Increased Intracranial Pressure Without Hydrocephalus Associated With Spinal Cord Tumor: Literature Review

Spinal cord tumors (SCTs) may rarely cause increased intracranial pressure without hydrocephalus (IICPWH). A review of the English literature published after 1970 revealed 29 cases of IICPWH secondary to SCT. The following data were acquired: demographics, tumor characteristics, ophthalmic and neurological manifestations, and cerebral spinal fluid (CSF) features. We summarize the existing literature regarding various theories of pathophysiology, spinal imaging recommendations, and treatment modalities used in managing such patients. Patients with papilledema who also have neurological signs or symptoms of myelopathy or elevated CSF protein particularly in the setting of an atypical demographic for pseudotumor cerebri should raise a suspicion for a spinal tumor and prompt further investigation with a spinal MRI.

Perspective Increased Intracranial Pressure Without Hydrocephalus Associated With Spinal Cord Tumor: Literature Review Yujia Zhou, MD, MS, Collin M. McClelland, MD, Michael S. Lee, MD Downloaded from http://journals.lww.com/jneuro-ophthalmology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 05/04/2022 Abstract: Spinal cord tumors (SCTs) may rarely cause increased intracranial pressure without hydrocephalus (IICPWH). A review of the English literature published after 1970 revealed 29 cases of IICPWH secondary to SCT. The following data were acquired: demographics, tumor characteristics, ophthalmic and neurological manifestations, and cerebral spinal fluid (CSF) features. We summarize the existing literature regarding various theories of pathophysiology, spinal imaging recommendations, and treatment modalities used in managing such patients. Patients with papilledema who also have neurological signs or symptoms of myelopathy or elevated CSF protein particularly in the setting of an atypical demographic for pseudotumor cerebri should raise a suspicion for a spinal tumor and prompt further investigation with a spinal MRI. Journal of Neuro-Ophthalmology 2021;41:13–18 doi: 10.1097/WNO.0000000000001026 © 2020 by North American Neuro-Ophthalmology Society I ncreased intracranial pressure (IICP) without hydrocephalus secondary to spinal cord tumor (SCT) is a rare phenomenon. Patients with SCT who develop IICP often present with hydrocephalus (approximately 1% of all SCT) (1), and many do not have papilledema (2). In the absence of hydrocephalus, these patients may present with symptoms (e.g., headache, diplopia, nausea, and pulse synchronous tinnitus) or signs (papilledema and sixth nerve palsy) of IICP. Meanwhile, these patients may erroneously receive a diagnosis of idiopathic intracranial hypertension because brain neuroimaging does not reveal a cause of the IICP and lumbar puncture (LP) shows an elevated opening pressure (OP). Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota. The authors report no conflicts of interest. Address correspondence to Michael S. Lee, MD, Department of Ophthalmology and Visual Neurosciences, MMC 493 420 Delaware Street, SE Minneapolis, MN 55455; E-mail: [e-mail] Zhou et al: J Neuro-Ophthalmol 2021; 41: 13-18 The types and locations of the SCT associated with IICP without hydrocephalus (IICPWH) mostly occur in thoracolumbar or lumbosacral regions (3). Benign and malignant tumors have been reported, but they may have different mechanisms affecting the cerebral spinal fluid (CSF) dynamic (4–6). The diagnosis of IICPWH secondary to SCT becomes more challenging in the absence of symptoms and signs of spinal myelopathy. Herein, we review the English literature regarding IICPWH secondary to SCT. We describe the ophthalmic and CSF characteristics and propose a diagnostic paradigm for spinal imaging. The management of SCT is outside the scope of this review and will not be discussed. METHODS Medline search that includes keywords of “papilledema AND spinal cord tumor,” “increased intracranial pressure AND spinal cord tumor,” “raised intracranial pressure AND spinal tumor,” “pseudotumor cerebri AND spinal cord tumor” were used. The reference lists were reviewed for pertinent articles missed in the original search. The following cases were excluded: 1. Hydrocephalus or ventricular enlargement 2. Intracranial lesions such as metastasis of the spinal tumor on brain imaging 3. Non-English language results 4. Published before 1970, because MRI was not routinely available. Findings There were a total of 29 cases of IICPWH associated with SCT with a mean age of presentation of 36.5 (13–72) years; 13 (44.8%) were women. Seven (24.1%) presumably initially presented to an ophthalmologist. These patients received spinal cord imaging because brain imaging did not reveal any abnormalities, they endorsed 13 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective symptoms or signs of a spinal cord lesion, demonstrated unexplained elevated CSF protein, and/or the IICP was treatment refractory. Tumor Characteristics A variety of tumor types, both benign and malignant, at different spinal cord levels have been described (Table 1). Among the 29 cases reviewed here, the most common tumor type was ependymoma (24.1%), followed by astrocytoma (13.8%) and schwannoma (13.8%), which cumulatively constitutes more than half of the cases. Sixty-two percent of the SCT were located caudal to the cervical spine with 20.1% involving both the cervical and infracervical spine. In the majority of cases, patients underwent spinal MRI. In some of the older cases, X-ray of the skull or spine, isotope cisternography, myelography, pneumoencephalogram, and CSF flow study with technetium were utilized (7–10). Ophthalmic Manifestations Among the 29 cases, 28 patients presented with papilledema on their initial visit, and one patient (Case 23) (4) subsequently developed papilledema with tumor recurrence. Two cases had severe or high-grade papilledema (Case 21 and 28) (11,12). Table 2 summarizes presenting symptoms and examination findings. Most patients had visual disturbance on presentation (23 patients, 79.3%), most commonly reduced visual acuity, visual field defect or enlargement of the blind spot, transient visual obscurations, and esotropia or abducens nerve palsy. Other signs and symptoms included diplopia, metamorphopsia, decreased contrast sensitivity, relative afferent pupillary defect, and retrobulbar pain. One patient was found to have comitant exophoria on examination, but there was no direct correlation with the IICP (13). In addition to papilledema, some cases showed optic nerve pallor or atrophy, nerve fiber layer hemorrhage, subretinal and retinal hemorrhage, macular edema, TABLE 1. Tumor characteristics of the 29 cases Case 1. 2. 3. 4. 5. Ammerman (1974) Bomb (1977) Luxon (1978) Ridsdale (1978) Phanthumchinda (1989) 6. Hardten (1992) 7. Kobayashi (1996) 8. Haslbeck (1999) 9. Zhang (2000) 10. Zhang (2000) 11. Costello (2002) 12. Samson (2002) 13. Sa’adah (2004) 14. Sa’adah (2004) 15. Bilic (2005) 16. Chen (2005) 17. 18. 19. 20. 21. 22. 23. Ghazi (2006) Porter (2006) Klase (2007) Al-Zain (2008) Colon (2009) Wu (2009) Lim (2012) 24. Ahmed (2013) 25. Ahmed (2013) 26. 27. 28. 29. 14 Bush (2014) Grixti (2016) Hussain (2016) Marzban (2016) Tumor Location Tumor Type L3 C2-C3 C3-C4 T11-L4 C4-C6 Myxopapillary ependymoma Angioblastoid meningioma Schwannoma Myxopapillary ependymoma Astrocytoma (Grade III) L1-l2 Meninges of cervical to sacral spine L3 to filum terminale L5 L1-L2 S1-S2 T11-L2 L1-L3 L1-L3 Meninges of entire spinal cord and cauda equina Masses at cervical and thoracic levels; meningeal involvement from lower medulla oblongata to cauda equina L3-L4 C7-T4 Lumbosacral cauda equina L4-S3 C3, C7, T4, T8, T12-L1, L2, S1 T2-T3 T1-T4. Recurrence: T1-T3 Paraganglioma Astrocytoma Paraganglioma (Grade I) Angiosarcoma Ependymoma Schwannoma Myxopapillary ependymoma Myxopapillary ependymoma Myxopapillary ependymoma Disseminated primary diffuse leptomeningeal gliomatosis Primitive neuroectodermal tumor (PNET) Meninges of lumbar roots, upper thoracic cord, and cerebellum Meninges from conus to cerebellum, roots of cauda equina L5 T8-T10 L3-S5 C6-7 Capillary hemangioma Astrocytoma (Grade III) Glioblastoma (Grade IV) Lipoma with incidental subdural hematoma PNET Schwannoma Astrocytoma (Grade I)/Malignantly transformed glioblastoma T-cell lymphoma Large B-cell non-Hodgkin lymphoma Paraganglioma Plasmacytoma Myxopapillary ependymoma Schwannoma (Grade I) Zhou et al: J Neuro-Ophthalmol 2021; 41: 13-18 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective TABLE 2. Ocular findings among 29 patients with IICPWH and SCT exudates, dilated veins, and lack of spontaneous venous pulsations. Isolated visual complaints and symptoms of IICP without spinal cord symptoms or signs occurred in 11 (37.9%) of 29 cases. These patients had visual acuities ranging from 20/15 to 20/400. Three (Case 18, 21, and 25) (6,11,14) of these 11 patients were started on acetazolamide and one (Case 15) (5) was given “diuretics,” presumably acetazolamide. Subsequently, 2 patients underwent optic nerve sheath fenestration (ONSF) (Case 21 and 25) (11,14). Among all 29 patients, 5 received a ventriculoperitoneal (VP) shunt (Case 15, 16, 18, 19, and 25) (5,6,14–16), one underwent lumboperitoneal (LP) shunting (Case 18) (6), one received a lumbar drain (Case 19) (16), and one received an external ventricular drain (Case 28) (12). Only one report (Case 19) (16) documented progression of vision loss after CSF diversion surgery. Two patients (Case 8 and 13) (17,18) had visual symptoms and sciatic pain at the time of initial presentation, and were given acetazolamide, which ameliorated their visual symptoms before the diagnosis and definitive treatment of the SCT. Eighteen patients experienced improved visual symptoms or papilledema after SCT resection or radiation therapy and/or chemotherapy. white blood cell (WBC) 0–5/uL, red blood cell (RBC) 0–5/uL, and glucose 45–80 mg/dL. A CSF analysis was described in 27 patients. In most cases, CSF was taken from LP (n = 25, 92.6%), whereas VP shunt (14), cistern puncture (8), spinal surgery (13) were used to obtain CSF as well. All the 27 patients tested had varying degrees of elevated CSF protein. Other common features of the CSF including elevated initial OP, low glucose, xanthochromia, or elevated RBC are shown in Table 3. Elevated CSF protein occurred in all reported patients with SCT-associated IICPWH (1,19), however, with a wide range of concentrations (46–4,500 mg/dL). The elevated protein may result from active secretion or breakdown products from the tumor or meningeal reaction to the tumor (13,19). High OP of CSF was reported in 20 (69.0%) of 29 patients, which confirmed the clinically suspected IICP in these patients. Normal OP was found in 4 cases; in 3 of those cases, the tumor was located rostral to the L2 space (20–22), thereby potentially falsely lowering the measured OP caudal to the tumor (22). Therefore, normal opening pressure in a patient with papilledema could be a red flag indicating a potential for a cervical or thoracic cord tumor. Three patients reportedly had their CSF samples checked for malignancy and the results were negative (Case 15, 16, and 23) (4,5,15). Among the 2 patients with spinal lymphoma (Case 24 and 25) (14), one had no atypical lymphocytes or cells in the initial few LPs, but was found to have atypical lymphocytes in a later CSF analysis; the other had increased percentage of CD19, CD10, and CD19+ B cells on CSF flow cytometry. Neither of the 2 patients’ CSF analysis was diagnostic of lymphoma. Neurologic Manifestations Pathophysiology The majority of the patients experienced spinal cord symptoms. Eighteen of 29 patients noted spinal cord symptoms at the time of presentation or retroactively recalled such symptoms, whereas 4 patients developed spinal cord symptoms after initial presentation. Reported spinal cord symptoms included paresthesias and paresis of the extremities, neck pain, low back pain, radiculopathy, saddle or perineal paresthesia, urinary difficulties, and gait disturbance. On examination, some patients showed limb muscle weakness, pathological reflexes, and/or positive Babinski sign. One patient developed dysarthria and dysphagia with disease progression (Case 16) (15). Other symptoms that may have resulted from IICP among the 29 cases included headache, nausea, vomiting, or impairment of smell or hearing. Twenty-one patients reported having varying degrees of headache at the time of presentation. Elevated ICP can manifest as hydrocephalus, papilledema, both, or neither; and it is not clear why some SCTs cause IICP and/or papilledema without ventricular enlargement. The occurrence of papilledema does not seem to relate to tumor type or spinal cord level (Table 1). Several authors have proposed theories regarding pathophysiology of the IICP from an SCT: Signs or symptoms/Exam Findings Number of Patients Reduced visual acuity Visual field defect/enlarged blind spot Transient visual obscuration Esotropia/abducens nerve palsy Diplopia 13 9 6 6 5 CSF Characteristics We define the normal range of the CSF components as protein 15–45 mg/dL, opening pressure 6–25 cm H2O, Zhou et al: J Neuro-Ophthalmol 2021; 41: 13-18 Elevated CSF protein High protein level may contribute to higher viscosity of CSF, causing resistance of CSF flow. However, CSF flow resistance is thought to be more likely due to the presence of protein molecules causing arachnoiditis or fibrosis of the arachnoid membrane (3,19,23). Fibrinogen is a common tumor-generated protein, which converts to fibrin in CSF (1). If fibrin clogs the arachnoid villi, the patient is more likely to develop IICPWH. However, if it blocks CSF reabsorption at the base of the cistern, this could cause hydrocephalus (24). CSF protein also could interfere with CSF reabsorption at the level of spinal roots (14). CSF protein concentration rostral to the SCT is usually one-tenth of that 15 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective TABLE 3. CSF characteristics before tumor treatment CSF Characteristics CSF protein elevated Opening pressure elevated Pleocytosis Abnormal glucose Xanthrochromia or elevated RBC Yes (n = Number of Patients, %) No (n = Number of Patients, %) Not Mentioned (n = Number of Patients, %) Mean (Range) 27 (100%) 18 (66.7%) 0 4 (14.8%) 0 5 (18.5%) 835 (46–4,500) mg/dL 34.2 (10–63) mmH2O 11 (40.7%) 8 (29.6%) 11 (40.7%) 6 (22.2%) 9 (33.3%) 2 (7.4%) 10 (37.0%) 10 (37.0%) 14 (51.9%) 71.5 (5–240) WBC/mm3 35.0 (3.6–51) mg/dL 12,702 (8–80,000) RBC/mm3 CSF, cerebral spinal fluid. caudal to the tumor (25) because the blockage of CSF by the SCT could lead to build-up of protein in the lower area. This could explain the high protein content if the site of LP is caudal to the tumor. If LP was done rostral to the tumor, there may be “spill-over” of protein from the lower area to the more superior spinal compartment, which leads to mild elevation of protein levels. For example, in Case 6, the CSF protein level was 2022 mg/dL at the time of LP, and the CSF sampling rostral to the tumor at the time of surgery revealed CSF protein of 182 mg/dL (1,26). The theory of “CSF reservoir” may explain the etiology for IICP in cases with normal or mildly elevated CSF protein (27). The protein concentration of 2 cases in our literature review was close to the normal range (16,20). There is a dynamic balance between the spinal CSF compartment and intracranial venous system, and increased ICP is the consequence of an imbalance between the 2 systems. The presence of an SCT causes the spinal CSF compartment to become more rigid, which can surpass the compensatory capacity of the intracranial vascular compliance (27,28). Subarachnoid bleeding from SCT Subarachnoid bleeding from the SCT may contribute to elevated ICP by irritating or clogging the arachnoid villi (9,20,29,30). The interaction between blood and leptomeninges can further increase CSF protein concentration (31). Tumors of the filum terminale or medullary conus are thought to more easily cause spinal subarachnoid hemorrhage (32). Among 11 cases with xanthochromia or elevated RBC in the CSF, tumors in 6 cases were attached to filum terminale or cauda equina (Case 1, 8, 13, 14, 21, and 25) (9,11,14,17,18). Myxopapillary ependymoma is associated with high likelihood of developing spinal subarachnoid hemorrhage because of its high vascularity (18). Four of the 6 myxopapillary ependymoma cases demonstrated xanthochromia or elevated RBC in the CSF (9,18,33). One patient had subarachnoid siderosis seen on MRI brain thought to result from chronic subarachnoid hemorrhage (Case 28) (12). 3. Malignant tumors may have an additional mechanism that causes elevated ICP. Diffuse craniospinal leptomeningeal 16 dissemination may increase resistance of CSF flow or cause arachnoiditis (4–6). The infiltrative process may also disrupt the spinal venous plexus and the venous medullary plexus, affecting the balance between venous pressure and CSF pressure (14). Leptomeningeal seeding can be seen as enhancement on MRI imaging (5,14,15,34). 4. Direct extension of the tumor to the foramen magnum was another proposed etiology in some cases (13,30,35). However, if this were the predominant mechanism for IICP, then hydrocephalus rather than isolated papilledema without hydrocephalus would be expected due to CSF outflow obstruction. When to Order Spine Imaging Papilledema, among other ophthalmic signs, should prompt the ophthalmologist or neurologist to order cranial neuroimaging. In the majority of patients with papilledema, spinal imaging is not indicated. Spinal imaging should be considered in patients with papilledema and symptoms compatible with myelopathy. To adequately assess for SCTrelated IICP, the clinician must inquire about symptoms of myelopathy (e.g., paresthesias and weakness, bowel and bladder dysfunction, gait difficulty, and back/neck pain) and perform an appropriate, directed neurologic examination. In the absence of localizing spinal cord signs or symptoms, spine imaging should be considered in cases with markedly elevated cerebrospinal fluid protein (.90 mg/dL) on LP. Among cases with a mildly elevated protein in the absence of a clear etiology, concomitant atypical demographic features (e.g., nonobese, male gender, .than 45 years old) for pseudotumor cerebri may prompt spinal imaging. Finally, patients with a treatment refractory pseudotumor cerebri syndrome may also warrant spinal imaging. Unless the neurologic examination localizes to a particular spine level, we recommend imaging the entire spine for the assessment of possible SCT-related IICP because SCTs at any level of the spine may result in IICP. Treatment Considerations Diagnosis and treatment of the underlying SCT remains the preferred management for SCT-related IICP. After the Zhou et al: J Neuro-Ophthalmol 2021; 41: 13-18 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective tumor identification, most patients undergo surgical resection of the tumor and/or radiation or chemotherapy. Surgery itself may accelerate seeding of tumor cells (1, 26) or cause new neurological symptoms (2). Most patients’ papilledema resolved or their visual symptoms improved after definitive treatment of the spinal tumor (20 of 29). The visual outcome of 6 patients was not reported and one patient’s vision seemed to stabilize and not return to baseline after tumor resection (Case 25) (9). Patients with SCT may receive treatment measures aimed at preserving vision in addition to their tumor. Two patients’ papilledema or visual symptoms subsided with medical management of acetazolamide and/or other medications (Case 8 and 13) (17,18). With progressive visual loss unresponsive to medical therapy, ONSF was performed in attempt to maintain vision in 2 patients (Case 21 and 25) (11,14,29). The visual outcome after ONSF was unknown in one patient and the other patient’s visual acuity worsened to counting fingers from 20/60. In some of the cases reviewed here, before or after the diagnosis of the tumor, patients were treated for the elevated ICP with a shunting procedure (15,16,29). Two cases reported that the VP shunt helped with patient’s headache (Case 15 and 18) (5,6) and the degree of symptomatic relief was not mentioned in the other cases after shunting. It has been suggested that shunting before definitive treatment of the tumor may cause reversal of pressure above and below the tumor, causing CSF to move upward, facilitating seeding of the tumor or causing worsening of spinal symptoms (1,15,16,29). A few days after placement of an LP shunt, one patient had new spinal symptoms of paresthesia of the trunk and plantar numbness of feet that were not present initially (Case 18) (16). Another patient who had VP shunt subsequently developed intracranial leptomeningeal and subarachnoid dissemination of the tumor and peritoneal mass and ascites, likely a complication of the VP shunt (Case 15) (5). CONCLUSIONS Papilledema and IICP without hydrocephalus can result from benign and malignant SCTs. Ophthalmologists and neurologists evaluating patients with papilledema should perform a careful neurologic review of systems screening for myelopathy and when indicated perform a focused neurological examination. 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