and bronchial lymph nodes revealed no
evidence of cancer. Thoracotomy with biopsy of a
mass in the left lung revealed a poorly differentiated
squamous cell (oat cell) carcinoma. No evidence of
metastasis was demonstrated by radioisotope scans
of bone, liver, and spleen or after aspiration of bone
marrow.
In November 1973, retinal vessels were threadlike
and had periarteriolar sheathing (Fig. 1), but the
fundi appeared unchanged otherwise. An electrore-
tinogram (ERG) demonstrated no photopic response
and a 10% scotopic response bilaterally. The arm to
retina circulation time was 30 seconds during fluo-
rescein angiography. Low flow prevented distinc­
tion between onset of choroidal and retinal flow.
Ten days of treatment with prednisone, 100 mg/day,
did not improve visual function or alter periarter­
iolar sheathing. Bilateral carotid arteriograms dem­
onstrated no abnormal findings. Computerized
transaxial tomography of the brain demonstrated no
lesions. The left upper lung field was irradiated with
5,000 roentgens in November. Despite her blindness
and localized lung cancer, the patient was ambula­
tory and active at home. In January and March 1974,
160-mg dose of lomustine (CCNU) were adminis­
tered.
In April 1974, after a brief, febrile illness, she
died. An autopsy was performed 26 hours after
death. Death was believed to be secondary to an
undiagnosed febrile illness and bronchogenic carci­
noma. Autopsy demonstrated (1) chronic bronchitis,
emphysema, and pneumonia; (2) undifferentiated
small cell carcinoma of the left lung with,metastatic
foci in liver; and (3) mild coronary and generalized
atherosclerosis. Fig. 1 (Sawyer and associates). Case 1. Retinal
Careful examination of the carotid, basilar, and arteries and their branches are markedly narrowed,
ophthalmic arteries showed only minimal athero­ and in places they exhibit periarteriolar sheathing;
sclerosis. Examination of the visual pathways from top, right eye (AFIP Neg. 75-8027) and bottom, left
the retina to the occipital cortex, including the eye (AFIP Neg. 75-8028).
unroofing of both optic canals and complete dissec­
tion of the chiasm, optic tracts, and occipital cortex, showed similar findings. The anterior segments,
revealed no gross or microscopic evidence of metas­ optic nerve heads, major choroidal vessels, and
tasis, inflammatory reaction, or degenerative disease posterior ciliary arteries revealed no significant ab­
other than changes in the photoreceptors. No normalities, and there was only slight thickening of
neuronal degeneration was found in the lateral ge- the walls of the choriocapillaris. The retinal pigment
niculate bodies. The méninges were free of carcino- epithelium showed mild to moderate autolytic
matous seeding. A single microscopic focus of neo- change. Significant pathologic findings were: (1)
plastic cells was present in the basis pontis. Stains advanced disintegration of inner and outer segments
for myelin and axons made on sections of optic of rods and cones; (2) widespread degeneration of
nerves, chiasm, and optic tracts showed no evidence the outer nuclear layer, most marked temporally;
of demyelination or of axonal degeneration. and (3) scattered melanophages in the outer retinal
Macroscopically, both eyes showed narrowed reti­ layers (Figs. 2-5). There was remarkably good pres­
nal arterioles. Histopathologically the two eyes ervation of retinal architecture and of cytologie
608 AMERICAN JOURNAL OF OPHTHALMOLOGY MAY, 1976

Fig. 2 (Sawyer and associates).

Case 1. Advanced degeneration of
photoreceptors and their nuclei in
center of macula. Pigmented macro­
phages are present along outer edge
of degenerated retina and in debris
between sensory retina and pigment
epithelium (hematoxylin and eosin,
x70; A F I P Neg. 75-1616).

Fig. 3 (Sawyer and as­

sociates). Case 1. At mid-
periphery of macula, pig­
mented macrophages are
present in outer plexiform
layer. Photoreceptors and
their nuclei are absent
(hematoxylin and eosin,
xlOO; AFIP Neg. 75-
1614).

Fig. 4 (Sawyer and as­

sociates). Case 1. Marked
degeneration of outer reti­
nal layers of macula with
pigmented macrophages
in outer plexiform layer
(hematoxylin and eosin,
X300; AFIP Neg. 75-
1611).

detail in the inner retinal layers. In several areas
minimal lymphocytic infiltration appeared around
retina] arterioles. The Feulgen method revealed no
extracellular deposits of DNA.
Case 2—"Endometrioid sarcoma" was diagnosed
by biopsy of a metastatic lesion in the vagina of a
62-year-old women in February 1968. 7 The pelvic
tumor was treated by radiation and subsequently by
surgical resection. The patient had been treated by
an ophthalmologist for three years because of mild
macular degeneration and several retinal holes. In
June 1968, visual acuity was R.E.: 20/25, and L.E.:
20/40. In July she first complained of night blind-
ness. There was no family history of retinal degener-
VOL. 81, NO. 5 CANCER AND PHOTORECEPTOR DEGENERATION
Fig. 5 (Sawyer and associates). Case 1. The archi­
tecture of inner layers of the peripheral retina is well
preserved. Photoreceptors are absent, and in some
areas there is complete loss of the outer nuclear layer
(hematoxylin and eosin, x l l 5 , top; x300, bottom;
AFIP Negs. 75-1615 and 75-1610, respectively).
ative disease. In August she had episodic visual
images of "gold, flickering specks . . . that shim­
mered in a circular pattern." Multiple dark spots
"like a swarm of bees" partially obscured her central
vision. In one month, her visual acuity had deterio­
rated to R.E.: 20/40, and L.E.: 20/200. Her pupils
reacted normally. Bilateral paracentral scotomas
were found by tangent screen examination. Minimal
degenerative changes were present in both maculae,
and the optic disks appeared normal. The retinal
arterioles had become markedly narrowed in the
Fig. 6 (Sawyer and associates). Case 2. Fundus photographs of right eye demonstrate narrowing of retinal
arterioles between June 1967 (left) and September 1968 (right). T h e same vessels are marked by arrows.
These and others between them are extremely attenuated (right) (AFIP Negs. 75-7595-4 and 75-7595-3,
respectively).
609
course of one year (Fig. 6). Angiography revealed a
delayed flow of fluorescein without definite retinal,
choroidal, or pigmentary defects. Roentgenograms
of the skull and optic foramina were normal. A
radioactive brain scan revealed no abnormality.
In November, visual acuity was R.E. 20/70, and
L.E.: hand motions. The right eye had a ring scoto-
ma between 5 and 30 degrees. A temporal crescent
remained in the visual field of her left eye (Gold-
mann V4e). Cytologie examination of cerebrospinal
fluid revealed malignant cells. Her whole brain was
irradiated with 3,000 roentgens, and she was given
four intrathecal injections of 2 0 m g o f methotrexate.
By January she was nearly blind, but her general
physical and neurologic condition remained good.
She developed cerebellar ataxia and died in Febru­
ary 1969 from an apparent overdose of drugs.
Autopsy showed no residual tumor in her pelvis.
Metastatic foci of anaplastic tumor cells were pres­
ent in the mesentery and ribs. Our review of sections
of the tumor revealed a completely undifferentiated,
highly cellular neoplasm that appeared consistent
with an oat cell type of bronchogenic carcinoma.
Neuropathologic examination demonstrated me-
ningeal carcinomatosis involving cerebellum and
spinal cord. No metastasis was found in the cerebral
hemispheres, optic nerves, or méninges.
Histologie sections of each eye were obtained for
review. The posterior ciliary arteries and choroidal
vessels, including the choriocapillaris and retinal
pigment epithelium, were well preserved and nor­
mal. The retinas of both eyes showed: (1) total loss
of inner and outer segments of the photoreceptors;
(2) almost complete loss of the outer nuclear layer;
(3) scattered melanophages in the outer retinal lay­
ers; and (4) preservation of architecture and cytolog­
ie detail in the inner retinal layers (Figs. 7 and 8).
610 AMERICAN JOURNAL OF OPHTHALMOLOGY
Several foci of infiltration by chronic inflammatory
cells were observed about the adventitia of retinal
arterioles.
Case 3—In January 1970, a 76-year-old woman
was seen because of painless blurred vision in her
right eye of three days' duration. 8 Visual acuity was
R.E.: 20/60, and L.E.: 20/30. The anterior segments
appeared normal. Intraocular pressures were within
normal limits. The visual field in her right eye was
reduced to a small central island of vision, while
that of her left was normal. The retinal arterioles
were attenuated, and the optic disks were slightly
pale. One week later a ring scotoma with loss of
peripheral nasal field was found in her left eye.
Visual field loss continued, and after two weeks only
a small central island in each eye remained. Visual
acuity was R.E.: 20/200, and L.E.: 20/120. The
circulation time during fluorescein angiography was
delayed to 21 seconds. Sedimentation rate was 18
mm/hour.
In March she complained of abdominal pain.
Fig. 8 (Sawyer and associates). Case 2. Complete
degeneration of photoreceptor cells and their nuclei
is seen in the peripheral retina. Pigmented macro­
phages are present in the outer plexiform layer
(hematoxylin and eosin, x305; AFIP Neg. 75-2444).
MAY, 1976
Fig. 7 (Sawyer and associates).
Case 2. Complete degeneration of
photoreceptor cells and their nuclei
is shown in the juxtapapillary reti­
na. There are pigmented macro­
phages in the degenerated outer
plexiforrrt layer. Chronic inflamma­
tory cells surround retinal arteriole
(hematoxylin and eosin, x l 9 5 ;
A F I P Neg. 75-2449).
Biopsy of a pelvic mass revealed an anaplastic small
cell tumor, presumably metastatic from the lung.
She died several days later.
A complete autopsy with neuropathologic exami­
nation was not performed, but the left eye was
obtained two hours after death. Our review of histo­
logie sections showed: (1) absence of inner and
outer segments of the photoreceptors; (2) severe
degeneration of the outer nuclear layer; and (3)
scattered melanophages in the outer retinal layers
(Fig. 9). A full complement of ganglion and bipolar
cells was present. Choroidal vessels, choriocapil-
laris, and retinal pigment epithelium appeared nor­
mal. A small atrophie focus was present in the optic
nerve. There were no detectable autolytic changes.
Fig. 9 (Sawyer and associates). Case 3. Complete
degeneration of photoreceptor cells and their nuclei
is shown in the peripheral retina. Pigmented macro­
phages are present in the outer plexiform layer
(hematoxylin and eosin, x300; AFIP Neg. 75-1603).
VOL. 81, NO. 5 CANCER AND PHOTORECEPTOR DEGENERATION
DISCUSSION
These three older patients with cancer
had early ophthalmologic symptoms and
signs of retinal origin; these are summa­
rized along with ocular histopathologic
findings in the Table. Two patients com­
plained of bizarre visual sensations such
as "swarms of bees" and "spaghetti-like"
lines. One patient had severe obscura­
tions of vision. Ringlike scotomas charac­
terized early visual field defects. Retinal
arteriolar narrowing was found in each
patient. Fundus photographs in the sec­
ond patient (Fig. 6) clearly depict this
development over a one-year period. A
flat ERG in the first patient indicated that
retinal degeneration was responsible for
her blindness. The second patient com­
plained of night blindness shortly before
onset of her visual deterioration. Neither
patient had significant pigmentary reti-
nopathy as shown by ophthalmoscopic
examination. Histopathologic examina­
tions in each case revealed widespread
severe degeneration of the outer retinal
layers and mild melanophagic activity.
The severity of the disintegration of
photoreceptors,.the marked loss of nuclei
from the outer nuclear layer, and the
presence of macrophages containing
phagocytosed granules from the retinal
pigment epithelium, together with the
remarkable preservation of other retinal
layers and the absence of noteworthy
TABLE
SUMMARY O F MAIN CLINICAL AND PATHOLOGIC OCULAR FINDINGS
Findings Case 1
Clinical
Episodic visual symptoms Present
Scotomas at onset Ringlike
Retinal arterioles Very narrow
Flat ERG or night blindness Present
Optic disk Normal appearance
Pathologic
Photoreceptors Total degeneration
Outer nuclear layer Widespread loss
of cells
Melanophages in retina Present
611
pathologic changes in the choriocapillaris
and retinal pigment epithelium in each of
the five eyes examined, clearly directed
our attention to the rods and cones as the
anatomic site responsible for the visual
loss of these patients. The results of
neuropathojogic examination in two of
these cases support this conclusion.
The clinical and pathologic findings in
these cases do not conform to recognized
hereditary, toxic, or vascular retinop-
athies. Senile pigmentary dystrophy ap­
pears in late life with insidious visual loss
developing in two or more years. 9,10
These patients had rapidly decreased vis­
ual acuity in one to four months and
complained of bizarre visual sensations
and obscurations. At the time of onset of
their visual complaints they had not been
exposed to any drugs known to produce
toxic retinopathies. 1 1 - 1 3 Ingestion of
bracken by sheep produces a rapidly pro­
gressive retinopathy 1 4 , 1 5 that closely cor­
responds to the pathologic findings we
have described (Fig. 10), but we are not
aware of a similar toxic retinopathy in
man. Occlusive disease of the posterior
ciliary arteries and atrophy of the chorio­
capillaris are associated with localized
alterations in the pigment epithelium,
pigmentary migration, and photoreceptor
cell degeneration. 1 6 - 1 8 Widespread
photoreceptor degeneration associated
with an intact pigment epithelium and
Case 2 Case 3
Present Present
Ringlike Ringlike
Very narrow Narrow
Present
Normal appearance Slight pallor
Total degeneration Total degeneration
Total loss Total loss
of cells of cells
Present Present
612 AMERICAN JOURNAL OF OPHTHALMOLOGY
Fig. 10 (Sawyer and associates). Bright blindness
in sheep (case presented by Ashton 15 ). There is
advanced degeneration of the photoreceptors, and
the outer nuclear layer is reduced to a single row of
nuclei; top, juxtapapillary retina (AFIP Neg. 75-
5625); and bottom, peripheral retina (hematoxylin
and eosin, x300; AFIP Neg. 75-5626).
normal posterior ciliary arteries and
choriocapillaris excludes a vascular basis
for the pathologic findings in these cases.
Each of these patients had concurrent
manifestations of photoreceptor damage
and of malignant neoplasms. In two cases
the cancer was believed to be a small cell
bronchogenic carcinoma. In the third
case, interpreted originally as endo-
metrioid sarcoma, our histopathologic re­
view revealed an undifferentiated small
cell neoplasm entirely consistent with
metastatic oat cell carcinoma of the lung.
The unusual development of photore­
ceptor degeneration within five months of
the discovery of a poorly differentiated
carcinoma suggests a pathogenetic rela­
tionship to the cancer that each patient
had. Blindness attributable to photore­
MAY, 1976
ceptor cell degeneration may be another
remote effect of cancer. In two of the
patients visual deterioration preceded
recognition of the cancer. Difficulty in
early diagnosis might be resolved by
electrophysiologic evaluation of the reti­
na when rapidly progressive and bizarre
visual deterioration is not readily ex­
plained by other studies.
Neurologic manifestations of cancer
not attributable to metastatic disease have
been recognized for 80 years.4*19 In 1964,
Greenberg, Diverties, and Woolner 19 re­
viewed and classified these syndromes.
Neuronal degeneration in these paraneo-
plastic syndromes has been observed in
the cerebellum, 2 0 sensory root ganglia, 21
anterior horn cells, 22 and cerebral cortical
neurons. 2 3 The photoreceptor cell degen­
eration we described in these three cases
may be analogous. Recent studies 2 4 have
shown that a number of pharmacological­
ly active, hormone-like substances may
be produced by oat cell carcinomas. One
or more of these substances or other prod­
ucts of the tumors may have been respon­
sible for the damage to the photoreceptor
cells.
SUMMARY
Three postmenopausal women devel­
oped photoreceptor degeneration one to
four months preceding or following dis­
covery of an anaplastic tumor. Two pa­
tients had transitory visual obscurations
and bizarre visual sensations. Ring scoto-
mas progressed to severe visual field loss.
Retinal arteries were markedly narrowed.
Electroretinograms revealed almost total
absence of response in one patient, and
another patient complained of the recent
onset of night blindness. In all three
patients severe degeneration of the photo­
receptor cells associated with melano-
phagic activity was shown histologically.
In two patients neuropathologic examina­
tion from the retinal bipolar cells to the
occipital cortex revealed no significant
alterations.
VOL. 81, NO. 5 CANCER AND PHOTORECEPTOR DEGENERATION
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