Leptomeningeal metastases: lllIndiurn-DTPA CSF flow studies Marc C. Chamberlain, MD, and Jody Corey-Bloom, MD, PhD

Article abstract-Thirty consecutive patients with cytologically documented leptomeningeal metastases (LM) underwent intraventricular "'indium-DTPA (In) CSF flow studies (FS).Sixteen patients (53%)had normal In FS. Fourteen patients (47%) had documented compartmentalization of the CSF system. I n four patients unsuspected CSF block was confined to the base of brain with limited spinal descent and poor cerebral convexity ascent of In. All patients received whole-brain irradiation and two were subsequently shown to have normal In FS. In 10 other patients, suspected (eight) and unsuspected (two) spinal blocks were seen. Patients with spinal blocks underwent C T myelography or spine MR and were subsequently treated with involved-field irradiation. Following radiation therapy, normal In FS were achieved in only two patients with documented spinal cord blocks. In conclusion, antegrade In FS in patients with LM are useful in defining levels of CSF blocks. Following treatment of patients with CSF blocks with involved-field irradiation, normal In FS can be restored in approximately one third. NEUROLOGY 1991;41:1765-1769

The clinical manifestations of leptomeningeal metastases (LM) are pleomorphic and encompass the entire ne~raxis.'-~ Diagnosis is complicated by the varied clinical presentations of LM, and also by the difficulties of demonstrating positive cerebrospinal fluid (CSF) cytolog~.~ For example, in only 55% of patients will the initial CSF examination confirm a pathologic diagnosis of LM. Further complicating management of patients with LM are the limited treatment modalities available and poor median survival of patients with LM.1-8Standard treatment of LM utilizes both involved-field irradiation to bulky or symptomatic disease and regional chemot h e r a p ~ . ' -Chemotherapeutic ~,~ agents are administered either by injection directly into the ventricular system via an Ommaya reservoir or by intrathecal administrat i ~ n . ' Following - ~ ~ ~ ~ intraventricular ~ instillation, chemotherapy is distributed by antegrade CSF flow. A potential source of treatment failure in patients with LM is failure to achieve a homogenous distribution of chemotherapy due to abnormalities in CSF In this prospective study, we evaluated 30 consecutive patients with LM by antegrade CSF flow using "'In-DTPA ventriculography (In FS). Following demonstration of CSF flow abnormalities, we delivered involved-field radiation therapy to anatomic regions of CSF flow block; we subsequently restudied the patients, using In FS. Methods. Study population. Thirty consecutive adult patients with cytologically documented LM were studied with intraventricular II'In-DTPA radionuclide CSF flow studies. Patients were accrued between April 1987 and June 1990 a t the University of California, San Diego. There were 19 men and 11

women, with a median age of 46 years and an age range of 23 to 74 years. Tumor histologies included lymphoma (16),breast (3),gastric (2), lung @), prostate (I), leukemia (2), melanoma (I), medulloblastoma (l),glioblastoma multiforme (l),and malignant schwannoma (1). Eleven patients (37%) had AIDS and AIDS-related lymphomas (eight systemic non-Hodgkins lymphomas and three primary CNS lymphomas). The remaining 19 patients (63%) were immunocompetent and included five patients (17%) with primary CNS tumors (two primary CNS lymphomas and one each with medulloblastoma, glioblastoma multiforme, and malignant schwannoma). Presenting neurologic examinations included 17 patients with spinal cord dysfunction (57%),11 with cranial neuropathies (37%), seven with multilevel dysfunction (23%), four with nonfocal examinations (13%), and three with hemispheric dysfunction (10%).Spinal cord dysfunction included patients with the following findings: ataxia (5), cauda equina syndrome (5), myelopathies (4), conus medullaris syndrome (3), radiculopathies (2), meningismus (l),and multilevel cord dysfunction (3). Cranial neuropathies included patients with dysfunction of t h e following nerves: optic nerve ( 4 ) , oculomotor (3), trigeminal (4), abducens (4), facial (5), cochlear (3), and multiple (6). Patients with hemispheric dysfunction presented with abulia (2) and right parietal lobe syndrome (1). Six patients had multilevel involvement of the neuraxis, including five patients with combined cranial neuropathies and spinal cord dysfunction and one patient with both cranial neuropathies and hemispheric dysfunction. Imaging techniques. Gamma imaging. Imaging was performed with a gamma camera (Elscint, Israel) equipped with a medium-energy collimator. Static images were acquired in a 128 X 128 pixel matrix using a dedicated computer. Studies were performed using a large field-of-view camera with dualenergy windows utilizing a 20% window centered over 174 keV and 247 keV gamma ray peaks of "'In. Each image was acquired for either 2 minutes or 100,000 counts.

From the Department of Neurosciences, University of California, San Diego, CA. Received January 15,1991. Accepted for publication in final form April 19,1991. Address correspondence and reprint requests to Dr. Marc C. Chamberlain,University of California, San Diego, Department of Neurosciences, 225 Dickinson Street, H-811-K, San Diego, CA 92103.

November 1991 NEUROLOGY 41 1765

Following sterile preparation of the overlying skin and removal of 2 cc of autologous CSF, 0.5 cc of I1'In-DTPA (median dose, 0.7 mCi; range, 0.5 to 0.9 mCi) was injected into the Ommaya reservoir (accessed with a 25-gauge butterfly needle). Sterile preparation included shaving the skin overlying the Ommaya reservoir, followed by sequentialalcohol and Betadine scrubs. &r the radionuclide was injected, the catheter system was flushed with 2 cc of autologous CSF. No barbotage of the Ommaya reservoir was performed. Thereafter, images were obtained every 5 minutes for 60 to 90 minutes, repositioning the patient and the scintillation camera as lllIn-DTPA flowed caudally. Cerebral images were obtained using both A P and lateral views while spinal cord images were obtained using PA views. lI1In-DTPAexternal markers were placed over the C-7 and L-5 spinous processes to facilitate localization during spinal descent of radionuclide. CSF compartments were defined as follows: ventricular system, basal cisterns/foramen magnum,cervical cord, thoracic cord, lumbar cord, and lateral cerebral convexities (sylvian cistern). Abnormal radionuclide flow studies were categorized accordingto location of the CSF flow abnormality and defined by the CSF compartment at which radionuclide block occurred. MR/CT imaging, Cranial CT examinations were performed on a GE 9800 scanner (General Electric, Milwaukee, WI). Contiguous 10 mm-thick axial sections were obtained from the foramen magnum to the vertex both before and after intravenous administration of iodinated contrast medium (Conray 43; Mallinckrodt, Inc., St. Louis, MO). Cranial MR examinations were performed on a 1.5-tesla superconducting magnet (Signa; General Electric, Milwaukee, WI). Using a spin-echo pulse sequence, axial T,-weighted (T,W: TR 3,000 msec/TE 80 msec) and proton density-weighted (PDW: TR 3,000 msec/TE 30 msec) images were initially acquired. Subsequently, both sagittal and axial or coronal T,-weighted (T,W:TR 600 msec/TE 25 msec) images were acquired. Slice thickness was 5 mm, with a 2.5-mm interval between successive slices in all instances; a 256 X 256 matrix was utilized. After intravenous administration of 0.1 mmol/kg gadoliniumDTPA Dimeglumine (Berlex Laboratories, Cedar Knolls, NJ), coronal or axial T,W sequences (TR 600 msec/TE 25 msec) were obtained. All postcontrast images were obtained within 30 minutes of gadolinium infusion. Spine MR (S-MR)studies were performed using a 1.5-tesla superconducting magnet (Signa; General Electric, Milwaukee, WI). Images were acquired both before and after the intravenous administration of gadolinium-DTPA Dimeglumine (Berlex Laboratories, Cedar Knolls, NJ) in a dose of 0.1 mmol/kg body weight. All postcontrast images were obtained within 30 minutes of gadolinium infusion. Surface coils were used as receiving coils in all cases; a rectangular 5" X 11" or a circular 5" diameter coil was used in the thoracic and cervical spinal regions, respectively. Precontrast imaging consisted of sagittal and axial TI-W images (TR 350-600 msec/TE 20 msec); PDW (TR 1,846-2,500msec/TE 30 msec) and T,-W (TR 1,846-2,500 msec/TE 60, 70 or 80 msec) sequences were obtained. Cardiac gaiting was utilized when the thoracic cord was studied. Flow-compensating pulse sequences were used in the cervical region. Slice thickness was 3 or 5 mm with 0.5 mm-interslicegaps in the sagittal plane. Slice thickness was 5 mm with interslice gaps of 1.0 to 2.5 mm in the axial plane. Field of view for sagittal images ranged from 20 to 24 cm with one excitation (NEX) for long TR sequences and two or four NEX for TI-Wsequences.

Results. Contrast-enhanced C T and MR of brain in this patient population with LM have been previously reported.l0 In summary, the following findings were demonstrated parenchymal volume loss (CT, 93%; MR, 1766 NEUROLOGY 41 November 1991

93%); abnormal enhancement (CT, 29%; MR, 71%); nodules (CT, 36%;MR, 43%);and hydrocephalus (CT, 7%; MR, 7%). Abnormal enhancement was characterized as sulcal/dural (CT, 21%; MR, 50%); cisternal (CT, 14%;MR, 29%);tentorial (CT, 0%;MR, 21%);and ependymal (CT, 7%;MR, 21%).Two categories of nodules were defined, including subarachnoid (CT, 29%; MR, 36%)and parenchymal (CT, 29%;MR, 43%). All patients with spinal dysfunction underwent spine imaging utilizing either S-MR or CT myelography (CT-M). Patients presenting with isolated cerebral dys-

function, cranial neuropathies, or nonfocal neurologic examination were not evaluated by spine imaging except for patients with CSF flow abnormalities a t the, base of brain (discussed below). CT-M or contrastenhanced S-MR were performed in 22 patients (eight, CT-M and 13 S-MR). Spine imaging technique was, dependent upon availability, and in all instances S-MR. was the procedure of first preference. Six categories of patients with spinal cord dysfunction were studied. The number of patients, the spine imaging technique, and results are as follows: five cauda equina syndrome (CT-M: 1 + , 2-; S-MR 2+); three conus medullaris syndrome (CT-M: l + ; S-MR: 1+, 1-); four myelopathy (CT-M: 1-; S-MR 3+); two ataxia (S-MR: 2-); two radiculopathy (S-MR: 2-); and one meningismus (S-MR: 1-). In summary, eight of 17 patients (47%)with spinal cord dysfunction studied were positive, two by CT-M and six by S-MR. Five of eight patients (63%)showed evidence for CSF spinal compartmentalization by spine imaging. Forty-eight antegrade "'In-DTPA CSF flow studies were performed in 30 patients (table l),among whom 14 patients underwent multiple I n FS (11 patients: 2 studies; 3 patients: 3 studies). Six patients underwent lumbar In FS, including four patients with base-of-brain block documented by intraventricular infusion. Sixteen patients had normal I n FS, with the following median (range) time (minutes) to CSF compartment appearance: ventricular system, 1 (0 to 5); basal cisterns/foramen magnum, 5-10 (5 to 15);cervical cord, 15 (5 to 20); thoracic cord, 20 (10 to 30); lumbar cord, 30 (25 to 50); and lateral cerebral convexity, 50 (35 to 90). One patient was referred for study after receiving whole-brain irradiation for unclear indications. I n four patients who had documented base-of-brain block, CSF flow was arrested at the level of the basal cisterns/foramen magnum prior to the initiation of therapy (table 1: patients 7, 22, 28, and 30). In all four patients, block was clinically unsuspected either by neurologic examination or by neuroradiographic studies (normal contrast-enhanced cranial CT and MR studies). In one additional patient, block was suspected based on neuroradiographic studies, although it was not confirmed by In FS. In this patient, because of "'InDTPA unavailability, a n In FS was performed during whole-brain irradiation and shown to be normal. Prior to treatment, all five patients with base-of-brain block underwent spine imaging (S-MR: 2; CT-M: 3) and lumbar In FS. No evidence for spinal compartmentalization was documented. In addition, neither contrast nor radionuclide material ascended above the base of brain.

Table 1. Compartmental appearance of ll'In-DTPA Time after injection (mins) Pt

AgelSex

1 2

26/M 29/M

3 4 5 6 7

46/M 36/M 28/M 26/M $231~

8 9 10 11 12

34/M 23/M 30/M 25/M 39/M

13

62F

14

4 0 ~

15 16

63/M $SOP

17 18

$ 2 5 ~ 25/M

19

28F

20 21

59F 38F

22

$58F

23 24 25 26 27 28

37F 6OF 74m 70/M 57/M $47F

29

49/M

30

$63/M

mCi 'In-DTPA 0.8 0.6 0.7t 0.6 0.8 0.6 0.7 0.6 0.77 0.68 0.6 0.8 0.593 0.9 0.77 0.5t 0.67 0.8457 0.7 0.67 0.6 0.5 0.67 0.77 0.82 0.657 0.837 0.7 0.657 0.6 0.7 0.7 0.8 0.7t 0.6 0.7 0.7 0.67 0.7 0.7 0.67 0.619 0.7t 0.7 0.57 0.8187

Block upper lumbar.

Ventricular system

Basal cisterns/ Foramen magnum

Cervical cord

Thoracic cord

Lumbar cord

5 5 5 0 1 0 0-5 0 0 0-1 5 0 1-2 5 5 5 5 3 0-5 0-5 5 0-5 0 5 0-3 1-10 0-30 0-5 0-5 1 5 1-2 5 5 0-5 0 0 2-5 0 5 0 1 1

20 10-15 15 15-20 15 10-15 15 10 5-10 15 10 5-7 35 20 5-10 10 10-15 15 15-20 10-15 10-30 10-15 15-45# 5-60?? 25-50 15-20 15-20 10 15 5-15

30 20-30 30 20-25 20 15-25 20-25

40 30-60* 30-60* 30 30 25-30 30-35 30 20-30 40 35 40-50

5 1

10-15 5 5 5-10 5 5 5-10 5-30 5 5 10 5 1-2 10-30 10 5 5 5 5-10 5-10 5-10 5-10 5 5 5 15-20 5-10 5-10 3 5-10 2-5 10-30 5-30 5 5-10 5 5 5-10 10-45 5 1-5 1-3 5-55 5-45

3

7

-

5-10 15-20 10 10 15 10 5-10 3-5 -

10-20

-

15 10-20 20 20 10-30 40-605 25-60s 15-25 20 20-40 20-25 20-25 15-25 20-451 20 -

-

30-50 25-55* 45-60* 30-60' 30-60' 45-50 -

25-30 -

-

20-25 20-25 20 20 15-25 -

10-20 20-25 10-15 25 20-25 -

15-20 10-40 10-20 85

30-60* 30-60* 30 30 35-45 25-30 30-35 25 30-50* 30-35 25-30 45-65* 25-50* 90

Lateral cerebral convexities 50 50 60 35 50 60 45-50 -

35 45 50 50 55 55 55 60 60 45 55 60 60 45 40-45 90 90 50 55 60 35 40 50 45 45 35 60 45-50 -

45 55 60 90

f Block lower thoracic.

t Postinvolved field irradiation.

ll Block upper thoracic.

$ Clinically unsuspected blocks.

##

Block cervical.

All five patients were treated with whole-brain irradiation (median dose, 27 Gy; range, 25 to 30 Gy), followed by post-treatment flow studies. CSF flow was restored to normal in only two of four patients (50%)with pretreatment-documented CSF blocks. Ten of 17 patients with spinal cord dysfunction and documented spinal cord block had CSF flow arrested a t the following sites (table 1: patients 2,12,13,14,16,17,

18, 19, 26, 29): cervical cord (2), thoracic cord (2), and upper lumbar cord (6). Positive studies were seen in patients with ataxia, myelopathy, cauda equina syndrome, or conus medullaris syndrome. Six of ten pat i e n t s underwent I n FS prior t o initiation of radiotherapy. Four of ten patients were studied following radiation therapy, due either to late referral (1) or inability to obtain "'In-DTPA (3). Clinically unNovember 1991 NEUROLOGY 41 1767

Table 2. Comparative spinal cord imaging of CSF compartmentalization

Imaging study CT myelography Spine MR ll'In-DTPA CSF flow study

Ataxia

Cauda equina

(2)

(5)

0 2

:3 (1+)

+

2 (1 )

2 (2+) 5 (5 )

+

Category spinal cord dysfunction Conus medullaris Meningismus Myelopathy (3) (1) (4) 1 (I+) 2 (I+) 3 (2+)

0 1 1

Radiculopathy (2)

1 3

0 2

4 (2+)

2

(n) Number of patients studied. ( n + ) Number of studies demonstrating abnormal CSF communication.

juspected blocks by In FS were seen in two patients with myelopathy (one cervical and one thoracic cord), both of whom had positive S-MR with apparently normal CSF communication (table 2). Clinically suspected blocks were believed to be present in eight patients with either cauda equina syndrome (5) or conus medullaris syndrome (3). Neuroradiographic studies (table 2) were positive for block of CSF flow in three of five patients (60%)with cauda equina syndrome (CT-M: 1+, 2 -; SM R 2 +) and in two of three patients (67%)with conus medullaris syndrome (CT-M: l + ;S-MR: 1+, 1-). All five patients with cauda equina syndrome and two of three patients with conus medullaris syndrome were positive by In FS for spinal cord block. A single patient with isolated ataxia and a normal S-MR had evidence of spinal block by In FS; otherwise, no spinal CSF flow abnormalities were observed in patients with isolated ataxia, meningismus, cerebral dysfunction, cranial neuropathies, or with nonfocal neurologic examinations. All 10 patients were treated with involved-field irradiation (median dose, 31 Gy; range, 28 to 15 Gy), followed by post-treatment In FS. In only two of ten patients (20%) was CSF flow restored to normal. In one patient with clinically unsuspected cervical block, postradiation In FS demonstrated a new base-of-brain block.

Discussion. Radionuclide ventriculography provides a safe physiologic assessment of the functional anatomy of the CSF CSF circulates through the ventricular system and subarachnoid space that surrounds both the brain and spinal cord.15 Normally, CSF flows anteriorly in the lateral ventricles through the foramen of Monro and into the third ventricle. The CSF flows caudally from the third ventricle through the aqueduct of Sylvius into the fourth ventricle. Exit of CSF from the fourth ventricle is directed into the dorsal spinal subarachnoid space through the foramen of Magendie and into the basal cisterns through the lateral foramina of L u ~ c h k a . ~Di ~ -Chiro13 '~ demonstrated that passage of CSF through the foramen of Magendie into the vallecula and the beginning of downward flow into the dorsal cervical subarachnoid space precedes exit of CSF from the foramina of Luschka. CSF then flows caudally through the dorsal spinal subarachnoid space, followed by ascent of CSF in the ventral spinal subarachnoid space. Completion of the normal pattern of CSF circulation is by ascent from the basal cisterns toward the superior sagittal sinus by way of migration over the 1768 NEUROLOGY 41 November 1991

cerebral convexities and along medial routes through the suprasellar and quadrigeminal cisterns. Normal times of radionuclide appearance in CSF compartments in this study are similar to those reported in the literature. This pattern of CSF circulation predicts time to appearance of regionally administered chemotherapy when given antegrade by Ommaya reservoir administration. Unlike prior studies, the present flow study constituted a 90-minute study, with scintiscans obtained every 5 minutes. This technique permitted detection of CSF flow to the level of the sylvian fissures (lateral cerebral convexities) and, as a result, may have underestimated high-convexity CSF flow blocks as demonstrated by G r 0 s ~ m a n . lIn ~ Grossman's study, 70% of patients with LM had abnormalities in CSF flow, among whom 30% had flow abnormalities over the cerebral convexities defined as failure of radionuclide ascent at 4 hours postinjection. Aside from base-ofbrain blocks, there was no obstruction to the level of the sylvian fissures documented at 40 minutes post-ll'InDTPA injection in our study. We presently are performing a single delayed scintiscan a t 4 hours postinjection to assess for high-convexity block. Anatomic assessment of CSF spaces is traditionally evaluated by enhanced cranial MR or CT imaging and enhanced S-MR imaging or CT-M. In aprevious report regarding LM, we demonstrated the advantages of cranial MR over CT with enhancement.'O Unfortunately, no comparable large studies exist regarding intradural extramedullary spinal Pending such studies, CT-M remains the standard by which to judge enhanced S-MR imaging. It is, however, clear from the literature that intradural (either intra- or extramedullary) metastatic spinal disease is optimally evaluated with gadolinium-enhanced S-MR.'"-'* In this study, four patients with base-of-brain block to CSF flow demonstrated by "'In-DTPA CSF flow studies were negative when studied by both enhanced cranial MR and CT imaging. Furthermore, of 10 patients with arrested spinal CSF flow documented by "'In-DTPA CSF flow studies, only five were positive for spinal CSF block, either by enhanced S-MR imaging ( 3 )or CT-M ( 2 ) .The results of this study, therefore, suggest that "'In-DTPA CSF flow studies are more sensitive in demonstrating compartmentalization of CSF pathways than are either enhanced S-MR imaging, CT-M, or enhanced cranial MR/CT imaging. The reasons for this increased sensitivity may reflect the dynamic nature of "'In-DTPA

References CSF flow studies, wherein radionuclide is passively carried by CSF bulk flow in a physiologic antegrade man1. Theodore WH, Gendelman S. Meningeal carcinomatosis. Arch ner. Neurol 1981;38696-699. A number of potential causes for the failure of re2. Wasserstrom WR, Glass J P , Posner JB. Diagnosis and treatment metastases from solid tumors: experience with gional chemotherapy to control LM are ~ p e r a n t . ~ - ~ - ~ - of~ leptomeningeal #'~ 90 patients. Cancer 1982;49:759-772. These include (1)de novo or acquired drug resistance; 3. Bleyer WA. Current status of intrathecal chemotherapy for (2) incomplete distribution of drug within CSF spaces; human meningeal neoplasms. Natl Cancer Inst Monogr (3) inability to achieve adequate CSF drug levels; (4) 1977;46:171-178. failure to control primary tumor; (5) toxicity, both neu4. CollinsJM. Pharmacokinetics of intraventricular administration. J Neurooncol 1983;1:283-291. rologic and systemic, of regional chemotherapy; and (6) 5. 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November 1991 NEUROLOGY 4 1 1769

Leptomeningeal metastases: 111Indium−DTPA CSF flow studies Marc C. Chamberlain and Jody Corey-Bloom Neurology 1991;41;1765 DOI 10.1212/WNL.41.11.1765 This information is current as of November 1, 1991 Updated Information & Services

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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1991 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.