Universidade Federal de São Paulo (UNIFESP) Department of Neurology and NeurosurgeryUniversidade Federal de São Paulo (UNIFESP) Department of RadiologyUniversidade Federal de São Paulo (UNIFESP) Department of PathologyUniversidade Federal de São Paulo (UNIFESP) Paediatric Oncology Institute Department of PaediatricsUNIFESP, Department of Neurology and NeurosurgeryUNIFESP, Department of RadiologyUNIFESP, Department of PathologyUNIFESP, Paediatric Oncology Institute Department of PaediatricsSciEL

Carrete Junior, Henrique

Gonçalves, André Leite

Masruha, Marcelo Rodrigues

Silva, Nasjla Saba da

Stávale, João Norberto

Vilanova, Luiz Celso Pereira

Arquivos de Neuro-Psiquiatria

André Leite Gonçalves

Marcelo Rodrigues Masruha

Henrique Carrete Jr

João Norberto Stávale

Nasjla Saba da Silva

Luiz Celso Pereira Vilanova

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Primary diffuse leptomeningeal gliomatosis Gliomatose leptomeningea primária difusa

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Arq Neuropsiquiatr 2008;66(1):85-87 85PRIMARY DIFFUSE LEPTOMENINGEAL GLIOMATOSISAndré Leite Gonçalves1, Marcelo Rodrigues Masruha1, Henrique Carrete Jr2,  João Norberto Stávale3, Nasjla Saba da Silva4, Luiz Celso Pereira Vilanova1GLIOMATOSE LEPTOMENINGEA PRIMÁRIA DIFUSAUniversidade Federal de São Paulo (UNIFESP), São Paulo SP, Brazil:  1Department of Neurology and Neurosurgery; 2Department of Radiology; 3Depart-ment of Pathology; 4Department of Paediatrics / Paediatric Oncology Institute.Received 12 June 2007, received in final form 23 October 2007. Accepted 24 November 2007.Dr. André Leite Gonçalves – Division of Child Neurology / Departamento de Neurologia e Neurocirurgia - Rua Botucatu 720 – 04023-900 São Paulo SP - Brasil. E-mail: goncalvesnp@yahoo.com.brGlioma arising primarily from the leptomeninges is ex-tremely rare and often diagnosed only in postmortem ex-amination. It is thought to derive from heterotopic nests of neuroglial tissue within the leptomeninges, which are present in 1% of necropsies. Primary leptomeningeal glio-ma can be in the form of a solitary tumour or a diffuse tu-mour involving intracranial or spinal cord leptomeninges1. We report a case of primary diffuse leptomeningeal gliomatosis (PDLG) established by meningeal biopsy. CASEA 13-year-old boy initiated symptoms at age of 7 years, with a partial complex seizure. He remained stable until the age of 8, when he presented another seizure. At this time he was ad-mitted in coma into the critical care unit, and underwent treat-ment for viral encephalitis with acyclovir for 14 days. He was discharged with clinical improvement. Afterwards he present-ed recurrent headaches.Two years later he was admitted with headache, neck stiff-ness, drowsiness and vomiting. At this time an intracranial hy-pertension syndrome was identified. The cranial MRI showed a communicating hypertensive hydrocephalus that required a ven-triculoperitoneal shunt. He was stable up to the age of 11, when a dysfunction of the ventriculoperitoneal shunt was identified and the shunt was changed. At this time etiologic investigation for chronic meningitis was initiated. Histoplasma capsulatum was considered the probable agent, because of his positive epide-miology and he underwent treatment with fluconazole. He was treated for two years and referred to our service.On admission at our hospital, at age of 13, he complained of sporadic headache, which was being treated with sodium valpro-ate and fluconazole, with no seizures in the last year. During the investigation, different lumbar punctures were performed with elevated protein levels (up to 5.4 g/L), but glucose levels were normal. CSF white blood cells were up to 80/mm³. No neoplas-tic cells were detected. Acid fast bacilli smear, culture and tu-berculosis DNA polymerase chain reaction (PCR) technique were all negative. Mycological analysis for histoplasmosis, paracoc-cidioidomycosis, aspergillosis and candidiasis were all negative. Immunological reactions to syphilis, toxoplasmosis, cytomega-lovirus, cysticercosis and brucellosis were negative. Electroen-cephalograms revealed a generalized asynchronous slowing of background waves.Cranial CT showed diffuse calcifications in the basal cisterns suggesting some consequence of inflammatory process (Fig 1A). Fig 1. (A) Axial CT demonstrates calcification along the surfaces of frontal and temporal lobes, suprasellar region and cerebellar vermis. Postgadolinium axial (B) and coronal (C) T1-weighted MR images. Note extensive enhancement of basal cisterns extend-ing into lateral fissures after contrast (B and C). In C, note thickening of the left lateral ventricle ependyma. Sagital T1-weight-ed postcontrast (D) MR images of lumbar spine demonstrate markedly leptomeningeal enhancement. Arq Neuropsiquiatr 2008;66(1)86Leptomeningeal gliomatosisGonçalves et al.Non-enhanced cranial and spinal cord MRI was normal. Postg-adolinium images revealed diffuse enhancement in cerebral sul-ci, cerebellar vermis, basal, pontine and ambient cisterns (Fig 1B and 1C) and in the spinal cord (Fig 1D) with no evidence of intra-parenchymal involvement. A meningeal biopsy was performed and histologic examina-tion revealed an astrocytic glial proliferation in the subarach-noid space (Fig 2A) with a positive stain for glial fibrillary acid-ic protein (Fig 2B), conclusive for a low-grade glioma. Based on this result, associated with clinical and radiological data, a di-agnosis of primary leptomeningeal gliomatosis, low grade glio-ma type was made.During this period, he was assessed by the oncology team and initiated temozolomide cycles, completing 22 cycles asso-ciated to neuroaxis radiotherapy. He progressed with scarce sei-zures, using valproate (Depakote) and acetazolamide (Diamox) and presented longitudinal nasal hemianopsy that evolved to complete involvement of the visual field. After the temozolo-mide cycles, initiated chemotherapy sessions with ciisplatin and etoposide. At 16 years of age, he did not resist to a pulmonary infection and died after a cardiac and –respiratory arrest.DISCUSSIONPDLG is a rare disease. It is characterized by a glioma, usually an astrocytoma, which arises in the leptomeninges of the brain or spinal cord with no involvement of intrapa-renchymatous tissue2. Two anatomical and clinical forms have been described: a nodular form and a diffuse form3,4, which corresponds to our observation.Debono et al.3 recently reviewed the literature on this subject and found only 30 cases previously reported. The mean age of clinical onset was 35 years, ranging from 9 to 71 years, with no sex predominance. The neurological symptoms are mainly related to intracranial hypertension (83.8% of cases), followed by multiple cranial nerve palsy (35.5%) and epilepsy (29.03%). Other signs include hemi-paresis and tetraparesis, behavioural changes, confusion, visual loss and gait disturbances, back pain, meningeal signs and coma.CSF findings usually show an increase in protein levels with low or moderate pleocytosis3. Repeated CSF exami-nations are usually negative for malignant cells; moreover, distinguishing chronic aseptic meningitis from leptomen-ingeal carcinomatosis or gliomatosis may be difficult since malignant cells can be misinterpreted as benign macro-phages. In assessing patient’s risk, immunocytochemistry with appropriate immunostains for GFAP or cytokeratins and epithelial membrane antigen (EMA) may be helpful4-7. However immunocytochemistry is not used in routine cy-tological evaluation but frequently performed in the CSF after a positive brain biopsy.Neuroradiological findings include ventriculomegaly with diffuse or focal leptomeningeal contrast enhance-ment. The spinal cord is predominantly involved, either associated or not with contrast enhancement of the basal cisterns, cerebellum, brainstem and convexity3. A pattern of non-enhancing nodular lesions on the leptomeninges was described. In our patient these findings are similar to those reported in the literature with diffuse enhance-ment in cerebral sulci, cerebellar vermis, basal, pontine and ambiens cisterns and in the entire spinal cord with no evidence of intraparenchymal involvement1,3.Surgical meningeal biopsy is necessary in cases of chronic aseptic meningitis with areas of contrast enhance-ment to determine the primary cause of this disease. In this case, meningeal biopsy was decisive to determine the eti-ology of the disease and to establish the proper treatment. Differential diagnoses include carcinomatous men-ingitis and autoimmune and inflammatory processes af-fecting the meninges, such as tuberculous meningitis3,8-10. Treatment is intended to reduce the intracranial pressure. Some patients undergo a CSF diversion procedure in the form of ventriculoperitoneal or another alternative route shunting3.Craniospinal radiation therapy and chemotherapy can be employed. Beauchesne et al.9 obtained a complete clinical and radiological remission for 15 months after a Fig 2. (A) HE, Meningeal biopsy show-ing astrocytic glial proliferation in the sub-arachnoid space with a; (B) GFAP, positive stain for glial fibrillary acid-ic protein, conclusive for a low-grade glioma.Arq Neuropsiquiatr 2008;66(1) 87Leptomeningeal gliomatosisGonçalves et al.course of corticospinal tract radiation therapy and che-motherapy. In our patient, remission occurred after com-plete treatment, that is, thirty months later.The prognosis is generally poor and survival depends on tumour grade and patients do not survive as long as ours. In this case, the long evolution, for nine years, is probably due to the fact it is a low-grade glioma. REFERENCES	 1.	 Kastenbauer	S,	Danek	A,	Klein	W,	et	al.	Primary	diffuse	leptomenin-geal	gliomatosis:	unusual	MRI	with	non-enhancing	nodular	lesions	on	the	cerebelar	surface	and	spinal	leptomeningeal	enhancement.	J	Neu-rol	Neurosurg	Psychiatry	2000;69:385-388.	 2.	 Asworth	B,	Gordon	A.	Leptomeningeal	gliomatosis.	J	Neurol	Neuro-surg	Psychiatry	1994;57:471-473.	 3.	 Debono	B,	Derrey	S,	Rabehenoina	C,	Proust	F,	Freger	P,	Laquerrière	A.	Primary	diffuse	multinodular	leptomeningeal	gliomatosis:	case	report	and	review	of	the	literature.	Surg	Neurol	2006;65:273-282.	 4.	 Wechsler	LD,	Gross	RA,	Miller	DC.	Meningeal	gliomatosis	with	“neg-ative”	CSF	cytology:	the	value	of	GFAP	staining.	Neurology	1984;	34:	1661-1665.	 5.	 Bilic	M,	Welhs	CT,	Rumboldt	Z,	Hoda	RS.	Disseminated	primary	dif-fuse	leptomeningeal	gliomatosis:	a	case	report	with	liquid	based	and	conventional	smear	cytology.	Cytojournal	2005;2:1-5.	 6.	 Dietrich	PY,	Aapro	MS,	Rieder	A,	Pizzolato	GR.	Primary	diffuse	lepto-meningeal	gliomatosis	(PDLG):	a	neoplastic	cause	of	chronic	meningi-tis	simulating	tuberculous	meningitis.	J	Neuroncol	1993;15:275-283.		 7.	 Thomas	JE,	Falls	E,	Velasco	ME,	Zaher	A.	Diagnostic	value	of	immuno-cytochemistry	in	leptomeningeal	tumor	dissemination:	a	report	of	two	cases.	Arch	Pathol	Lab	Med	2000;124:759-761.	 8.	 Barborie	A,	Dunn	EM,	Bridges	LR,	Bamford	JM.	Primary	diffuse	lepto-meningeal	gliomatosis	predominantly	affecting	the	spinal	cord:	case	re-port	and	review	of	the	literature.	J	Neurol	Neurosurg	Psychiatry	2001;	70:256-258.	 9.	 Beauchesne	P,	Pialat	J,	Duthel	R,	et	al.	Aggressive	treatment	with	com-plete	remission	in	primary	diffuse	leptomeningeal	gliomatosis.	J	Neu-roncol	1998;37:161-167.10.	 Rees	JH,	Balakas	N,	Agathonikou	A,	et	al.	Primary	diffuse	leptomen-ingeal	gliomatosis	simulating	tuberculous	meningitis.	J	Neurol	Neuro-surg	Psychiatry	2001;70:120-122.	

Gliomatose leptomeningea primária difusa

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Gliomatose leptomeningea primária difusa

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