All-Cause Morbidity and Mortality of Treatment with Intrathecal Chemotherapy via Ommaya:
10-year experience at a single institution
Kevin R. Carr, B.S.2
Jonathan A. Forbes, M.D.1
Rimal Hanif
Ato Wallace, B.S.2
Paul Moots, M.D. 3
Allen K. Sills, M.D. 1
1Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville,
Tennessee, USA
2Vanderbilt School of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
3Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Running head: Morbidity and mortality of treatment with IT methotrexate
Corresponding Author:
Allen K. Sills
Department of Neurological Surgery
1161 21st Avenue S., Rm. T4224 MCN
Vanderbilt University Medical Center
Nashville, TN 37232-2380
Telephone: (615) 422.5000
Fax: (615) 343.8104
Email: allen.sills@vanderbilt.edu
Page 1 of 16
Reprint Requests:
Allen K. Sills
Department of Neurological Surgery
1161 21st Avenue S., Rm. T4224 MCN
Vanderbilt University Medical Center
Nashville, TN 37232-2380
Telephone: (615) 422.5000
Fax: (615) 343.8104
Email: allen.sills@vanderbilt.edu
Key words: morbidity, mortality, treatment with intrathecal methotrexate, CNS lymphoma
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All-Cause Morbidity and Mortality of Treatment with Intrathecal Methotrexate via Ommaya:
10-year experience at a single institution
Background:
Individual studies have described both the medical morbidity of treatment with intrathecal
methotrexate and the surgical morbidity of Ommaya placement. However, information
regarding the all-cause morbidity of intrathecal treatment with methotrexate following Ommaya
placement is lacking.
Methods:
The authors retrospectively studied complications associated with Ommaya insertion and
subsequent intraventricular methotrexate therapy in patients with various CNS neoplasms over
a 10 year period. In total, 65 patients were treated with intraventricular methotrexate
chemotherapy using an Ommaya reservoir and intraventricular catheter system. Surgical
morbidity of Ommaya insertion and medical morbidity related to intrathecal methotrexate
therapy were assessed.
Results:
Regarding surgical complications, 9 out of 65 (15.4%) patients suffered infection of the Ommaya,
3 of whom required hardware removal. 3 out of 66 (4.5%) patients suffered an intracranial
hemorrhage as a result of surgery—fatal in one (1.5%). In total, 12 of 65 patients (18.5%)
experienced some form of surgical morbidity.
Regarding medical complications, 8 out of 65 (12.3%) patients experienced acute chemical
arachnoiditis. Another 4 of 65 (6.2%) patients experienced sub acute myelopathy of the central
nervous system and 8 (12.3%) suffered from chronic leukencephalopathy. No episodes of acute
fulminant brain edema were recorded. In total, 15 of 65 patients (23.0%) experienced some
form of medical morbidity.
Conclusions:
Altogether 30 of 65 (46%) patients experienced significant complication(s) as a result of
Ommaya reservoir insertion and/or subsequent intrathecal methotrexate therapy. This
information should prove useful for practitioners considering the risk-benefit analysis of
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permanent reservoir insertion for intrathecal methotrexate therapy in patients with various CNS
neoplasms.
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Introduction
The Ommaya catheter is an indwelling ventricular access device commonly used for intrathecal
chemotherapy, precluding the need for repeated intrathecal punctures. Although an Ommaya
reservoir is the preferred route of intrathecal methotrexate administration, achieving
significantly higher ventricular drug concentrations, Ommaya placement is associated with
attendant surgical morbidity (Bleyer, Poplack et al 1978). Specifically, surgical morbidity can
include device malfunction, device, infection, and intracranial hemorrhage. Reasons for high
rate of infection with Ommaya reservoir include: 1) myelosuppression secondary to
chemotherapy administration; 2) many patients suffering from hematologic malignancies are
severely immunocompromised. Surgical morbidity as a result of Ommaya placement is well
characterized by various studies highlighted in Table 1.
Surgical
complications
secondary to
Ommaya
implantation:
a literature
study
Author/year
Total Complications
Infection
Hemorrhage
Death
(Lishner,
Perrin et al.
1990)
11/106 (10.3%)
10/106
(9.4%)
2/106 (1.9%)
--
(Sandberg,
Bilsky et al.
2000)
10/107 (9.3%)
2/107
(1.8%)
3/107 (2.8%)
2/107 (1.8%)
(Chamberlain,
Kormanik et
al. 1997)
19/120 (15.8%)
9/120
(45%)
--
--
(Schlegel, Pels
et al. 2001)
5/20
(25%)
Page 5 of 16
(Greenfield
and Schwartz
2008)
3/20
(15%)
Table 1. Surgical complications secondary to Ommaya implantation: a literature study
Methotrexate is a potent chemotherapeutic agent that is widely used as monotherapy or
multitherapy for CNS tumors, including primary CNS lymphoma and leptomeningeal
dissemination. While this chemotherapeutic agent has found favor as the primary treatment
agent for several CNS tumors, it occasionally is associated with significant neurotoxicity.
Methotrexate toxicity usually manifests subacutely, within one to two weeks after
administration. Patients often present with stroke-like symptoms, such as sensory deficits,
paresis, and aphasia, with resolution of clinical and radiological findings within one week to a
month of presentation (Agarwal, Vijay et al. 2011; Tufekci, Yilmaz et al. 2011) . Occasionally
patients can present with acute neurological deficits, within one to two hours following
administration—often associated with confusion, disorientation and/or seizures. These
symptoms, though acute, usually resolve completely with dexamethasone and folinic acid
(Tufekci, Yilmaz et al. 2011). Medical morbidity secondary to intrathecal methotrexate is
described in various studies, listed in Table 2.
Medical
complications
associated with
intrathecal
methotrexate
administration: a
literature study
Author/year
Leukoencephalopathy Myelopathy
Death
(Schlegel, Pels et
2/20 (10%)
--al. 2001)
(Chamberlain,
1/120
Kormanik et al.
2/120 (1.7%)
-(0.83%)
1997)
(Greenfield and
3/20 (15%)
--Schwartz 2008)
(Weigel, Senn et
1/3 (33.3%)
-2/3 (66.7%)
al. 2004)
Table 2. Medical Complications associated with intrathecal methotrexate administration: a
literature study
Individual studies have described either medical morbidity of treatment with intrathecal
methotrexate or surgical morbidity of Ommaya placement. To the authors’ knowledge, this is
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the first study to report all-cause surgical and medical morbidity and mortality of intrathecal
treatment with methotrexate following Ommaya placement.
Methods
Morbidity/Mortality Assessment:
Surgical morbidity as a result of Ommaya placement was classified as (1) infectious (2)
hemorrhagic and (3) death suffered from the operation.
Medical morbidity secondary to methotrexate administration occurring within a window of
causality was stratified as (1) acute chemical arachnoiditis, (2) sub-acute myelopathy (3) chronic
leukencephalopathy (4) fulminant brain edema and (5) other. The treatment window was
defined as two months following placement of Ommaya reservoir and initiation of intrathecal
methotrexate adminstration. Acute chemical arachnoiditis was diagnosed in patients with a
combination of headaches, fever, nuchal rigidity, or back pain. Subacute myelopathy describes
patients who presented with myelopathy of the long fiber tracts, with clinically associated
paraparesis or paraplegia. The categorization of chronic leukencephalopathy was reserved for
patients who presented with confusion, irritability, somnolence, ataxia, dementia, seizures or
coma. Fulminant brain edema is a radiologic classification for clinically significant bulbar or
brainstem deficits.
Patient Population:
The study highlighted a cohort of 65 patients recorded from 2001-2011 who received intrathecal
methotrexate therapy via an Ommaya reservoir catheter at the Vanderbilt University Medical
Center. There were 30 (46.1%) females and 35 (53.9%) males. Patients’ ages ranged from 4
months to 78 years old, with an average age of 42 years and a median age of 43 years. 13
patients were older than 60 years at the time of operation.
As previous studies have suggested a link between methotrexate toxicity and ventricular
obstruction secondary to tumor morphology, patients were retrospectively stratified using
physical tumor characteristics into one of three groups: (1) bulky tumors suggestive of CSF
blockage, (2) intra-axial tumors without the likelihood of occlusion, or (3) CNS lesions in the
absence of intra-axial tumors (Table 3). Bulky tumors were characterized by the presence of
intracerebral lesions along the ventricular foramina. These lesions were assessed based on their
likelihood of causing hydrocephalus secondary to CSF flow obstruction. Of the patients assessed,
8 had bulky tumors suggestive of possible obstruction, 14 had intracranial tumors not indicative
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of possible obstruction and the rest (43) showed no evidence of intra-axial CNS lesions.
Radiologic assessment was made via magnetic resonance imaging studies obtained at the
Vanderbilt University School of Medicine.
Tumor Characteristics
Total
Male
Female
Intra-axial bulky
8 | 11.3%
5
3
tumor
Intra-axial none15 | 21.1 %
6
8
bulky tumor
None intra-axial
43 | 60.56 %
24
19
tumor
Total
35
30
Table 3. Tumor characteristics based on radiographic likelihood to cause CSF obstruction
Of the patients identified 20(30.8%) patients had a primary diagnosis of acute lymphocytic
leukemia, 11 patients hadlarge B cell lymphoma [LBCL], 3 had Burkett’s lymphoma, 5 had acute
myelogenous leukemia, while the remaining patients presented with either carcinomatous
meningitis, chronic myelogenous leukemia or other lesions (Table 4).
Age Range
Diagnosis
Large B Cell Lymphoma
Acute myelogenous
leukemia (AML)
Acute lymphocytic
leukemia (ALL)
Metastatic
carcinomatous
meningitis
Burkett’s lymphoma
Male
Female
41-78
34-61
8
3
3
2
4 ms – 64
11
9
36-70
1
8
30-59
3
0
*Other
9
8
Total
35
30
Table 4. Age, sex and Primary diagnosis of patient population receiving intrathecal MTX via and
ommaya reservoir. [* Other includes, Anaplastic T Cell leukemia, Mantle Cell lymphoma,
Follicular Celllymphoma, Medulloblastoma, NK T Cell lymphoma
Treatment:
Prior to placement of Ommaya catheter, patients were induced with general anesthesia and
prepped and draped in the usual fashion. Following incision and burr hole placement, the
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intrathecal catheter was introduced into the lateral ventricles using intraoperative navigation.
The reservoir was subsequently connected and placed with a subgaleal pocket.
Patients presented to the Medical Center with various diagnoses in varied states of
advancement. Intrathecal treatment regimens were thus stratified per their presenting
diagnoses and comorbidities. Of the cohort assessed patients either received methotrexate
monotherapy or multitherapy.29 patients (44.6%) received methotrexate only, with the
majority, 55% receiving additional chemotherapy agents. Additional chemotherapy included,
among others, CystosineArabinoside, Depocyt ®, Vincristine, Xeloda®, ICE ®, ESAP®, RICE® multitreatments. The median number of intrathecal chemotherapy administration was 2, with only 3
patients receiving ≥2 treatments during the period of study. Medical morbidity was assessed
similarly for both groups, multitherapy defined as Intrathecal Methotrexate administration in
addition to any other agent administered within the window of time associated with
methotrexate morbidity.
Results
12 of 65 patients (18.5%) experienced some form of surgical morbidity from Ommaya
placement—9 patients (13.8%) suffered infection of the Ommaya device, 3 of whom required
hardware removal. 3 (4.6%) patients suffered an intracranial hemorrhage, fatal in 1 (1.5%)
(Table 5). 3 patients had both surgical and medical complications as a result of the treatment
and 5 patients had at least two medical or surgical complications. Of the patients found to have
infections, 2 patients developed hemorrhages.
Surgical
morbidity
associated
with
intrathecal
Ommaya
implantation
Age
Male
Female
Range
Hemorrhage
31-48
2
1
Infection
28-64
6
3
Table 5. Of the patients presenting with surgical morbidity, 75% were due to infections
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One death due to surgical intervention was reported in our study, a 48-year-old Caucasian male
with a diagnosis of multiple myeloma with CNS involvement. The patient prior to surgical
intervention had presented with enlarging plasmacytomas with left sided gaze palsy and
headaches. Head CT showed significant clivus involvement of his lesions with severe right
carotid canal erosion. Subsequent to Ommaya implantation the patient developed intracerebral
hemorrhages identified by multiple Ommaya taps and postoperative CT. The patient became
obtunded, and developed intermittent apnea and worsening respiratory acidosis and died four
days after insertion of Ommaya reservoir.
There were 9 reported cases of infections related to Ommaya reservoir implantation. 50% of the
cases were due to coagulase negative staphylococcus. One infected patient died while receiving
treatment after developing a subarachnoid hemorrhage identified on CT. Blood samples were
found to have grown Capnocytophaga species and Stomatococcusmucillaginosis and he was
unsuccessfully treated with IV levofloxacin, cefipime and metronidazole for a
concomitantClostridium difficile gastrointestinal infection. Only 3 (33.3%) patients required
Ommaya shunt removal due to their infections, as the rest of the patients had resolution of
infection with antibiotics.
Infectious
complications
due to Ommaya
implantation
Patient
Diagnosis
Number/Age
1/42
Mantle Cell
Lymphoma
2/40
CML
3/28
ALL
4/64
LBCL
5/31
ALL
Organism
Management
Outcome
Coagulase
Negative
Staphylococcus
Coagulase
Negative
Staphylococcus
Coagulase
Negative
Staphylococcus
Propionibacterium
Acnes
IV Vancomycin + po
Rifampin
Resolved
IV Vancomycin
Resolved
IV Vancomycin,
Cefipime,Levaquin &
ommaya removal
Po Rifampine, Levaquin
Resolved
Capnocytophaga
Species,
StomatococcusMu
cillaginosus
IV Levaquin, Cefipime,
Metronidazole
Died
Page 10 of 16
Resolved
6/64
Primary CNS
Lymphoma
7/44
8/54
NK Cell
Lyphoma
TALL
9/52
ALL
10/38
ALL
Coagulase
Negative
Staphylococcus
None identified
IV Vancomycin
Resolved
IV Levaquin, Vancomycin
Resolved
MRSA
IV Vancomycin,
Zyvoxx&ommaya removal
IV Cefipime,
Vancomycin&ommaya
removal
IV vancomycin,
polevaquin
Resolved
Coagulase
Negative
Staphylococcus
Streptococcus
alpha
Transferred
Resolved
Table 6. Coagulase negative staphylococcus was the primary agent for infectious complications
Of the 65 patients in our cohort, 18 (27.6%) developed some medical morbidity due to
treatment intervention. 8 (12.3%) patients developed acute chemical arachnoiditis, 4 (6.2%)
developed subacute myelopathy, and 8 (12.3%) developed chronic leukoencephalopathy (Table
7). None of the patients developed fulminant brain edema. One patient developed both
characteristics of subacute myelopathy and chronic leukencephalopathy, while another
developed acute chemical arachnoiditis and subacute myelopathy some time later. The average
age however for patient who developed at least some medical morbidity was slightly higher
than the total cohort at 48.9 years old.
Medical
morbidity
associated
with
intrathecal
methotrexate
administration
Age range
Acute chemical
arachnoiditis
Subacute Myelopathy
Fulminant brain edema
Chronic
leukencephalopathy
Male
Female
26-70
5
3
26-65
--
3
0
1
0
4-65
4
4
Table 7. Medical morbidity associated with intrathecal methotrexate administration
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Of the cohort, nine (9), 13.8% patients who received intrathecal methotrexate chemotherapy in
addition to some other chemical treatment developed medical morbidity. Additionally, nine (9)
patients developed chemical morbidity secondary to intrathecal methotrexate administration
alone. Of that patients with chemical multitherapy who developed chemical morbidity 44.4%
was due to acute chemical arachnoiditis and 22.2% presented with symptomas consistent with
sub-acute myelopathy. Twenty seven (27) patients, 41.5% of the cohort received multitherapy
without documented medical complications.
Patient Number
1
Treatments
Medical Complications
Taxotere
Chronic Leukencephalopathy
Intrathecal Methotrexate
2
Intrathecal Depocyt
Acute Chemical Arachnoiditis
Intrathecal Methotrexate
3
Intrathecal Methotrexate
Acute Chemical Arachnoiditis
Vincristine
Daunomycin
4
ECOG Trial ® [Methotrexate,
Chronic Leukencephalopathy
Procarbazine, Vincristine,
Rituximab]
Temodar, Rituxan
Intrathecal Methotrexate
5
Intrathecal Methotrexate
Sub-Acute Myelopathy
Vincristine
6
Intrathecal methotrexate
Acute Chemical Arachnoiditis
Cystosine Arabinose,
Cyclophosphamide
7
Intrathecal Methotrexate
Acute Chemical Arachnoiditis
Cyclophosphamide
8
Intrathecal Methotrexate
Chronic Leukencephalopathy
Temozolamide
9
Intrathecal Methotrexate
Sub-Acute Myelopathy
Topotecan
Table 7. The majority of chemical complications associated with chemical multitherapy were
acute chemical arachnoiditis
Discussion
This is the first study to report all-cause morbidity and mortality of intrathecal treatment with
methotrexate following Ommaya placement. While the intrathecal administration of
methotrexate via the Ommaya reservoir is an improvement over lumbar access (Bleyer and
Poplack 1979), the morbidity associated with chemotherapy administration via Ommaya is
Page 12 of 16
nonetheless substantial. Several studies have documented a rate of surgical complications due
to Ommaya placement similar to that found in our study. In a series of 20 patients with primary
CNS lymphoma, 19 (95%) of whom underwent Ommaya placement for intraventricular
chemotherapy with several agents, 4 (21.0%) patients suffered infection of Ommaya reservoir
(Schlegel, Glasmacher et al 2001).
In another study of 120 patients undergoing Ommaya reservoir placement for treatment of
leptomeningeal metastases, 2 patients (2%) had malpositioned catheters, 6 (5%) developed
unidirectional catheter obstruction, 2 (2%) developed delayed pressure necrosis of the skin
overlying the Ommaya reservoir, and 4 (3%) developed Staphylococcus epidermidis meningitis
related to Ommaya reservoir placement. In all, 14 patients (12%) developed surgical
complications related to Ommaya placement, of whom 6 patients (6%) underwent replacement
of Ommaya reservoir. 5 (4%) additional patients suffered from Staphylococcus
epidermidis meningitis more than 30 days after Ommaya placement; therefore, these infections
were not considered surgical complications of Ommaya placement and were instead believed to
be secondary to iatrogenic introduction of bacteria during chemotherapy administration via the
Ommaya reservoir. Of the 9 patients who developed bacterial meningitis, the first 2 underwent
replacement of Ommaya reservoir in addition to antibiotic therapy, while the remaining 7 were
successfully treated with intravenous and intraventricular vancomycin in conjunction with oral
rifampin. Therefore, antibiotic treatment without surgical replacement of Ommaya reservoir
appears to be an effective method to prevent reoperation. Similarly, in our cohort, 6 of 9
patients (66%) with infection secondary to Ommaya placement were treated with antibiotics
alone and did not require replacement of Ommaya device (Chamberlain, Kormanik et al 1987).
Similarly, in our cohort, there were 9 (13.8%) patients who sustained an infection due to
Ommaya implantation. The majority of our cases were found to be due to coagulase-negative
Staphylococcus species, and 6 of 9 (75%) patients were treated with antibiotics alone.
In both of the previous two studies, the surgical morbidity is significantly higher than that found
by (Sandberg, Bilsky et al. 2000), who demonstrated a 9.3% surgical complication rate. In the
cohort of 107 patients, intrathecal Ommaya implantation was assisted in 72.6% of patients by
intraoperative fluoroscopic guidance. No such assistance was utilized in our study. Nonetheless,
there still is significant morbidity associated with the technical aspect of the reservoir’s
implantation with even the utilization of frameless stereotaxy in patient populations,
(Greenfield and Schwartz 2008) producing 13.3% and 6.6% infection and hemorrhage rates,
lrespectively.
Methotrexate is a potent chemotherapeutic agent and is widely used to treat leptomeningeal
dissemination and primary CNS lymphoma (PCNSL). In a series of 20 patients with primary CNS
lymphoma, 19 (95%)of whom underwent Ommaya placement for intraventricular
chemotherapy with methotrexate among other agents, 9 (45%) patients developed
Page 13 of 16
neurotoxicity believed to be methotrexate induced. 2 (10%) patients developed fully reversible
transient encephalopathies, 1 (5%) developed subacute encephalopathy that resolved over
months, and 6 (30%) developed leukoencephalopathy, of whom 4 patients suffered no cognitive
impairment, 1 suffered severe cognitive impairment, and 1 died (Schlegel, Glasmacher et al
2001).
In a case report of 3 patients with PCNSL, severe complications related to intrathecal
methotrexate administration were described, including 2 patients who died secondary to
fulminant brain edema and 1 patient who developed severe dementia, gait disturbance and
urinary incontinence due to leukoencephalopathy (Weigel, Senn et al 2003). Since bulky disease
was present in all three patients, the authors surmised that CSF flow abnormalities may have
been present, even though no CSF flow studies were performed. Impaired CSF clearance
exposes normal brain tissue to toxic drug concentrations. There are data to show that all
patients with bulky leptomeningeal metastasis have impaired CSF flow studies. In addition,
standard cross-sectional imaging did not identify CSF flow disturbances in up to 70% of patients.
Therefore, CSF flow studies performed prior to intrathecal drug administration may be
considered of prognostic significance.
None of the patients receiving methotrexate in our series died due to methotrexate toxicity or
developed fulminant brain edema. The most common complication was chemical arachnoiditis,
which is common with intrathecal chemotherapy and may be treated with concurrent
administration of corticosteroids. A significant proportion of our patients had bulky tumor
burden and likely had impaired CSF flow contributing to methotrexate toxicity. Therefore, in the
future patients with bulky tumor burden may benefit from CSF flow studies to determine
suitability for intrathecal chemotherapy.
In order to prevent neurotoxicity secondary to intrathecal methotrexate in patients with bulky
intracranial tumors, alternate treatment strategies may be proposed. High-dose intravenous
methotrexate alone provided therapeutic CSF concentrations, yet a lower cumulative
concentration when compared to intrathecal methotrexate administration, and was successfully
used in the treatment of PCNSL. Additionally, a case-controlled retrospective study matching
patients treated with systemic methotrexate with or without intrathecal methotrexate found no
difference in survival, disease control, or neurotoxicity. Therefore, high-dose intravenous
methotrexate may preclude the need for intrathecal methotrexate and for Ommaya reservoir
placement with regard to reducing neurotoxicity secondary to intrathecal methotrexate and
surgical morbidity secondary to Ommaya placement.
Limitations
Page 14 of 16
This study is limited in that it is a retrospective analysis. Assessment of overall morbidity and
mortality significantly after the post-operative phase was limited due to high rates of patient
loss to follow-up. Additionally, treatment of various cancers demonstrated great variability in
chemotherapeutic regimen.
Conclusion
Intrathecal MTX administration via Ommaya reservoir for the treatment of CNS tumors
continues to present with significant morbidity. Though this treatment modality presents
significant advances in intrathecal chemotherapy administration, there is much room for
improvement of post-operative morbidity and mortality.
Page 15 of 16
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