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Show Neuro-Ophthalmological Features of Primary Diffuse Leptomeningeal Gliomatosis Susana Noval, MD, PhD, Santiago Ortiz-Perez, MD, Bernardo F. Sanchez-Dalmau, MD, Gerardo Ruiz-Ares, MD, Javier Arpa, MD, PhD, Alfredo Ada´n, MD, PhD Abstract: We performed an in-depth study of the neuro-ophthalmologic signs and symptoms of a rare but fatal disease known as primary diffuse leptomeningeal glio-matosis (PDLG). Two new cases of PDLG are described, and 22 published cases reviewed. Papilledema and sixth nerve palsy are the most common neuro-ophthalmic findings. Other abnormalities include third and fourth nerve palsies, nystagmus, and vision loss. Involvement of the visual system may be part of the initial presentation of PDLG. Journal of Neuro-Ophthalmology 2011;31:299-305 doi: 10.1097/WNO.0b013e31821ee5c2 2011 by North American Neuro-Ophthalmology Society Primary diffuse leptomeningeal gliomatosis (PDLG) is a rare and fatal disease characterized by diffuse in-filtration of the meninges by neoplastic glial cells without evidence of tumor within the parenchyma of the brain or spinal cord. These neoplastic cells are thought to arise from heterotopic glial nests in the leptomeninges (1,2). Cooper and Kernohan (3) proposed the following diagnostic cri-teria: no apparent attachment of extramedullary meningeal tumor to the neural parenchyma, no evidence of primary neoplasia within the neuraxis, and the existence of distinct leptomeningeal encapsulation around the tumor. The mean age of clinical onset is 34 years, but it may appear at any age, ranging from 1 to 80 years (1,2,4). PDLG shows male predominance (5). The most striking features include rapid onset, short prodromal phase, and an aggressive course. Clinical presentation includes a variety of neurological symptoms, including headache, cranial nerve involvement, vomiting, meningismus, and decreased mental status (4). Raised intracranial pressure is the most constant sign as a result of communicating hydrocephalus, with papilledema and sixth nerve palsy as the most frequent neuro-ophthal-mic signs reported (1,6). Visual symptoms are often vague at initial clinical presentation (7), and blindness usually develops late in the course of the disease (1,8,9). Diagnosis of PDLG is often challenging because the clinical picture is similar to chronic infectious meningitis or polyradiculopathy, and cerebrospinal fluid (CSF) analysis is frequently nonspecific (5,10). Tuberculous meningitis is often suspected as the initial diagnosis, and patients may be started on antituberculosis therapy (1). We describe 2 patients with PDLG who presented with prominent visual symptoms. Their clinical course is added to the clinical profile of other cases of PDLG. CASE REPORTS Case 1 A 19-year-old woman was seen in consultation for headaches and behavioral changes. Six days later, she complained of a sudden reduction of vision in the right eye. Bilateral sixth nerve palsies and neck stiffness developed rapidly. On ex-amination, visual acuity was light perception, right eye, and 20/20, left eye, and bilateral papilledema was noted. Brain MRI and MRA were unremarkable. Lumbar puncture demonstrated an elevated opening pressure of 50 cm H2O with low glucose of 29 mg/dL (normal: 55-75 mg/dL), increased protein of 49 mg/dL (normal: 15-45 mg/dL), and 10 white blood cells per cubic millimeter. Treatment for presumed tuberculous meningitis was started with isoniazid, rifampicin, ethambutol, pyr-azinamide, and prednisone. However, visual acuity fell to light perception in both the eyes, with pupils reacting poorly Departments of Ophthalmology (SN) and Neurology (GR-A, JA), Hospital University La Paz, Madrid, Spain; Vissum Mirasierra (SN), Madrid, Spain; Department of Ophthalmology (SO-P, BFS-D, AA), Hospital University Clinic I Provincial, Barcelona, Spain; Institut Clı´nic d'Oftalmologia (BFS-D), Barcelona, Spain; and Instituto de Microcirugı´a Ocular (AA). Barcelona, Spain. The authors report no conflicts of interest. Address correspondence to Susana Noval MD, PhD, Melchor Ferna´ndez Almagro St. 18 6 A, Madrid 28029, Spain; E-mail: sunoval@hotmail.com Noval et al: J Neuro-Ophthalmol 2011; 31: 299-305 299 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. to light. Within one month, diffuse optic atrophy was present bilaterally. Blood tests, immunologic studies, and tumoral markers were normal. Repeat lumbar puncture revealed CSF adenosine deaminase activity of 21.9 U/L (.20 U/L sup-portive of the diagnosis of tuberculous meningitis). CSF cultures and serologies were negative, and cytology did not show the presence of malignant cells. Brain and meningeal biopsies were nondiagnostic. Six weeks after the onset of symptoms, MRI revealed widespread meningeal thickening of the brain and the spinal cord and enhancing nodular lesions (Fig. 1). The patient continued to deteriorate clinically de-veloping respiratory insufficiency and tetraparesis. She died 22 weeks after the presentation. Postmortem examination revealed diffuse, whitish, granular thickening of the me-ninges. The subarachnoid space was infiltrated with glial cells, which had numerous Rosenthal fibers and expressed glial fibrillary acidic protein and the p53 gene (Fig. 2A). The glial cells surrounded and compressed the vasculature, some cranial nerves, and the pineal gland. The lower brainstem showed extensive hemorrhagic necrosis. No evidence of a primary tumor was found in the brain or spinal cord parenchyma. Case 2 A 17-year-old woman presented with generalized weakness, vomiting, and epigastric pain, and 4 days later, she de-veloped diplopia. Examination documented vision of 20/20 in both eyes, with bilateral sixth nerve palsies and a partial right third nerve palsy. Three days later, she complained of visual impairment in the right eye and was found to have acuity of light perception, right eye and 20/20, left eye. A right relative afferent pupillary defect was detected, and the fundi were normal. Optic disc pallor developed in the right eye over the course of several weeks. Brain MRI demonstrated diffuse leptomeningeal en-hancement without evidence of intraparenchymal lesions (Fig. 3A). Analysis of CSF did not show malignant cells but increased protein of 77 mg/dL (normal: 15-48 mg/dL), FIG. 1. Case 1. Contrast-enhanced T1 MRI showing meningeal thickening with enhancement (arrows) of the brain (A) and spinal cord (B, C). 300 Noval et al: J Neuro-Ophthalmol 2011; 31: 299-305 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. pleocytosis (10 white blood cells/mm3), and low glucose of 27 mg/dL (normal: 55-75 mg/dL) were detected. A diagnosis of probable tuberculous meningitis was made, and an empiric treatment with antituberculous medications and steroids was initiated. The patient developed cognitive dysfunction, meningeal signs, and hydrocephalus that required placement of a ventriculoperitoneal shunt. Follow-up brain MRI showed additional lesions in the subarachnoid space including the skull base and the spinal cord (Fig. 3B). A brain biopsy was performed, which disclosed anaplastic glial cells within the leptomeninges consistent with PDLG (Fig. 2B, C). Treatment included radiotherapy (brain, spinal cord) and chemotherapy with temozolomide. No significant im-provement was observed. The patient slowly deteriorated and died due to respiratory failure 15 months after initial presentation. DISCUSSION PDLG is a rare condition that produces a clinical picture similar to chronic infectious meningitis (9). Due to the variability of clinical presentation, clinical diagnosis is often challenging, and meningeal biopsy is required (1). Differ-ential diagnosis includes infectious meningoencephalitis, meningeal carcinomatosis, secondary meningeal glioma-tosis, and autoimmune and inflammatory diseases affecting the meninges (11,12). Early in the course of the disease, MRI of the central nervous system may be normal. With progression of the disease, ventriculomegaly and diffuse or focal contrast-enhancing leptomeningeal thickening with no discernible intraaxial component are the most frequent neuroimaging findings. These leptomeningeal abnormalities may be re-stricted to the spinal cord or may be associated with contrast enhancement of the basal cisterns, cerebellum, brainstem, and cerebral hemispheres. Ischemic changes have also been FIG. 2. Case 1. A. Positive immunostaining (arrows) for glial fibrillary acidic protein (3200). Case 2. B. Proliferation of spindle cells with many Rosenthal fibers (arrows) (hematoxylin and eosin, 340). C. Cellular pattern with oval nuclei and scant atypia (hematoxylin & eosin 3200). FIG. 3. Case 2. A. T2 axial MRI demonstrating marked meningeal thickening (arrows). B. One week later, T1 sagittal contrasted MRI showing irregular thickening and enhancing of the spinal cord meninges (arrows). Noval et al: J Neuro-Ophthalmol 2011; 31: 299-305 301 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. Literature review of neuro-opthalmological features of primary diffuse leptomeningeal gliomatosis Author, Year Age, Years (Sex) Visual Symptoms-Signs at Presentation Later Visual Symptoms-Signs Neurosurgery Anti-TB Therapy Treatment Survival (Months) Sumi et al, 1968 (22) 61 (M) - III NP, amaurosis, pupillary areflexia Sphenoid bone biopsy - Antibiotics 5 Bhrany et al, 1974 (17) 46 (F) Small pupils with sluggish reaction, left VI NP, papilledema - VPS, brain biopsy - - 22 Bailey et al, 1985 (20) 53 (M) Diplopia, left VI NP Bilateral VI NP VPS Yes Steroids, amphotericin, 5-fluocytosine 3 Kitahara et al, 1985 (27) 15 (F) Nystagmus on lateral gaze, upward gaze palsy, papilledema - VPS - Intrathecal ACNU, brain radiation 42 Davila et al, 1993 (24) 38 (M) - Multidirectional nystagmus, left ophthalmoplegia - - Intrathecal methotrexate, brain radiation 3 Giordana et al, 1995 (18) 49 (F) Diplopia, papilledema, bilateral VI NP - VPS, SMB - Intrathecal methotrexate, AraC 4 Rogers et al, 1995 (28) 21 (M) Papilledema, left VI NP Optic disc pallor RE, papilledema LE, gaze-evoked nystagmus VPS, BMB - Neuroaxis radiation 50 Kobayashi et al, 1996 (29) 60 (M) Blurred vision, papilledema with retinal hemorrhage - BMB - Spinal radiation, antineoplastic drugs 11 Olivera-Leal et al, 1997 (23) 24 (F) Acute visual loss, pupillary areflexia, left medial rectus paresis - - - Antibiotics, steroids 4 Verslegers et al, 1998 (30) 7 (M) Diplopia, anisocoria, right VI NP BMB - - 8 Paulino et al, 1999 (8) 9 (F) Diplopia, strabismus and papilledema Blindness BMB - Steroids, etoposide, carboplatin, vincristine, intraventricular topotecan, craniospinal irradiation Unknown Trivedi et al, 2000 (14) 81 (M) Vertical diplopia, left IV NP - Brain biopsy - - 7 Corsten et al, 2001 (6) 44 (M) - Nystagmus on right lateral gaze VPS, SMB Yes Steroids, neuroaxis radiation Unknown Rees et al, 2001 (9) 34 (F) Papilledema, bilateral VI NP Blindness VPS, BMB Yes Steroids 4 302 Noval et al: J Neuro-Ophthalmol 2011; 31: 299-305 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. (continued) Author, Year Age, Years (Sex) Visual Symptoms-Signs at Presentation Later Visual Symptoms-Signs Neurosurgery Anti-TB Therapy Treatment Survival (Months) Baborie et al, 2001 (1) 71 (M) Intermittent diplopia, no palsy or papilledema Bilateral VI NP, papilledema with hemorrhages - Yes Steroids 6 Tsui et al, 2001 (25) 23 (F) Blurred disc margin Bilateral VI NP with normal ICP - Yes - 2 Bohner et al, 2005 (31) 25 (M) Right VI NP - SMB - Vincristine, carboplatin 5 Yomo et al, 2007 (5) 52 (M) - Bilateral VI NP, papilledema VPS, BMB - Antibiotics, thiamine, neuroaxis radiation, ranimustine, interferon 3 Watanabe et al, 2008 (12) 48 (F) Diplopia, visual field defects, right VI NP, papilledema - BMB - Neuroaxis radiation, ACNU, interferon 11 Ko et al, 2009 (10) 24 (M) Diplopia, blurred vision, acuity: HM in RE, 20/50 in LE, bilateral VI NP, papilledema Elevated optic nerves nasally with temporal pallor Ventriculostomy, BMB - Steroids, vancomycin, aztreonam, cyclophosphamide 6 Jicha et al, 2009 (4) 24 (M) Intermittent horizontal diplopia, papilledema - BMB - Steroids, temozolomide, BCNU, radiotherapy 15 19 (M) Tunnel vision, papilledema III NP with fixed pupil BMB - Steroids, temozolomide, craniospinal radiation 13 Current study 19 (F) Acute visual loss: light perception bilaterally, nonreactive pupils, bilateral VI NP, papilledema - VPS, BMB Yes Steroids 5 17 (F) LP vision in right eye, bilateral VI NP, right III NP, No papilledema - VPS, BMB Yes Steroids. Neuroaxis radiation, temozolomide 15 BMB, brain meningeal biopsy; F, female; HM, hand motions; ICP, intracranial pressure; LE, left eye; LP, light perception; M, male; NP, nerve palsy; RE, right eye; SMB, spinal meningeal biopsy; TB, tuberculosis; VPS, ventriculoperitoneal shunt. Noval et al: J Neuro-Ophthalmol 2011; 31: 299-305 303 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. reported and may be secondary to vascular compression by the neoplastic cells (1,4,6). As in our 2 patients, analysis of the CSF is often nondiagnostic demonstrating changes consistent with meningitis (1,9,13,14). Malignant cells were not detected in any of the CSF cytology studies performed in our patients, similar to previous reports of PDLG (1,11,15). Meningeal biopsy is necessary to confirm the diagnosis of PDLG. The leptomeninges are usually diffusely affected at the skull base and around the brainstem, while skip areas are found over the convexities, explaining the failure of some diagnostic biopsies, as in our first patient (4,6,10,15-17). It has been recommended that the biopsy be performed with MRI guidance to improve the diagnostic accuracy (16). At times, the histopatholgic features of PDLG may resemble other neoplasms of the central nervous system, including oligodendroglioma, astrocytoma, ependymoblastoma, primi-tive neuroectodermal tumor and glioblastoma multiforme (15,18-20). Papilledema has been noted in most cases, but it may be detected without ocular symptoms (9,16,21). Table 1 summarizes PDLG cases in which visual symptoms or signs have been reported. While visual loss usually occurs in the late stages of PDLG, it may occur early in the course of the disease (10,23), as in our 2 patients. Double vision is the most common visual complaint, primarily due to sixth nerve palsy. Third nerve palsy has been described in 4 patients (4,22,23), including our case 2, and only 1 reported patient presented vertical diplopia due to fourth nerve palsy (14). Cranial nerves have been involved in more than half of the published cases of PDLG (24). Intracranial pressure may be the cause of most sixth nerve palsies, but diplopia is not always accompanied by papilledema (2), and direct infiltration of the ocular motor nerves has been found in many cases (1,18,22-24). Nystagmus has also been docu-mented in the course of the disease and is typically gaze evoked (4). Our patients showed early, severe, and irreversible visual loss. This developed in spite of steroid therapy and, in the first case, persisted after the immediate placement of ex-ternal CSF drainage. Our second patient developed light perception in 1 eye in the absence of optic disc edema. Clearly, visual loss in PDLG may occur by mechanisms other than raised intracranial pressure. Direct tumor in-filtration of the anterior visual pathways is one potential cause (1,17). Another is a focal vasculitic process due to the extension of tumor cells along the Virchow-Robin spaces that surround the cerebral vasculature (4,24,25). This may lead to an occlusive vasculopathy (2,26), causing not only visual loss but brainstem ischemia as well. Currently, there is no curative treatment for PDLG. Brain and spinal radiotherapy and a variety of chemo-therapeutic agents have been used. The combination of temozolomide with radiotherapy has been suggested to improve the prognosis of PDLG (7,12). Jicha et al (5) treated 4 patients in this manner, achieving clinical stability for at least 8 months in 3 patients, and 1 patient remains alive at 41 months. This protocol was used in our second case, and only a partial response was observed with survival of 15 months. 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