- Email: [email protected]
Primary Amelanotic Leptomeningeal Melanomatosis in a Child: A Rare but Severe Disease
Case Report
Primary Amelanotic Leptomeningeal Melanomatosis in a Child: A Rare but Severe Disease Alexandru Szathmari1, Romain Perbet3, Marc Hermier2, Federico Di Rocco1, Didier Frappaz4, Carmine Mottolese1
Key words Amelanotic central nervous system melanoma - Melanocytic tumors of the nervous system - Pediatric brain tumors - Primary leptomeningeal melanomatosis -
Abbreviations and Acronyms CSF: Cerebrospinal fluid CT: Computed tomography MRI: Magnetic resonance imaging NCM: Neurocutaneous melanosis PLM: Primary leptomeningeal melanomatosis From the 1Pediatric Neurosurgery Unit, and 2Department of Radiology, Neurological and Neurosurgical Hospital, Hospices Civils de Lyon, Lyon 1 University, Bron; 3 Pathological Center, Bron East Hospital Center, Hospices Civils de Lyon, Lyon 1 University, Bron; and 4Institut d’hémato-oncologie pédiatrique, Lyon, France To whom correspondence should be addressed: Alexandru Szathmari, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2016) 92:581.e15-581.e20. http://dx.doi.org/10.1016/j.wneu.2016.06.039
- BACKGROUND:
Primary leptomeningeal melanomatosis (PLM) is a rare and aggressive form of nonmetastatic invasion of leptomeninges by malignant melanocytic cells. Clinical presentation includes nonspecific meningism with various forms of cerebrospinal fluid circulation or absorption disorders leading to hydrocephalus.
- CASE
DESCRIPTION: A 5-year-old child with PLM without neurocutaneous melanosis presented with cystic enlargement of the brainstem surrounding cisterns and hydrocephalus requiring occipitoaxial decompression and endoscopic cystostomy. Initial cerebrospinal fluid cytology screening and frontal meningeal and brain biopsy specimens showed negative results. The diagnosis of unpigmented (amelanotic) malignant melanocytic cells was made after a biopsy specimen of the bulbar leptomeninges was obtained. Despite continuous management of hydrocephalus and chemotherapy, the disease progressed, and the patient died 11 months after diagnosis.
- CONCLUSIONS:
To the best of our knowledge, this is the first report of an amelanotic form of PLM without association of neurocutaneous melanosis in a child. This case report illustrates the difficulty of diagnosis in the absence of cutaneous lesions and lack of melanin.
Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2016 Elsevier Inc. All rights reserved.
INTRODUCTION Primary melanocytic tumors of the central nervous system are rare neoplasms that have a wide spectrum of clinical and pathologic manifestations. Patients may present at any age with focal intraaxial lesions or diffuse leptomeningeal involvement.1 In children, the tumors may be related to neurocutaneous melanosis syndrome (NCM), a rare congenital syndrome characterized by the presence of large or numerous congenital cutaneous melanocytic nevi and benign or malignant melanocytic tumors of the leptomeninges.2,3 A few cases without associated NCM have also been described in children.4 The presence of melanin in tumor cells or in associated inflammatory cells leads to the diagnosis. Pathologic studies show leptomeningeal macroscopic pigmentation predominating at the base of the brain. In rare cases, these cells may
be not pigmented, resulting in a more difficult diagnosis that is based on immunohistochemistry.1 We report a patient with an unpigmented (amelanotic) primary leptomeningeal melanomatosis (PLM) without associated NCM. To our knowledge, this is the first report describing an amelanotic PLM in a child. CASE REPORT A 5-year-old girl with severe headaches and vomiting and no particular familial or personal history was admitted to the pediatric unit. Initial computed tomography (CT) and craniospinal magnetic resonance imaging (MRI) showed slight left parietal enlargement of cerebral sulci that appeared bright on T2 fluid attenuated inversion recovery sequence, with leptomeningeal enhancement after injection of contrast agent, in the same area (Figure 1A and B). A few days later, the patient presented with seizures. CT scan was unchanged, but papilledema was seen on funduscopy. A complete
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serologic work-up showed no particular abnormalities. Initial cerebrospinal fluid (CSF) bacterial, fungal, and cytology screening was negative. Seizure control was achieved with intravenous phenytoin. She was admitted to the pediatric intensive care unit 3 weeks after the initial presentation. At admission, the patient was sleepy, without motor or cranial nerves deficit, but she rapidly deteriorated with intracranial hypertension signs including bradycardia. A new MRI scan showed a slight increase in the size of the fourth ventricle and cystic dilation of the cisterna magna (Figure 1C). Brainstem compression was suspected, necessitating an emergent minimal suboccipital craniotomy followed by endoscopic cystostomy and fourth ventricle plexus coagulation. CT performed immediately postoperatively showed no complication, and MRI confirmed the presence of a good CSF flow through the cisternae and fourth ventricle (Figure 2). The patient’s postoperative condition was favorable for 2 weeks with only a
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CASE REPORT ALEXANDRU SZATHMARI ET AL.
PRIMARY AMELANOTIC LEPTOMENINGEAL MELANOMATOSIS IN A CHILD
Figure 1. Initial magnetic resonance imaging showed enlargement of left parietal sulci on T2 fluid attenuated inversion recovery sequence (A) and left cortical leptomeninges on
slight residual positive Babinski sign on the right side. Sudden deterioration occurred 5 weeks after admission with altered consciousness, tonic-clonic seizures, and tetraventricular hydrocephalus on CT scan. A shunt was inserted emergently with temporary relief of symptoms. Despite the shunt, she showed progressive deterioration with vomiting requiring shunt externalization secondary to persistent ventricular dilation at 7 weeks after admission. Treatment for possible shunt infection was also started (bacterial then fungal origin suspected). Despite treatment, cerebellar signs progressively developed with persistent nausea and vomiting. MRI showed persistent leptomeningeal diffuse gadolinium enhancement, but fungal and bacterial testing was
gadolinium-enhanced T1-weighted sequence (B). Slight increase of the fourth ventricle and cystic dilation of cisterna magna (C).
negative. The multidisciplinary team decided to perform a complementary bone marrow study and right frontal meningeal and cerebral biopsies 19 weeks after admission; all results were negative. The patient’s neurologic examination and general status continued to deteriorate with narrowing and compression at the bulbar level by leptomeningeal thickening on MRI performed 21 weeks after admission (Figure 3). In an attempt to relieve the medulla, a further surgery was performed with occipital-cervical posterior decompression, and a new biopsy specimen was obtained at that time. Perioperative histopathologic examination revealed a tumoral process with a suspected undifferentiated tumor or atypical teratoid/ rhabdoid tumor. Definitive histopathologic
examination revealed a densely cellular tumor consisting of irregular clusters of large epithelioid cells with an eosinophilic cytoplasm but without pigment. Nuclei were irregular with a prominent nucleolus. Numerous mitotic figures have been seen. Immunostaining was positive for MART-1 antibody (HMB-45) and antimelanosomal antibody (Melan-A) (Figure 4). Etoposide and carboplatin that had been initiated after surgery were replaced by temozolomide after definitive diagnosis 24 weeks after admission. Despite chemotherapy, clinical deterioration continued with fluctuant altered consciousness, tetraparesis, and seizure. Her status continued to degrade with coma, electrical status epilepticus, and finally irreversible cardiorespiratory arrest 45 weeks after admission. DISCUSSION
Figure 2. Postoperative T1 sagittal (A) and flow-sensitive phase-contrast (B) sequences with permeable cisterns.
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Melanomatosis is the malignant form of diffuse leptomeningeal melanocytosis, and its incidence is unknown.5 Its origin is the same as for all melanocytic neoplasms, as they are derived from melanocytes from the neural crest early during embryogenesis. In this period, the melanocytic precursors, the melanoblasts, migrate via a dorsolateral path mainly to the skin, but a few migrate to other peripheral structures, including mucosal surfaces, leptomeninges, inner ear, and uvea.6 Physiologically, melanocytes are found within leptomeninges around the brainstem on the ventral part of the medulla oblongata.7 The role of these
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CASE REPORT ALEXANDRU SZATHMARI ET AL.
PRIMARY AMELANOTIC LEPTOMENINGEAL MELANOMATOSIS IN A CHILD
Figure 3. Sagittal T1 sequence after gadolinium injection showing diffuse thick leptomeningeal enhancement with bulbar anterior constraint.
melanocytes is unclear, but it has been suggested that they might have a detoxification action.8 The first report of a primary melanocytic neoplasm dates from 1859 by Virchow.9 The clinical and histologic diagnosis of this pathology remains difficult and challenged by the differential diagnosis of metastatic melanoma. An extensive proliferation of brain basal leptomeningeal melanocytes mainly occurs in children in the setting of NCM.1 Other known associations are neurofibromatosis type 1 and Sturge-Weber syndrome.3,5 However, a malignant form of this condition may occur without NCM.10 In our case, neither the presence of skin nevi nor other syndromes were documented, and there was no familial history of hereditary illness. We reviewed the literature by searching PubMed using the terms “primary brain melanomatosis” and “diffuse melanotic brain lesions.” We retained only publications describing a diffuse form of melanomatosis but without associated NCM as in the case described here. The presence of melanin pigmentation was also documented (Table 1). Clinical Findings Clinical presentation is not specific, and it may mimic a wide variety of other conditions, including subacute meningitis, viral encephalitis,21 lymphoma, tuberculosis,22 lymphoma, leukemia, metastatic carcinoma, acute neurosarcoidosis,17 and idiopathic hypertrophic cranial pachymeningitis.23 More often, it presents as benign intracranial hypertension syndrome, hydrocephalus, cerebellar dysfunction, seizures, syringomyelia, cranial nerve palsy, intracranial hemorrhage, sphincter dysfunction, and neuropsychiatric symptoms.5,12,13,15,17,19,21 In our case, initial symptoms were those of nonspecific intracranial hypertension with fluctuant but progressive deterioration despite medical and surgical treatment. Initial decompression of the posterior fossa and cystostomy provided only temporary benefit, and CSF cytology did not reveal any evidence of the disease in the initial period.
Figure 4. Hematoxylin-eosin-saffron staining 200 (A) and 400 (B) showing a densely cellular tumor consisting of irregular clusters, sheets, or nests. Cells are large and epithelioid and have eosinophilic cytoplasm without pigment. Nuclei are irregular with prominent nucleoli. There are numerous mitotic figures. Immunostaining with HMB-45 400 (C) and with Melan-A antibodies 400 (D).
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Radiology Radiologic appearance is not characteristic showing only a subarachnoid hyperdensity on CT after intravenous
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Reference
Sex/Age (years)
Symptoms
MRI at Presentation
CSF Cytology (Tumoral Cells)
Histology
Amelanotic or Pigmented Cells
Treatment
Survival (months)
M/20
Progressive headache, nausea, Slight enhancement surrounding Second screening vomiting (7 months) cerebellopontine angles positive
Postmortem diagnosis (autopsy)
A
VP shunt IV and intrathecal chemotherapy
5
Pirini et al., 200312
F/68
ICH, confusion, gait disturbance DLE and sylvian fissure
Negative
Postmortem diagnosis (autopsy)
P
VP shunt > temporary relief
36
Demir et al., 200813
M/32
Headache, vomiting, complex partial seizures
Brain and spinal DLE
ND
Postmortem diagnosis (autopsy)
P
No
Bocquillon et al., 201014
F/24
ICH, transient hemiparesis
Pachyleptomeningitis
Negative
Biopsy
P
Chemotherapy 6 months after initial presentation
Liubinas et al., 20105
M/43
Headache, drowsiness, confusion
DLE and sylvian fissure
Negative
Biopsy
P
No
Zadro et al., 201015
M/34
Papilledema, paraparesis, cognitive impairment
DLE
Negative
Biopsy
P
Radiotherapy
Arias et al., 201116
F/40
Headache, visual impairment, meningismus
Hydrocephalus, DLE on T1-WI
Negative
Biopsy
P
VP shunt
12
Lee et al., 201317
M/17
Headache, nausea, vomiting
Right hyperdense T lesion on CT ND
Biopsy
P
Chemotherapy and wholebrain radiotherapy
ND
Ng et al., 201318
F/43
Seizure, headaches, SAH, hydrocephalus
Hydrocephalus, slight hyperdensity on CT suspicious for SAH
ND
Biopsy
P
VP shunt
2
Trinh et al., 201419
M/51
Progressive headache, fatigue, Brain and spinal DLE on MRI imbalance
Negative
Biopsy
P
Chemotherapy, radiotherapy
3
Kim et al., 201520
F/66
Headache for months
CT with slight spontaneous temporal DLE
Positive
No
P
ND
ND
Present case, 2016
F/5
Headache, vomiting, convulsions
Focal enlargement of parietal Initially negative sulci Gd T1-WI and cystic dilation of brainstem surrounding cisternas
Repeated biopsy
A
VP shunt, chemotherapy
11
<2 9 <1 2
Data were obtained from PubMed search using the terms “primary brain melanomatosis” and “diffuse melanotic brain lesions.” Only publications describing a diffuse form of melanomatosis but without associated neurocutaneous melanosis were retained. MRI, magnetic resonance imaging; CSF, cerebrospinal fluid; M/F, male/female; P/A, amelanotic/pigmented; VP, ventriculoperitoneal; IV, intravenous; ICH, intracranial hypertension; DLE, diffuse leptomeningeal enhancement; ND, not determined; T1-WI, T1-weighted imaging; CT, computed tomography; SAH, subarachnoid hemorrhage; Gd, gadolinium; T, temporal lobe.
CASE REPORT
PRIMARY AMELANOTIC LEPTOMENINGEAL MELANOMATOSIS IN A CHILD
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Tosaka et al., 200111
ALEXANDRU SZATHMARI ET AL.
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Table 1. Data from the Literature
CASE REPORT ALEXANDRU SZATHMARI ET AL.
administration of contrast agent. On MRI, spontaneous hyperintensity of the brain surface on T1-weighted images or low T2 signal intensities may be evidenced owing to the paramagnetic proprieties of the melanin.24 Other substances that cause high T1 intensity in the central nervous system are fat, subacute blood, and occasionally calcium.25 In amelanotic forms, MRI findings range from hypointensity to isointensity on T1weighted images to moderate hyperintensity on T2-weighted images.6 In the present case, no T1 hyperintensity was evident, and there was only nonspecific focal enlargement of parietal sulci with abnormal leptomeningeal enhancement after injection of gadolinium. That could represent leptomeningeal inflammation, tumoral infiltration (which was the correct hypothesis a posteriori), or a postseizure anomaly. The enlargement of the fourth ventricle and the cisterna magna may be explained by pial and subpial tumor cell infiltration with impairment in CSF circulation and hydrocephalus. Enlargement of the basal cisternae was described in a case of amelanotic PLM associated with NCM.26 In this case, progression of the illness became apparent with the appearance and accentuation of arachnoidal T1 gadolinium enhancement. The leptomeningeal thickening was particularly important in the prebulbar area with a marked anterior constraint (Figure 3). Cytopathology Analysis of CSF obtained by lumbar puncture or at surgery is usually altered with nonspecific findings, such as high protein content, increased red blood cells, normal or low glucose, or sterile leukocytosis. The presence of pleomorphic neoplastic cells with intracytoplasmic melanin pigments and mitoses is characteristic.20 However, negative cytology is not unusual (Table 1). In the present case, cytology was negative. After diagnosis, careful review of cytology showed elements in favor of the presence of neoplastic cells within the CSF obtained 2 months after the beginning of the hospitalization. The nonspecific aspect and lack of melanin pigment were interpreted as secondary inflammatory cells in the context of fungal infection.
PRIMARY AMELANOTIC LEPTOMENINGEAL MELANOMATOSIS IN A CHILD
The difficulty of the cytologic diagnosis has already been emphasized by several authors.11,19,22 In the absence of melanin deposits, diagnosis can be made only by immunostaining.11 Histopathology Melanomatosis corresponds to the malignant form of melanocytosis, a diffuse proliferation of cells with histologic and cytologic features similar to a malignant melanoma with brain invasion or necrosis.27 The presence of melanin in tumor or in associated inflammatory cells is characteristic, and it may be visible in cases of direct surgical approach5,14 as well as others (Table 1). In rare cases, these cells may not be pigmented, and diagnosis is more difficult based on immunohistochemistry, as most tumors react with HMB-45, Melan-A, or S-100 protein. There is no expression of glial fibrillary acidic protein, neurofilament proteins, cytokeratin, or epithelial membrane antigen.1 In our case, even after repeated endoscopic exploration, no visual evidence of leptomeningeal involvement could be found. The definitive histopathologic diagnosis revealed a nonpigmented (amelanotic) form of melanomatosis. The presence of nodular lesions28 or diffuse forms11 of amelanotic lesions in adults has already been reported, but this is the first amelanotic PLM to our knowledge in a child with no history of cutaneous lesions. Management PLM has a poor prognosis. Management is challenged by the confusing initial clinical presentation, making the diagnosis difficult and sometimes obtained only postmortem.12,29 The role of surgery is limited to the treatment of the associated hydrocephalus and to the direct biopsy mandatory for histologic diagnosis. However, in our case, the initial supratentorial meningeal and brain biopsies were not contributive. This may be explained by the choice of the biopsy site, distant from the radiologic abnormalities, as the second biopsy specimen obtained at the level of the basal cistern was positive. Chemotherapy and radiotherapy were not effective (Table 1). In one case, neoadjuvant chemotherapy followed by whole-brain radiotherapy showed partial therapeutic response only after 8 supplementary sessions of
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chemotherapy, but long-term progression of the disease is not detailed.17 In some cases with hydrocephalus, progression of the disease seems to be controlled better with only a shunt, but generally survival does not exceed a few months.12,16 In our case, initial treatment addressed cisternal dilation because local brainstem compression was suspected, and this was followed by shunting. Even with active management of CSF circulation or absorption disorders, the benefit was short-term. CONCLUSIONS Diagnosis of PLM is a challenging task because of the lack of specificity of the initial presentation and its rare incidence, especially in cases without NCM. To our knowledge, this is the first report of amelanotic PLM not associated with NCM in a child. This case report illustrates the difficulty of diagnosis in the absence of cutaneous lesions and lack of melanin. Careful and repeated cytology screening of CSF with immunostaining is mandatory in case of nonbacterial meningismus. Negative result would request brain biopsy at the level of abnormal radiological findings that have to be well addressed in order to improve the chance for a positive diagnosis. REFERENCES 1. Brat DJ, Perry A. Melanocytic lesions. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee W, eds. WHO Classification of Tumors of the Central Nervous System. Lyon, France: IARC Press; 2007: 181-183. 2. Kadonaga JN, Barkovich AJ, Edwards MS, Frieden IJ. Neurocutaneous melanosis in association with the Dandy-Walker complex. Pediatr Dermatol. 1992;9:37-43. 3. Di Rocco F, Sabatino G, Koutzoglou M, Battaglia D, Caldarelli M, Tamburrini G. Neurocutaneous melanosis. Childs Nerv Syst. 2004;20: 23-28. 4. Allcutt D, Michowiz S, Weitzman S, Becker L, Blaser S, Hoffman HJ, et al. Primary leptomeningeal melanoma: an unusually aggressive tumor in childhood. Neurosurgery. 1993;32:721-729 [discussion: 729]. 5. Liubinas SV, Maartens N, Drummond KJ. Primary melanocytic neoplasms of the central nervous system. J Clin Neurosci. 2010;17:1227-1232. 6. Greco Crasto S, Soffietti R, Bradac GB, Boldorini R. Primitive cerebral melanoma: case
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report and review of the literature. Surg Neurol. 2001;55:163-168 [discussion: 168]. 7. Goldgeier MH, Klein LE, Klein-Angerer S, Moellmann G, Nordlund JJ. The distribution of melanocytes in the leptomeninges of the human brain. J Invest Dermatol. 1984;82:235-238. 8. Tolleson WH. Human melanocyte biology, toxicology, and pathology. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2005;23:105-161. 9. Virchow R. Pigment und diffuse Melanose der Arachnoides. Virchows Arch Pat Anath Phisiol. 1859; 16:180-182. 10. Kusters-Vandevelde HV, Kusters B, van Engen-van Grunsven AC, Groenen PJ, Wesseling P, Blokx WA. Primary melanocytic tumors of the central nervous system: a review with focus on molecular aspects. Brain Pathol. 2015;25:209-226. 11. Tosaka M, Tamura M, Oriuchi N, Horikoshi M, Joshita T, Sugawara K, et al. Cerebrospinal fluid immunocytochemical analysis and neuroimaging in the diagnosis of primary leptomeningeal melanoma. Case report. J Neurosurg. 2001;94:528-532. 12. Pirini MG, Mascalchi M, Salvi F, Tassinari CA, Zanella L, Bacchini P, et al. Primary diffuse meningeal melanomatosis: radiologic-pathologic correlation. AJNR Am J Neuroradiol. 2003;24:115-118. 13. Demir MK, Aker FV, Akinci O, Ozgultekin A. Case 134: primary leptomeningeal melanomatosis. Radiology. 2008;247:905-909. 14. Bocquillon P, Berteloot AS, Maurage CA, Mackowiak-Cordoliani MA, Pasquier F, Bombois S. Primitive leptomeningeal malignant melanoma: a rare etiology of pachymeningitis and leptomeningitis. Rev Neurol (Paris). 2010;166:927-930.
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PRIMARY AMELANOTIC LEPTOMENINGEAL MELANOMATOSIS IN A CHILD
15. Zadro I, Brinar VV, Barun B, Ozretic D, Pazanin L, Grahovac G, et al. Primary diffuse meningeal melanomatosis. Neurologist. 2010;16:117-119. 16. Arias M, Alberte-Woodward M, Arias S, Dapena D, Prieto A, Suarez-Penaranda JM. Primary malignant meningeal melanomatosis: a clinical, radiological and pathologic case study. Acta Neurol Belg. 2011;111:228-231. 17. Lee HJ, Ahn BC, Hwang SW, Cho SK, Kim HW, Lee SW, et al. F-18 fluorodeoxyglucose PET/CT and post hoc PET/MRI in a case of primary meningeal melanomatosis. Korean J Radiol. 2013;14: 343-349. 18. Ng RYT, Siu DYW, Wong GKC, Ng HK, Poon WS. An uncommon mimic of spontaneous subarachnoid haemorrhage. Hong Kong Med J. 2013;19: 80-81. 19. Trinh V, Medina-Flores R, Taylor CL, Yonas H, Chohan MO. Primary melanocytic tumors of the central nervous system: report of two cases and review of literature. Surg Neurol Int. 2014;5:147. 20. Kim DH, Choi CY, Lee CH, Joo M. Primary intracranial leptomeningeal melanomatosis. J Korean Neurosurg Soc. 2015;58:554-556. 21. Nicolaides P, Newton RW, Kelsey A. Primary malignant melanoma of meninges: atypical presentation of subacute meningitis. Pediatr Neurol. 1995;12:172-174.
24. Barkovich AJ, Frieden IJ, Williams ML. MR of neurocutaneous melanosis. AJNR Am J Neuroradiol. 1994;15:859-867. 25. Wehrli FN. The basis of MR contrast. In: Atlas SW, ed. MRI of the Brain and Spine. New York: Raven Press; 1991:23-38. 26. Vanzieleghem BD, Lemmerling MM, Van Coster RN. Neurocutaneous melanosis presenting with intracranial amelanotic melanoma. AJNR Am J Neuroradiol. 1999;20:457-460. 27. Brat DJ, Giannini C, Scheithauer BW, Burger PC. Primary melanocytic neoplasms of the central nervous systems. Am J Surg Pathol. 1999;23:745-754. 28. Schulz C, Waldeck S. Primary amelanotic meningeal melanomatosis. Fortschr Neurol Psychiatr. 2012;80:402-406. 29. Monso G, Vernet A, Cusi V, Mateo M, Vilaseca MA. Primary leptomeningeal melanomatosis in a 6-year-old child. Rev Neurol. 1996;24: 87-90.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 16 April 2016; accepted 9 June 2016
22. Grant DN. Primary meningeal melanomatosis: limitations of current diagnostic techniques. J Neurol Neurosurg Psychiatr. 1983;46:874-875.
Citation: World Neurosurg. (2016) 92:581.e15-581.e20. http://dx.doi.org/10.1016/j.wneu.2016.06.039 Journal homepage: www.WORLDNEUROSURGERY.org
23. Bang OY, Kim DI, Yoon SR, Choi IS. Idiopathic hypertrophic pachymeningeal lesions: correlation between clinical patterns and neuroimaging characteristics. Eur Neurol. 1998;39:49-56.
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WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2016.06.039
Primary Amelanotic Leptomeningeal Melanomatosis in a Child: A Rare but Severe Disease Alexandru Szathmari1, Romain Perbet3, Marc Hermier2, Federico Di Rocco1, Didier Frappaz4, Carmine Mottolese1
Key words Amelanotic central nervous system melanoma - Melanocytic tumors of the nervous system - Pediatric brain tumors - Primary leptomeningeal melanomatosis -
Abbreviations and Acronyms CSF: Cerebrospinal fluid CT: Computed tomography MRI: Magnetic resonance imaging NCM: Neurocutaneous melanosis PLM: Primary leptomeningeal melanomatosis From the 1Pediatric Neurosurgery Unit, and 2Department of Radiology, Neurological and Neurosurgical Hospital, Hospices Civils de Lyon, Lyon 1 University, Bron; 3 Pathological Center, Bron East Hospital Center, Hospices Civils de Lyon, Lyon 1 University, Bron; and 4Institut d’hémato-oncologie pédiatrique, Lyon, France To whom correspondence should be addressed: Alexandru Szathmari, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2016) 92:581.e15-581.e20. http://dx.doi.org/10.1016/j.wneu.2016.06.039
- BACKGROUND:
Primary leptomeningeal melanomatosis (PLM) is a rare and aggressive form of nonmetastatic invasion of leptomeninges by malignant melanocytic cells. Clinical presentation includes nonspecific meningism with various forms of cerebrospinal fluid circulation or absorption disorders leading to hydrocephalus.
- CASE
DESCRIPTION: A 5-year-old child with PLM without neurocutaneous melanosis presented with cystic enlargement of the brainstem surrounding cisterns and hydrocephalus requiring occipitoaxial decompression and endoscopic cystostomy. Initial cerebrospinal fluid cytology screening and frontal meningeal and brain biopsy specimens showed negative results. The diagnosis of unpigmented (amelanotic) malignant melanocytic cells was made after a biopsy specimen of the bulbar leptomeninges was obtained. Despite continuous management of hydrocephalus and chemotherapy, the disease progressed, and the patient died 11 months after diagnosis.
- CONCLUSIONS:
To the best of our knowledge, this is the first report of an amelanotic form of PLM without association of neurocutaneous melanosis in a child. This case report illustrates the difficulty of diagnosis in the absence of cutaneous lesions and lack of melanin.
Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2016 Elsevier Inc. All rights reserved.
INTRODUCTION Primary melanocytic tumors of the central nervous system are rare neoplasms that have a wide spectrum of clinical and pathologic manifestations. Patients may present at any age with focal intraaxial lesions or diffuse leptomeningeal involvement.1 In children, the tumors may be related to neurocutaneous melanosis syndrome (NCM), a rare congenital syndrome characterized by the presence of large or numerous congenital cutaneous melanocytic nevi and benign or malignant melanocytic tumors of the leptomeninges.2,3 A few cases without associated NCM have also been described in children.4 The presence of melanin in tumor cells or in associated inflammatory cells leads to the diagnosis. Pathologic studies show leptomeningeal macroscopic pigmentation predominating at the base of the brain. In rare cases, these cells may
be not pigmented, resulting in a more difficult diagnosis that is based on immunohistochemistry.1 We report a patient with an unpigmented (amelanotic) primary leptomeningeal melanomatosis (PLM) without associated NCM. To our knowledge, this is the first report describing an amelanotic PLM in a child. CASE REPORT A 5-year-old girl with severe headaches and vomiting and no particular familial or personal history was admitted to the pediatric unit. Initial computed tomography (CT) and craniospinal magnetic resonance imaging (MRI) showed slight left parietal enlargement of cerebral sulci that appeared bright on T2 fluid attenuated inversion recovery sequence, with leptomeningeal enhancement after injection of contrast agent, in the same area (Figure 1A and B). A few days later, the patient presented with seizures. CT scan was unchanged, but papilledema was seen on funduscopy. A complete
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serologic work-up showed no particular abnormalities. Initial cerebrospinal fluid (CSF) bacterial, fungal, and cytology screening was negative. Seizure control was achieved with intravenous phenytoin. She was admitted to the pediatric intensive care unit 3 weeks after the initial presentation. At admission, the patient was sleepy, without motor or cranial nerves deficit, but she rapidly deteriorated with intracranial hypertension signs including bradycardia. A new MRI scan showed a slight increase in the size of the fourth ventricle and cystic dilation of the cisterna magna (Figure 1C). Brainstem compression was suspected, necessitating an emergent minimal suboccipital craniotomy followed by endoscopic cystostomy and fourth ventricle plexus coagulation. CT performed immediately postoperatively showed no complication, and MRI confirmed the presence of a good CSF flow through the cisternae and fourth ventricle (Figure 2). The patient’s postoperative condition was favorable for 2 weeks with only a
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CASE REPORT ALEXANDRU SZATHMARI ET AL.
PRIMARY AMELANOTIC LEPTOMENINGEAL MELANOMATOSIS IN A CHILD
Figure 1. Initial magnetic resonance imaging showed enlargement of left parietal sulci on T2 fluid attenuated inversion recovery sequence (A) and left cortical leptomeninges on
slight residual positive Babinski sign on the right side. Sudden deterioration occurred 5 weeks after admission with altered consciousness, tonic-clonic seizures, and tetraventricular hydrocephalus on CT scan. A shunt was inserted emergently with temporary relief of symptoms. Despite the shunt, she showed progressive deterioration with vomiting requiring shunt externalization secondary to persistent ventricular dilation at 7 weeks after admission. Treatment for possible shunt infection was also started (bacterial then fungal origin suspected). Despite treatment, cerebellar signs progressively developed with persistent nausea and vomiting. MRI showed persistent leptomeningeal diffuse gadolinium enhancement, but fungal and bacterial testing was
gadolinium-enhanced T1-weighted sequence (B). Slight increase of the fourth ventricle and cystic dilation of cisterna magna (C).
negative. The multidisciplinary team decided to perform a complementary bone marrow study and right frontal meningeal and cerebral biopsies 19 weeks after admission; all results were negative. The patient’s neurologic examination and general status continued to deteriorate with narrowing and compression at the bulbar level by leptomeningeal thickening on MRI performed 21 weeks after admission (Figure 3). In an attempt to relieve the medulla, a further surgery was performed with occipital-cervical posterior decompression, and a new biopsy specimen was obtained at that time. Perioperative histopathologic examination revealed a tumoral process with a suspected undifferentiated tumor or atypical teratoid/ rhabdoid tumor. Definitive histopathologic
examination revealed a densely cellular tumor consisting of irregular clusters of large epithelioid cells with an eosinophilic cytoplasm but without pigment. Nuclei were irregular with a prominent nucleolus. Numerous mitotic figures have been seen. Immunostaining was positive for MART-1 antibody (HMB-45) and antimelanosomal antibody (Melan-A) (Figure 4). Etoposide and carboplatin that had been initiated after surgery were replaced by temozolomide after definitive diagnosis 24 weeks after admission. Despite chemotherapy, clinical deterioration continued with fluctuant altered consciousness, tetraparesis, and seizure. Her status continued to degrade with coma, electrical status epilepticus, and finally irreversible cardiorespiratory arrest 45 weeks after admission. DISCUSSION
Figure 2. Postoperative T1 sagittal (A) and flow-sensitive phase-contrast (B) sequences with permeable cisterns.
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Melanomatosis is the malignant form of diffuse leptomeningeal melanocytosis, and its incidence is unknown.5 Its origin is the same as for all melanocytic neoplasms, as they are derived from melanocytes from the neural crest early during embryogenesis. In this period, the melanocytic precursors, the melanoblasts, migrate via a dorsolateral path mainly to the skin, but a few migrate to other peripheral structures, including mucosal surfaces, leptomeninges, inner ear, and uvea.6 Physiologically, melanocytes are found within leptomeninges around the brainstem on the ventral part of the medulla oblongata.7 The role of these
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CASE REPORT ALEXANDRU SZATHMARI ET AL.
PRIMARY AMELANOTIC LEPTOMENINGEAL MELANOMATOSIS IN A CHILD
Figure 3. Sagittal T1 sequence after gadolinium injection showing diffuse thick leptomeningeal enhancement with bulbar anterior constraint.
melanocytes is unclear, but it has been suggested that they might have a detoxification action.8 The first report of a primary melanocytic neoplasm dates from 1859 by Virchow.9 The clinical and histologic diagnosis of this pathology remains difficult and challenged by the differential diagnosis of metastatic melanoma. An extensive proliferation of brain basal leptomeningeal melanocytes mainly occurs in children in the setting of NCM.1 Other known associations are neurofibromatosis type 1 and Sturge-Weber syndrome.3,5 However, a malignant form of this condition may occur without NCM.10 In our case, neither the presence of skin nevi nor other syndromes were documented, and there was no familial history of hereditary illness. We reviewed the literature by searching PubMed using the terms “primary brain melanomatosis” and “diffuse melanotic brain lesions.” We retained only publications describing a diffuse form of melanomatosis but without associated NCM as in the case described here. The presence of melanin pigmentation was also documented (Table 1). Clinical Findings Clinical presentation is not specific, and it may mimic a wide variety of other conditions, including subacute meningitis, viral encephalitis,21 lymphoma, tuberculosis,22 lymphoma, leukemia, metastatic carcinoma, acute neurosarcoidosis,17 and idiopathic hypertrophic cranial pachymeningitis.23 More often, it presents as benign intracranial hypertension syndrome, hydrocephalus, cerebellar dysfunction, seizures, syringomyelia, cranial nerve palsy, intracranial hemorrhage, sphincter dysfunction, and neuropsychiatric symptoms.5,12,13,15,17,19,21 In our case, initial symptoms were those of nonspecific intracranial hypertension with fluctuant but progressive deterioration despite medical and surgical treatment. Initial decompression of the posterior fossa and cystostomy provided only temporary benefit, and CSF cytology did not reveal any evidence of the disease in the initial period.
Figure 4. Hematoxylin-eosin-saffron staining 200 (A) and 400 (B) showing a densely cellular tumor consisting of irregular clusters, sheets, or nests. Cells are large and epithelioid and have eosinophilic cytoplasm without pigment. Nuclei are irregular with prominent nucleoli. There are numerous mitotic figures. Immunostaining with HMB-45 400 (C) and with Melan-A antibodies 400 (D).
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Radiology Radiologic appearance is not characteristic showing only a subarachnoid hyperdensity on CT after intravenous
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Reference
Sex/Age (years)
Symptoms
MRI at Presentation
CSF Cytology (Tumoral Cells)
Histology
Amelanotic or Pigmented Cells
Treatment
Survival (months)
M/20
Progressive headache, nausea, Slight enhancement surrounding Second screening vomiting (7 months) cerebellopontine angles positive
Postmortem diagnosis (autopsy)
A
VP shunt IV and intrathecal chemotherapy
5
Pirini et al., 200312
F/68
ICH, confusion, gait disturbance DLE and sylvian fissure
Negative
Postmortem diagnosis (autopsy)
P
VP shunt > temporary relief
36
Demir et al., 200813
M/32
Headache, vomiting, complex partial seizures
Brain and spinal DLE
ND
Postmortem diagnosis (autopsy)
P
No
Bocquillon et al., 201014
F/24
ICH, transient hemiparesis
Pachyleptomeningitis
Negative
Biopsy
P
Chemotherapy 6 months after initial presentation
Liubinas et al., 20105
M/43
Headache, drowsiness, confusion
DLE and sylvian fissure
Negative
Biopsy
P
No
Zadro et al., 201015
M/34
Papilledema, paraparesis, cognitive impairment
DLE
Negative
Biopsy
P
Radiotherapy
Arias et al., 201116
F/40
Headache, visual impairment, meningismus
Hydrocephalus, DLE on T1-WI
Negative
Biopsy
P
VP shunt
12
Lee et al., 201317
M/17
Headache, nausea, vomiting
Right hyperdense T lesion on CT ND
Biopsy
P
Chemotherapy and wholebrain radiotherapy
ND
Ng et al., 201318
F/43
Seizure, headaches, SAH, hydrocephalus
Hydrocephalus, slight hyperdensity on CT suspicious for SAH
ND
Biopsy
P
VP shunt
2
Trinh et al., 201419
M/51
Progressive headache, fatigue, Brain and spinal DLE on MRI imbalance
Negative
Biopsy
P
Chemotherapy, radiotherapy
3
Kim et al., 201520
F/66
Headache for months
CT with slight spontaneous temporal DLE
Positive
No
P
ND
ND
Present case, 2016
F/5
Headache, vomiting, convulsions
Focal enlargement of parietal Initially negative sulci Gd T1-WI and cystic dilation of brainstem surrounding cisternas
Repeated biopsy
A
VP shunt, chemotherapy
11
<2 9 <1 2
Data were obtained from PubMed search using the terms “primary brain melanomatosis” and “diffuse melanotic brain lesions.” Only publications describing a diffuse form of melanomatosis but without associated neurocutaneous melanosis were retained. MRI, magnetic resonance imaging; CSF, cerebrospinal fluid; M/F, male/female; P/A, amelanotic/pigmented; VP, ventriculoperitoneal; IV, intravenous; ICH, intracranial hypertension; DLE, diffuse leptomeningeal enhancement; ND, not determined; T1-WI, T1-weighted imaging; CT, computed tomography; SAH, subarachnoid hemorrhage; Gd, gadolinium; T, temporal lobe.
CASE REPORT
PRIMARY AMELANOTIC LEPTOMENINGEAL MELANOMATOSIS IN A CHILD
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Tosaka et al., 200111
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Table 1. Data from the Literature
CASE REPORT ALEXANDRU SZATHMARI ET AL.
administration of contrast agent. On MRI, spontaneous hyperintensity of the brain surface on T1-weighted images or low T2 signal intensities may be evidenced owing to the paramagnetic proprieties of the melanin.24 Other substances that cause high T1 intensity in the central nervous system are fat, subacute blood, and occasionally calcium.25 In amelanotic forms, MRI findings range from hypointensity to isointensity on T1weighted images to moderate hyperintensity on T2-weighted images.6 In the present case, no T1 hyperintensity was evident, and there was only nonspecific focal enlargement of parietal sulci with abnormal leptomeningeal enhancement after injection of gadolinium. That could represent leptomeningeal inflammation, tumoral infiltration (which was the correct hypothesis a posteriori), or a postseizure anomaly. The enlargement of the fourth ventricle and the cisterna magna may be explained by pial and subpial tumor cell infiltration with impairment in CSF circulation and hydrocephalus. Enlargement of the basal cisternae was described in a case of amelanotic PLM associated with NCM.26 In this case, progression of the illness became apparent with the appearance and accentuation of arachnoidal T1 gadolinium enhancement. The leptomeningeal thickening was particularly important in the prebulbar area with a marked anterior constraint (Figure 3). Cytopathology Analysis of CSF obtained by lumbar puncture or at surgery is usually altered with nonspecific findings, such as high protein content, increased red blood cells, normal or low glucose, or sterile leukocytosis. The presence of pleomorphic neoplastic cells with intracytoplasmic melanin pigments and mitoses is characteristic.20 However, negative cytology is not unusual (Table 1). In the present case, cytology was negative. After diagnosis, careful review of cytology showed elements in favor of the presence of neoplastic cells within the CSF obtained 2 months after the beginning of the hospitalization. The nonspecific aspect and lack of melanin pigment were interpreted as secondary inflammatory cells in the context of fungal infection.
PRIMARY AMELANOTIC LEPTOMENINGEAL MELANOMATOSIS IN A CHILD
The difficulty of the cytologic diagnosis has already been emphasized by several authors.11,19,22 In the absence of melanin deposits, diagnosis can be made only by immunostaining.11 Histopathology Melanomatosis corresponds to the malignant form of melanocytosis, a diffuse proliferation of cells with histologic and cytologic features similar to a malignant melanoma with brain invasion or necrosis.27 The presence of melanin in tumor or in associated inflammatory cells is characteristic, and it may be visible in cases of direct surgical approach5,14 as well as others (Table 1). In rare cases, these cells may not be pigmented, and diagnosis is more difficult based on immunohistochemistry, as most tumors react with HMB-45, Melan-A, or S-100 protein. There is no expression of glial fibrillary acidic protein, neurofilament proteins, cytokeratin, or epithelial membrane antigen.1 In our case, even after repeated endoscopic exploration, no visual evidence of leptomeningeal involvement could be found. The definitive histopathologic diagnosis revealed a nonpigmented (amelanotic) form of melanomatosis. The presence of nodular lesions28 or diffuse forms11 of amelanotic lesions in adults has already been reported, but this is the first amelanotic PLM to our knowledge in a child with no history of cutaneous lesions. Management PLM has a poor prognosis. Management is challenged by the confusing initial clinical presentation, making the diagnosis difficult and sometimes obtained only postmortem.12,29 The role of surgery is limited to the treatment of the associated hydrocephalus and to the direct biopsy mandatory for histologic diagnosis. However, in our case, the initial supratentorial meningeal and brain biopsies were not contributive. This may be explained by the choice of the biopsy site, distant from the radiologic abnormalities, as the second biopsy specimen obtained at the level of the basal cistern was positive. Chemotherapy and radiotherapy were not effective (Table 1). In one case, neoadjuvant chemotherapy followed by whole-brain radiotherapy showed partial therapeutic response only after 8 supplementary sessions of
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chemotherapy, but long-term progression of the disease is not detailed.17 In some cases with hydrocephalus, progression of the disease seems to be controlled better with only a shunt, but generally survival does not exceed a few months.12,16 In our case, initial treatment addressed cisternal dilation because local brainstem compression was suspected, and this was followed by shunting. Even with active management of CSF circulation or absorption disorders, the benefit was short-term. CONCLUSIONS Diagnosis of PLM is a challenging task because of the lack of specificity of the initial presentation and its rare incidence, especially in cases without NCM. To our knowledge, this is the first report of amelanotic PLM not associated with NCM in a child. This case report illustrates the difficulty of diagnosis in the absence of cutaneous lesions and lack of melanin. Careful and repeated cytology screening of CSF with immunostaining is mandatory in case of nonbacterial meningismus. Negative result would request brain biopsy at the level of abnormal radiological findings that have to be well addressed in order to improve the chance for a positive diagnosis. REFERENCES 1. Brat DJ, Perry A. Melanocytic lesions. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee W, eds. WHO Classification of Tumors of the Central Nervous System. Lyon, France: IARC Press; 2007: 181-183. 2. Kadonaga JN, Barkovich AJ, Edwards MS, Frieden IJ. Neurocutaneous melanosis in association with the Dandy-Walker complex. Pediatr Dermatol. 1992;9:37-43. 3. Di Rocco F, Sabatino G, Koutzoglou M, Battaglia D, Caldarelli M, Tamburrini G. Neurocutaneous melanosis. Childs Nerv Syst. 2004;20: 23-28. 4. Allcutt D, Michowiz S, Weitzman S, Becker L, Blaser S, Hoffman HJ, et al. Primary leptomeningeal melanoma: an unusually aggressive tumor in childhood. Neurosurgery. 1993;32:721-729 [discussion: 729]. 5. Liubinas SV, Maartens N, Drummond KJ. Primary melanocytic neoplasms of the central nervous system. J Clin Neurosci. 2010;17:1227-1232. 6. Greco Crasto S, Soffietti R, Bradac GB, Boldorini R. Primitive cerebral melanoma: case
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report and review of the literature. Surg Neurol. 2001;55:163-168 [discussion: 168]. 7. Goldgeier MH, Klein LE, Klein-Angerer S, Moellmann G, Nordlund JJ. The distribution of melanocytes in the leptomeninges of the human brain. J Invest Dermatol. 1984;82:235-238. 8. Tolleson WH. Human melanocyte biology, toxicology, and pathology. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2005;23:105-161. 9. Virchow R. Pigment und diffuse Melanose der Arachnoides. Virchows Arch Pat Anath Phisiol. 1859; 16:180-182. 10. Kusters-Vandevelde HV, Kusters B, van Engen-van Grunsven AC, Groenen PJ, Wesseling P, Blokx WA. Primary melanocytic tumors of the central nervous system: a review with focus on molecular aspects. Brain Pathol. 2015;25:209-226. 11. Tosaka M, Tamura M, Oriuchi N, Horikoshi M, Joshita T, Sugawara K, et al. Cerebrospinal fluid immunocytochemical analysis and neuroimaging in the diagnosis of primary leptomeningeal melanoma. Case report. J Neurosurg. 2001;94:528-532. 12. Pirini MG, Mascalchi M, Salvi F, Tassinari CA, Zanella L, Bacchini P, et al. Primary diffuse meningeal melanomatosis: radiologic-pathologic correlation. AJNR Am J Neuroradiol. 2003;24:115-118. 13. Demir MK, Aker FV, Akinci O, Ozgultekin A. Case 134: primary leptomeningeal melanomatosis. Radiology. 2008;247:905-909. 14. Bocquillon P, Berteloot AS, Maurage CA, Mackowiak-Cordoliani MA, Pasquier F, Bombois S. Primitive leptomeningeal malignant melanoma: a rare etiology of pachymeningitis and leptomeningitis. Rev Neurol (Paris). 2010;166:927-930.
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15. Zadro I, Brinar VV, Barun B, Ozretic D, Pazanin L, Grahovac G, et al. Primary diffuse meningeal melanomatosis. Neurologist. 2010;16:117-119. 16. Arias M, Alberte-Woodward M, Arias S, Dapena D, Prieto A, Suarez-Penaranda JM. Primary malignant meningeal melanomatosis: a clinical, radiological and pathologic case study. Acta Neurol Belg. 2011;111:228-231. 17. Lee HJ, Ahn BC, Hwang SW, Cho SK, Kim HW, Lee SW, et al. F-18 fluorodeoxyglucose PET/CT and post hoc PET/MRI in a case of primary meningeal melanomatosis. Korean J Radiol. 2013;14: 343-349. 18. Ng RYT, Siu DYW, Wong GKC, Ng HK, Poon WS. An uncommon mimic of spontaneous subarachnoid haemorrhage. Hong Kong Med J. 2013;19: 80-81. 19. Trinh V, Medina-Flores R, Taylor CL, Yonas H, Chohan MO. Primary melanocytic tumors of the central nervous system: report of two cases and review of literature. Surg Neurol Int. 2014;5:147. 20. Kim DH, Choi CY, Lee CH, Joo M. Primary intracranial leptomeningeal melanomatosis. J Korean Neurosurg Soc. 2015;58:554-556. 21. Nicolaides P, Newton RW, Kelsey A. Primary malignant melanoma of meninges: atypical presentation of subacute meningitis. Pediatr Neurol. 1995;12:172-174.
24. Barkovich AJ, Frieden IJ, Williams ML. MR of neurocutaneous melanosis. AJNR Am J Neuroradiol. 1994;15:859-867. 25. Wehrli FN. The basis of MR contrast. In: Atlas SW, ed. MRI of the Brain and Spine. New York: Raven Press; 1991:23-38. 26. Vanzieleghem BD, Lemmerling MM, Van Coster RN. Neurocutaneous melanosis presenting with intracranial amelanotic melanoma. AJNR Am J Neuroradiol. 1999;20:457-460. 27. Brat DJ, Giannini C, Scheithauer BW, Burger PC. Primary melanocytic neoplasms of the central nervous systems. Am J Surg Pathol. 1999;23:745-754. 28. Schulz C, Waldeck S. Primary amelanotic meningeal melanomatosis. Fortschr Neurol Psychiatr. 2012;80:402-406. 29. Monso G, Vernet A, Cusi V, Mateo M, Vilaseca MA. Primary leptomeningeal melanomatosis in a 6-year-old child. Rev Neurol. 1996;24: 87-90.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 16 April 2016; accepted 9 June 2016
22. Grant DN. Primary meningeal melanomatosis: limitations of current diagnostic techniques. J Neurol Neurosurg Psychiatr. 1983;46:874-875.
Citation: World Neurosurg. (2016) 92:581.e15-581.e20. http://dx.doi.org/10.1016/j.wneu.2016.06.039 Journal homepage: www.WORLDNEUROSURGERY.org
23. Bang OY, Kim DI, Yoon SR, Choi IS. Idiopathic hypertrophic pachymeningeal lesions: correlation between clinical patterns and neuroimaging characteristics. Eur Neurol. 1998;39:49-56.
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