Journal of Neuro-Ophthalmology, September 1994, Volume 14, Issue 3

A diagnostic quartet in leptomeningeal infiltration of the optic nerve sheath.

A rare case of optic leptomeningeal carcinomatosis secondary to a rectal adenocarcinoma is recorded. The presentation of rectal disease with blindness is unique. A diagnostic quartet of symptoms and signs of leptomeningeal infiltration of the optic nerve sheath is proposed and its value emphasized by the inability of further investigation to confirm the clinical diagnosis. The investigation and treatment of leptomeningeal carcinomatosis is reviewed.

Journal of Neum- Oi'hlhalmoloxy 14(3): 175- 182, 1994. € 1994 Raven Press, Ltd., New York A Diagnostic Quartet in Leptomeningeal Infiltration of the Optic Nerve Sheath Robert McFadzean, F. R. c. s. Ed., Donal Brosnahan, F. R. c. s. Ed., David Doyle, M. D., James Going, M. R. c. Path., Donald Hadley, F. R. C. R., and William Lee, M. D. A rare case of optic leptomeningeal carcinomatosis sec­ondary to a rectal adenocarcinoma is recorded. The pre­sentation of rectal disease with blindness is unique. A diagnostic quartet of symptoms and signs of leptomen­ingeal infiltration of the optic nerve sheath is proposed and its value emphasized by the inability of further in­vestigation to confirm the clinical diagnosis. The inves­tigation and treatment of leptomeningeal carcinomatosis is reviewed. Key Words: Optic leptomeningeal carcinomatosis- Diagnostic quartet- Rectal adenocarcinoma. From the Departments of Neuro- ophthalmology ( R. McF., D. B.), Neuropathology ( D. D., J. G.), and Neuroradiology ( D. H.), Institute of Neurological Sciences, and Department of Ophthalmic Pathology ( W. L.), Tennent Institute, University of Glasgow, Scotland. Address correspondence and reprint requests to Dr. Robert McFadzean, Department of Neuro- ophthalmology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, Scotland. Meningeal carcinomatosis is an uncommon con­dition but may be the first sign of an underlying malignancy in 50- 75% of patients ( 1,2). Common primary carcinomas that metastasize to the central nervous system include lung, breast, and gastro­intestinal tract, in particular, adenocarcinomas ( 1- 11). Simultaneous leptomeningeal and in­tramedullary spinal metastases may occur ( 3). The differential diagnosis is from subacute/ chronic me­ningoencephalitis due to tuberculosis, sarcoidosis, and fungal infection ( 1,2,5,7,8,12). Although carcinoma of the rectum in the general population is not uncommon, metastatic spread to the meninges is rare ( 13- 16). In most patients with primary gastrointestinal cancer, metastasis to the leptomeninges takes place via perineural spaces ( 9). With the advent of more effective treatment of rectal carcinoma and a longer survival of patients ( 17), it is likely that the incidence of meningeal carcinomatosis will increase ( 8). Although treat­ment of the latter has to date been relatively inef­fective, early diagnosis appears to improve the therapeutic results ( 8,18). This paper reports the fifth recorded case of meningeal carcinomatosis secondary to rectal car­cinoma ( 13- 16). Although meningeal carcinomato­sis was diagnosed clinically, the primary lesion was only identified at autopsy. A quartet of symp­toms and signs diagnostic of leptomeningeal infil­tration of the optic nerve sheaths is presented and its value stressed by the failure of technological investigation to specifically confirm the clinical di­agnosis. Early diagnosis is based on clinical examination combined with imaging and cerebrospinal fluid ( CSF) studies, along with a search for tumor mark­ers in the blood and CSF. Confirmation requires 175 176 R. MCFADZEAN ET AL. the presence of metastatic carcinoma cells in the CSF, although these are not always identified. Ocular signs have been recorded in 91% of pa­tients with diffuse carcinomatous meningitis and include loss of vision, an ocular motility deficit, pupillary involvement, papilledema, and optic at­rophy ( 19). Other symptoms and signs comprise headaches, dementia, meningeal irritation, multi­ple cranial neuropathies, and spinal nerve root in­volvement ( 1,5,7,8,13). The clinical diagnosis is suggested by the simultaneous occurrence of symptoms or signs in more than one area of the neuraxis ( 5). Potential mechanisms for visual loss are paren­chymatous invasion, compression, demyelination, and impaired blood supply and/ or metabolism of the optic nerves and/ or more posterior visual path­ways ( 4,20- 24). More remote effects include sec­ondary hydrocephalus ( 4), retinal photoreceptor degeneration ( 22,25), and the production of a " toxic" substance ( 12). The term meningeal carcinomatosis is preferable to the more commonly used carcinomatous meningi­tis, as the condition is neoplastic and not inflam­matory. CASE REPORT History A 41- year- old male taxi driver complained of headaches with nausea for 2 weeks. The head­aches had become gradually more severe and were worse on lying down, coughing, and straining. During the preceding 5 days his vision had pro­gressively deteriorated until he was almost blind. He had recently recovered from a chest infection, but his general health was otherwise good. Strabismus surgery was carried out on his left eye when he was 10 years old, but there was no residual amblyopia nor significant deviation. He had suffered from no other serious illnesses, but had smoked 60 cigarettes per day for many years and was a heavy social drinker. Examination Visual acuity was reduced to light perception in the temporal field in each eye and the pupils were enlarged with minimal light reactions. There was a mild left ptosis and a small right divergent squint with bilateral asymmetrical, horizontal conjugate gaze weakness. However, the optic discs and ret­inae appeared healthy. Detailed clinical examination of all other systems revealed a few scattered rhonchi in the chest, but no other abnormality. Provisional Diagnosis As this patient clearly had headaches typical of raised intracranial pressure yet healthy optic discs, it was postulated that there must be a lesion ob­structing the flow of CSF along the subarachnoid space around both optic nerves. In conjunction with his blindness and enlarged and minimally re­acting pupils, the most likely diagnosis appeared to be leptomeningeal infiltration of the optic nerve sheath. The ptosis, divergent squint, and ocular motility deficit possibly reflected similar infiltra­tion in the basal cisterns. His heavy smoking his­tory and nonspecific chest signs with rapid deteri­oration suggested the possibility of a primary lung carcinoma with metastatic spread to the optic lep-tomeninges. Investigations A contrast- enhanced computed tomography ( CT) scan showed minimal chiasmal thickening with ventricular dilatation and low attenuation lat­eral to the anterior horns of the lateral ventricles ( Fig. 1). Magnetic resonance imaging ( MRI) con­firmed the hydrocephalus of the lateral ventricles with periventricular increased T2 signal. The mildly T2- weighted sequence ( SE 2,000/ 80) demon­strated an increase in the CSF signal in the basal cisterns, most marked in the interpeduncular re­gion. A chest radiograph was normal. However, a complete blood count revealed a hemoglobin level of 19.8 g/ dl, RBC count, 6.39 x 1012/ L, PCV L/ L 0.581, MCV fL 91, MCH pg 31, WBC count x 109/ L 11.5 ( neutrophilia), platelets 276 x 109/ L, and a normochromic and normocytic film with neutro­philia. An iliac crest bone marrow showed reactive megakaryocytic hyperplasia. The CSF opening pressure measured 55 cm, but on cytology there were only a few lymphocytes and no abnormal cells. CSF protein was 0.70 g/ L ( normal range: 0.10- 0.50 g/ L) and glucose 2.7 mmol/ L ( normal range: 2.5- 4.5 mmol/ L). Serum urea and electro­lytes and plasma protein electrophoresis were nor­mal, while liver function tests showed an in­creased AIT 93 IU/ L ( normal range: 10- 55 IU/ L). The CSF examination for cells and biochemistry was repeated on three occasions, the patient hav­ing been placed on continuous lumbar spinal drainage, with similar results. ; Neuw- Ophlhalnwl. Vol. 14, No. .3, 3994 LEPTOMENINGEAL INFILTRATION OF OPTIC NERVE SHEATH 177 FIG. 1. Contrast- enhanced CT scan with minimal chiasmal thickening and low attenuation lateral to the dilated anterior horns of the lateral ventricles. Treatment After institution of continuous lumbar spinal drainage, the patient was placed on dexametha-sone 4 mg orally qid. In view of his polycythemia, venesection was carried out. Progress In spite of the above measures progressive de­terioration took place and he died after 5 days. An autopsy was carried out. Pathology Brain At the base of the brain there was thickening of the leptomeninges in the interpenduncular fossa, both sylvian fissures, and around the vallecula and medulla. Paraffin sections showed mucin-secreting adenocarcinoma filling the subarachnoid space around the spinal cord, medulla, cerebel­lum, optic chiasm, and nerves ( Figs. 2 and 3) and calcarine cortex ( Fig. 4). In the latter the tumor cells appeared to pass along the perivascular Virchow- Robin spaces without actually invading or obliter­ating the blood vessels or causing histologic isch­emic cortical damage. Tiny deposits of tumor pen­etrated the cerebellar cortex, and there were a few tumor cells in the floor of the 4th ventricle. Optic nerves Macroscopically both optic nerves showed lep-tomeningeal thickening, which stopped 1.5 cm posterior to the globe. Microscopy revealed filling of the posterior part of the subarachnoid space around each optic nerve with metastatic tumor FIG. 2. Thickened right optic nerve ( x8). ; Neuw- Ophthalmol, Vol. 14. No. 3, 1994 178 R. MCFADZEAN ET AL. FIG. 3. Transverse section of both optic nerves with tumor infiltration of subarachnoid space ( arrowheads) ( x8). ( Fig. 5), including signet cell forms. There were no apparent ischemic changes, but the extreme pe­riphery of each nerve demonstrated axonal drop­out and demyelination. Unfortunately, the retina was autolyzed. Gastrointestinal system Circumferential carcinoma of the proximal rec­tum infiltrated the wall and the perirectal fat. His­tology showed a diffusely infiltrative mucoid sig­net- cell carcinoma ( Fig. 6). Lytnpho- reticular system The para- aortic nodes were massively replaced by metastatic carcinoma. Immunohistochemistry The malignant cells in the optic leptomeninges and rectum showed identical positivity for cytoker-atin ( Cam 5.2), epithelial membrane antigen, and carcinoembryonic antigen. They were also identi­cal morphologically and on mucin staining. Other systems There was no other evidence of metastatic dis­ease. Diagnosis The cause of this patient's sudden blindness was optic leptomeningeal carcinomatosis secondary to a primary rectal adenocarcinoma. FIG. 4. Invasion of a calcarine cortical sulcus with tumor cells ( x45). - - i , - • . • • • . t - - • J Ncuro- Ophthalmol, Vol. 14, No. .3, 1994 LEPTOMENINGEAL INFILTRATION OF OPTIC NERVE SHEATH 179 FIG. 5. Dense infiltration of subarachnoid space around the right optic nerve with tumor including signet cell forms ( ar­rowhead) ( x100). DISCUSSION It is well recognized that the diagnosis of meningeal carcinomatosis at presentation is diffi­cult, but early diagnosis may help to improve the therapeutic outcome ( 4,5,7,8,17,18). Ocular signs were identified in 39 of 43 patients with diffuse carcinomatous meningitis and included loss of vi­sion ( 44%), ocular motility deficits ( 50%), pupillary involvement ( 50%), papilledema ( 55%), and optic atrophy ( 12%) ( 19). Although there is general agreement about the frequency of pupillary and ocular motility involvement, there is disagreement about optic nerve involvement, ranging from 14% to 44% ( 1,5,19). A bilateral internuclear ophthal­moplegia has been described in one patient ( 26), and in two patients the visual loss appeared to simulate a bilateral retrobulbar optic neuropathy ( 27,28). Other well- recognized features are head­aches, dementia, meningeal irritation, multiple cranial neuropathies, and spinal nerve root in­volvement ( 1,5,7,8,13). The combination of headaches typical of raised intracranial pressure, blindness, sluggish or absent pupillary reflexes, but normal appearing optic discs, is a quartet of symptoms and signs diagnos­tic of leptomeningeal infiltration of the optic nerve sheaths. The clinical importance of this quartet is exemplified by the failure of subsequent techno­logical investigation to specifically confirm the di­agnosis, although the MRI magnet used was of low resolution. Nevertheless, the imaging changes FIG. 6. Rectal wall infiltrated by signet cell ( arrowhead) ( X100) carcinoma. > J / < i # i * i , * ** * r • « - i / I - - 0 , •' | Neuro- Ophlhalmol, Vol. 14, No. .?, 1994 280 R. MCFADZEAN ET AL. in this condition are nonspecific and have to be differentiated from inflammatory meningoenceph­alitis ( 29- 31). The increase in the CSF signal ob­served in the basal cisterns was due either to a local raised protein content or abnormal meninges ( 32,33). The CSF examination, although repeated on three occasions by an experienced histopathol-ogist, showed neither abnormal cells nor biochem­ical changes specifically compatible with menin­geal carcinomatosis. Pituitary apoplexy may produce similar symp­toms and signs, but is usually accompanied by fea­tures of endocrine and metabolic imbalance with a deterioration in conscious level, and signs of meningeal irritation ( 34,35). Other causes of acute/ subacute visual loss that are more readily recog­nized include intraocular lesions, giant cell arteri­tis, bilateral optic neuritis, chiasmal compression, bilateral occipital infarction, pseudotumor cerebri, rapidly expanding hydrocephalus, basal meningi­tis, hereditary optic atrophy, methanol intoxica­tion, and hysteria ( 20,23). This is only the fifth reported case of optic lep-tomeningeal carcinomatosis secondary to a rectal carcinoma ( 13- 16) and appears to be the first case to present with the rapid onset of blindness. How­ever, with improved diagnosis and treatment of rectal carcinoma ( 17), the incidence of this compli­cation may well increase. Unfortunately, this pa­tient had no gastrointestinal symptoms nor signs, the rectal lesion lying in the proximal rectum be­yond the range of the examining finger on rectal examination. Previously reported cases of this association pre­sented with headaches ( 3 patients) ( 13,15,16), ver­tigo ( 2 patients) ( 14,15), diplopia ( 1 patient) ( 16), deafness ( 1 patient) ( 14), ataxia ( 1 patient) ( 14), and lower limb pain ( 1 patient) ( 16). Rapid loss of vi­sion developed 4 months after the onset of head­aches in one patient ( 13). Headaches typical of raised intracranial pressure with or without papilledema are common pre­senting features of meningeal carcinomatosis ( 1,5, 8,19). Hence the initial investigation requires diag­nostic imaging in the form of CT and/ or MRI. Gad­olinium- enhanced MRI best delineates the extent of the meningeal lesion and may suggest the diag­nosis, although the changes are nonspecific ( 29- 31). Contrast CT is more effective than plain MRI ( 36,37) but less effective than gadolinium MRI in demonstrating the lesion ( 30). In this case, only plain MRI was used, as ethical permission to use gadolinium had not been obtained. Nevertheless, minor abnormalities were noted in the basal cis­terns, while a CT scan with contrast failed to dem­onstrate any abnormality in this area. The changes were, however, not diagnostic and the differential diagnosis included meningitis, encephalitis, and meningeal carcinomatosis. The specific diagnosis hinges on changes in the cerebrospinal fluid. A cytologic search for malig­nant cells may be positive, but repeated examina­tions may be necessary ( 1,5,8). Even when exam­ination is repeated three or four times, there may be a failure to detect malignant cells in 20% of cases ( 1,5). Malignant cells may be present in the CSF against an eosinophilic inflammatory background ( 38). Four specimens of CSF were centrifuged and subjected to detailed examination in this case, there being a plentiful supply of CSF while the patient was on continuous lumbar spinal drainage. Only a few lymphocytes were detected but no ab­normal cells, although the examination was carried out by a very experienced cytologist. Biochemical changes take the form of increased protein ( 1,5) and diminished glucose ( 39), but in this patient only the protein was mildly elevated, another non­specific change. Increased CSF pressure, which was extremely high in this patient, is a further common nonspecific funding, but the detection of tumor markers in the serum and CSF may be a useful adjunct to conventional cytology ( 8). Tumor markers that have been studied include monoclo­nal antibodies ( 40), carcinoembryonic antigen ( 8, 14- 16), beta- glucuronidase ( 8,41,42), lactic dehy­drogenase ( 8,41), beta2- microglobulin ( 42), the free amino acid pattern ( 43), and HMFG1 antigen ( 44). The latter is an epithelium- associated glycopro­tein, which was detected in the CSF of 18 of 20 meningeal carcinomatosis patients, and appears to be the most sensitive and specific tumor marker described ( 44). A search for tumor markers in the CSF in this patient might have proved helpful in reaching a precise diagnosis. Treatment to date has been largely palliative, in­cluding radiotherapy to the affected areas, chemo­therapy usually in the form of intrathecal meth­otrexate, steroids to reduce brain edema, and shunting procedures to relieve the effects of ob­structive hydrocephalus ( 7,8). Although treated patients have a longer life span than untreated ( 7,8), the results of therapy have been disappoint­ing, with the exception of a few cases of more pro­longed survival ( 7,8,17,45,48). The presence of CSF flow abnormalities has been demonstrated by radionuclide ventriculography in 70% of 27 pa­tients ( 46). Such abnormalities may prevent intra­thecal chemotherapy reaching the affected lepto-meninges and account not only for treatment fail­ures, but also treatment- related neurotoxicity. A / Ncuro- Ophllmlmul, Vol. 14. No. .!, 1994 LEPTOMENINGEAL INFILTRATION OF OPTIC NERVE SHEATH 181 new development involves the use of intrathecal antibody- guided irradiation, in which 131I is la­beled with monoclonal HMFGl antibody and the radiotherapy thus specifically directed to the neo­plastic cells ( 47,48). The absence of a specific diag­nosis in this case precluded adequate treatment. As visual loss rapidly progressing to blindness was a notable presenting feature, it is worth con­sidering the mechanisms involved. In this patient the optic nerves did not show evidence of paren­chymatous invasion, and although surrounded by neoplastic tissue in the subarachnoid space, there was no evidence of impaired axoplasmic flow with papilledema to suggest compression. Such demy-elinating and axonal degenerative changes as were present were mild, and there was no structural evidence of an impaired blood supply. Experimen­tally, in nonhuman primates substantial alter­ations may take place in optic nerve blood flow without anatomic structural damage ( 49). Using the xenon 133 inhalation technique, reductions in mean regional cerebral blood flow have been dem­onstrated in 88% of patients with leptomeningeal metastases ( 50). The predilection of tumor cells for occupying the Virchow- Robin spaces in the cere­bral cortex makes ischemia with impaired metabo­lism an attractive hypothesis ( 24). Of the more re­mote effects, hydrocephalus was rapidly relieved by continuous lumbar spinal drainage, and the loss of vision appears to be uncharacteristic of ret­inal photoreceptor degeneration ( 25). The notion of the production of a " toxic" substance by neo­plastic cells is a vague concept, which should be regarded with caution ( 51). CONCLUSION In spite of the advent of high technology medi­cine the early diagnosis of meningeal carcinomato­sis remains elusive. Nevertheless, this patient demonstrated a clinical diagnostic quartet in the form of typical raised CSF pressure headaches, blindness, sluggish or absent pupillary reflexes and normal optic discs characteristic of leptomen­ingeal infiltration of the optic nerve sheath, al­though the primary neoplasm remained occult. The precise mechanism causing the visual loss in such cases is obscure, but ischemia with metabolic derangement appears likely. However, in the ab­sence of an adequate method of measuring blood flow throughout the visual pathways, such a hy­pothesis is pure conjecture. The presentation of this patient with the sudden onset of blindness due to optic leptomeningeal carcinomatosis sec­ondary to a rectal adenocarcinoma appears to be unique. Acknowledgment: Appreciation is expressed to Mr. T. A. Hide, Consultant Neurosurgeon, and Dr. R. 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