|Year : 2006 | Volume
| Issue : 4 | Page : 240-248
An unusual case of chronic meningitis
KN Ramesha1, Sanjeev V Thomas1, VV Radhakrishnan2, Kameshwar Prasad3, NK Mishra4
1 Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India
2 Department of Neuropathology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India
3 Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
4 Department of Neuroradiology, All India Institute of Medical Sciences, New Delhi, India
Departments of Neurology, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Ramesha K N, Thomas SV, Radhakrishnan V V, Prasad K, Mishra N K. An unusual case of chronic meningitis. Ann Indian Acad Neurol 2006;9:240-8
| Case Presentation (KN Ramesha, Sanjeev V. Thomas)|| |
A 39-year-old lady (staff nurse) presented with headache and vomiting of two months duration, altered sensorium of one-week duration, accompanied with one episode of generalized tonic seizure two weeks prior to admission. She had contact with pulmonary tuberculosis. There was no fever, loss of appetite or weight loss. There was no history suggestive of internal malignancy, lump in the breast, respiratory symptoms, gynecological complaints, rashes or arthritis. Examination showed bilateral papilloedema and bilateral lateral rectus palsy with no other focal neurological deficits. Magnetic resonance imaging (MRI) of the brain revealed only basal exudates [Figure - 1]. Cerebrospinal fluid (CSF) showed lymphocytic pleocytosis with raised protein and normal glucose [Table - 1].
Hematology including ESR and peripheral smear study were normal. Hemoglobin 12.5 g/dl, total leucocyte count 9600 cells/mm 3, polymorphs 65%, lymphocytes 29%, eosinophils 6%, platelet count 290,000/mm 3- ESR 14 mm in one hour, peripheral smear study no evidence of anemia, immature cells or toxic granules. Mantoux test negative, X-ray chest normal, serum angiotensin converting enzyme and calcium levels normal, serum VDRL, HIV, HbsAg negative, Brucella More Details agglutination test negative, serum Anti nuclear antibodies, anti phospholipid antibodies and double stranded DNA anitbodies were negative. Ultrasound scan and computed tomography (CT) scan of the abdomen were normal, gynecological and breast examination normal, echocardiogram normal. Work up for tuberculosis, fungal or syphilitic infection, carcinomatous or vascultic meningitis was negative. CSF examination for polymerase chain reaction (PCR), smear and culture for M. tuberculosis as well as serology, smear and culture for Cryptococcus were negative. CSF -VDRL and cytology for malignant cells were also negative. Four vessel digital subtraction angiogram was also normal. She was started on four drug antitubercular treatment with steroids empirically. Later on antitubercular treatment was modified because of adverse drug reactions. During the hospital stay she had hyponatremia secondary to SIADH, which was managed with appropriate measures. Overall she showed significant improvement in her symptoms and at the time of discharge from the hospital (one month later) she had normal sensorium and no focal neurological deficits.
She was readmitted one month later for alteration of sensorium without focal deficits. Metabolic parameters were normal including liver function tests. An MR venogram revealed cortical venous sinus thrombosis [Figure - 2]. She was anticoagulated with partial improvement to her symptoms. Extensive work up for various etiologies was negative as mentioned. Screening for internal malignancy clinically as well as by investigations (CT scan of the abdomen and chest
X-ray) were noncontributory. Repeat imaging of the brain this time had shown early hydrocephalus without any focal lesions. Repeat CSF study showed raised protein, normal sugar and normal cell count. She was continued on modified ATT (INH, rifampicin, ofloxacin and ethambutol) along with steroids. She also required insulin for the steroid induced diabetes. During the hospital stay, she had few episodes of generalized tonic clonic seizures, which was treated with phenobarbitone. When she was discharged, she had normal sensorium and had no focal neurological deficits.
She was readmitted (eight months in to the illness), with alteration of sensorium and poor vision. Clinical examination revealed acute confusional state and secondary optic atrophy without any focal neurological deficits. Repeat MRI of the brain showed increase in the hydrocephalus with enhancing lesion in the posterior part of the third ventricle [Figure - 3]. Hence she was taken up for endoscopic third ventriculostomy with meningeal biopsy, which later showed normal histopathology. Biopsy of the lesion was avoided due to its high vascularity. Postoperatively she developed pseudomeningocoele from the biopsy site and refractory pyogenic meningitis. She expired 10 months after the onset of symptoms. An autopsy of the brain was done.
| Clinical Discussion (Kameshwar Prasad)|| |
This patient, a 39-year-old female presented with headache, vomiting, papilloedema and altered sensorium, which developed over a period of two months. The disease clearly had gradual onset and progressive course except temporary remissions ranging from one month to a few months and finally leading to death over a period of 10 months. The salient features of her illness are raised intracranial pressure (ICP), CSF suggestive of lymphocytic meningitis, progressively increasing hydrocephalus, generalized tonic-clonic seizures, alteration of sensorium with improvement for a month to few months in between, absence of focal neurological deficit, hyperplastic leptomeninges and lack of response to anti-tubercular treatment. There are two ways to approach the discussion of this case. One is to consider the salient features of the case including imaging and the entire clinical course and then discuss its differential diagnosis. Second approach could be to discuss the approach at initial presentation and subsequently incorporate the events developing during the course of illness, take each admission with its salient clinical features and imaging to formulate the clinical approach. I take the latter approach basically to enhance the educational value of the discussion.
At initial presentation, the patient clearly had increased ICP. She developed altered sensorium almost seven weeks after the onset of the disease. Alteration of sensorium occurs when there is either diffuse cerebral dysfunction or dysfunction of the ascending reticular activating system. These structures may be involved due to the primary disease or due to secondary consequences of the disease in the form of herniation syndromes and / or effect on vasculature and the cerebral blood flow to the above mentioned structures. The absence of any localizing feature requires consideration of conditions, which can present with raised ICP without focal neurological deficit and such conditions are listed in [Table - 2]. The diagnostic approach in such situation requires imaging of the brain which in this case was MRI of the brain, which revealed "Basal exudates". The next specific investigation is examination of CSF, which showed lymphocytic pleocytosis with raised protein and normal glucose. The clinical syndrome with these findings is often termed "chronic meningitis". The causes of chronic meningitis are listed in [Table - 3]. The common causes of chronic meningitis developing without any previously diagnosed illness (e.g., tuberculosis or cancer etc.) are infections. Of all the infections, tuberculosis is certainly the commonest in Indian settings. The history of contact with tuberculosis would lend credence to consideration of this condition as the first possibility and while investigating for other causes, anti-tubercular treatment is often started empirically as was done in this case. This is a typical linear approach of thinking in such a case. Lymphocytic pleocytosis and raised protein support the diagnosis. Normal glucose does not favour the diagnosis but is consistent with it. It is prudent to start ATT in such a case but diagnosis other than TBM must always be pursued with additional investigations as was done in this case.
Arriving at a specific etiology of chronic meningitis requires both linear as well as lateral thinking and dogged pursuit of various possibilities with an open mind. This patient did not show lasting improvement with anti-tubercular treatment. There was no evidence of active pulmonary tuberculosis and imaging showed relentless progression with hyperplastic meningeal thickening. She was afebrile. Her ESR was only 14, CSF for AFB stain and AFB cultures and PCR were negative. Therefore it is unlikely that she had tuberculous meningitis. Fungal meningitis is another important consideration in such a case. Of the various etiologies of fungal meningitis, the commonest is cryptococcal meningitis. Incidence of cryptococcal meningitis has increased with the emergence of AIDS and one should always look for this cause in a patient with chronic meningitis. Cryptococcal meningitis is practically ruled out in view of India-ink preparation, negative culture and negative serology. The patient was HIV negative and did not apparently have underlying immunodeficiency that predispose to cryptococcal meningitis, but many patients diagnosed as cryptococcal meningitis in our experience are immunocompetent. Meningitis due to other fungi cannot be ruled out but there is no evidence of fungal sinusitis or proptosis or pulmonary fungal infection to support in the other causes of fungal meningitis. If available, serologic tests that could be done are those for histoplasmosis, coccidoidomycosis and leptospirosis. Histoplasma meningitis is clinically similar to the other causes of chronic meningitis. Oral mucosal lesions are present in only 16% of patients and CSF cultures are positive in only 37 to 65% of case. Detection of serum and CSF antibodies to the fungus is the most sensitive (though less specific) test for histoplasmosis. This was probably not done in this case because MRI pointed towards a neoplastic cause. However, the diagnosis must be considered in every case of progressively deteriorating chronic meningitis.
One question of interest might be whether two negative PCRs for tuberculosis should have ruled out this possibility. In other words, is PCR for TB so sensitive that a negative test rules out the possibility? Theoretically, PCR can detect even one bacillus in the CSF and when this is negative twice, one may rule out this possibility. In evidence-based medicine texts, a phrase 'SnNOut' (Sensitive-Negative-Out) is used to emphasize this point. It means a highly sensitive (Sn) test, if negative (N), rules out (Out) the disease. [An analogous phrase for a highly specific test is 'SpPIn' (specific-positive-in), meaning thereby that highly specific test, if positive, rules in the disease]. However, in literature, the sensitivity of PCR for TB in CSF ranges from 70 to 85%. For ruling out the disease, we need sensitivity in the range of 95% or above. This discrepancy between the theoretical possibility and reported sensitivity may be due to the problems in design of the reported studies (for example, lack of a proper gold standard) or inherent problems in the PCR methodology. Here, I must stress that in view of its limited sensitivity; clinicians should not heavily rely upon PCR for TB in CSF to make a diagnosis of TBM, though in the given case, this diagnosis is very unlikely.
The other question that might be of interest is the value of meningo-cortical biopsy in the diagnosis of chronic meningitis in general and neoplastic meningitis in particular. The question assumes significance in this case because it was negative. However, positivity of biopsy depends on the site of sampling (whether sampled site was involved), the amount of the sample and stage of the disease (determining the extent of involvement). Not surprisingly, sensitivity of meningo-cortical biopsy in diagnosing the underlying disease ranges from 40% to 80%. A negative biopsy does not rule out the conditions under consideration, as in this case.
Absence of fever in the patient should prompt consideration of non-infectious causes of chronic meningitis [Table - 4]. Of all the causes listed in the table, the ones that can be fatal within 10 months needs to be considered.
There are no pointers to the diagnosis of Behcet's disease - like oral and genital ulcers, skin lesions, uveitis and the patient did not have lasting improvement with steroids. Sarcoidosis can simulate tuberculous meningitis but is unlikely in the view of absence of chest involvement, cranial nerve palsies, eye involvement or lasting improvement with steroids. Granulomatous angitis is unlikely in view of MRI findings and normal cerebral angiograms. Absence of uveitis rules out uveomeningoencephalitis and the fatal course in 10 months in clearly against benign lymphocytic meningitis.
This leaves neoplastic meningitis as a strong possibility. Neoplastic meningitis can result from primary meningeal neoplasia or metastatic involvement of meninges in a patient with hematologic malignancy or solid tumors. In the case of leukemia or lymphoma, meningeal involvement usually occurs in the setting of previously diagnosed case of the condition, but sometimes the patient may present with meningeal involvement as initial feature. Primary brain tumors, including gliomas, pinealomas, ependymomas and choroid plexus tumors may involve the meninges diffusely, sometimes without gross parenchymal involvement.
The patient improved with ATT and steroids, but most likely this was a non-specific response to steroids. Re-admission with altered sensorium in such a patient should prompt consideration of drug-resistant TBM along with all the other causes of chronic meningitis. Repeat imaging in such a case should include the entire neuraxis, because some neoplastic lesions may be prominent in the spinal subarachnoid space. For example, primary diffuse leptomeningeal gliomatosis may be associated with multinodular enhancement of spinal nerve roots; focal areas of enhancement may be seen in the conus medullaris or the entire spinal cord in cases with meningeal melanocytoma, melanocytic lung and breast cancer. Choroids plexus papillomas may have extensive metastasis to the craniospinal leptomeninges. In other words, spinal imaging may give clues towards the diagnosis.
A point worth emphasizing here is that if a patient progresses on antitubercular therapy, then empirical amphotericin B should be started if there is history of exposure to an area endemic for histoplasmosis, blastomycosis or coccidioidomycosis, even if the serologic tests for these infections are negative.
Few lines are in order about negative CSF cytology. The diagnostic yield of CSF cytology is not 100% even in patients with leptomeningeal malignancy. Reported rates for positive CSF cytology in patients with systemic malignancy in 30% to 45%. Positive rate increases with multiple CSF examinations. In one investigation, the positive rate increased from 45% to 80% as multiple examinations were done.
Rare diffuse meningeal neoplasm, which can present with diffuse leptomeningeal thickening and enhancement especially in the basal cisterns include: primary leptomeningeal sarcomatosis, primary diffuse leptomeningeal glioblastoma multiforme, meningeal melanocytoma, diffuse malignant melanomatosis. It is not possible to clinically arrive at the pathological identity of the neoplasm but the one, which has been commonly reported to simulate TBM, is the primary diffuse leptomeningeal glioblastoma multiforme. In absence of melanin in the MRI, it is not possible to confirm the diagnosis of melanin producing tumors.
Search for internal malignancy was certainly in order. In spite of extensive research, one cannot be sure that the leptomeningeal involvement is not due to metastases from solid malignancy. The two most frequent primary sites for leptomeningeal metastases are lung and breast. The search, therefore, must include a CT of the chest. Imaging studies done during the November admission of the case are not provided but presumably they were normal. A notable point during this admission was a report of cortical venous sinus thrombosis (CVT) on MR venogram and improvement of her symptoms with anticoagulation. While accepting that this must have been true, I may like to point out for the young readers that there are many fallacies in the diagnosis of CVT on MR venogram. Normal variation of cortical veins, quality of the images, secondary consequences of the intracranial disease or raised intracranial pressure or venous flow etc. pose difficulties in the making of diagnosis of CVT on MRV and one must be extremely careful while making this diagnosis on MRV.
The patient improved after second admission as well but the improvement lasted only a few months (no. of months not clearly spelt out in the case history) only to be admitted for the third time in March 2005. The MRI, this time, in addition to leptomeningeal pathology showed an enhancing lesion in the posterior part of the third ventricle. The meningeal biopsy was normal. The patient succumbed to her illness. By this time it was clear that mostly the diagnosis is neoplastic meningitis.
At this stage, let us go through our Neuroradiologist's opinion.
| Neuroradiology Discussion (NK Prasad)|| |
[Figure - 1]
| MR on First Admission|| |
Limited images of axial T 1 with contrast, T 2 and sagittal T 2 sections are provided. An irregular T 1 hyperintense lesion (possibly enhanced by contrast) is seen in the region of posterior third ventricle. Posterior aspect of midbrain, sulci on superior aspect of cerebellar hemispheres and medial occipital lobe sulci, also show similar T 1 hyperintensity, more marked on the right side. T 2 weighted images show a hyperintense area in the right dorsal thalamus without appreciable deformation of the third ventricle. The ventricular system and CSF spaces elsewhere are normal.
| MRI on Second Admission|| |
Limited T 1 axial and sagittal images with and without contrast and T 2 axial images are provided. The leptomeningeal T 1 hypeintense areas seen in the MRI of august '04 appear to have increased in their extent and in addition the tentorium is also showing similar appearance. Comparison of the non-contrast and contrast T1 images suggest the hyperintensity of these lesions to be due to contrast enhancement. The right thalamic hyperintense lesion is still seen, though sections comparable to the images of August '04 are not available for comment.
| Angiogram|| |
One frame each of right carotid angiogram (arterial AP and venous phase lateral) and right vertebral angiogram (arterial and venous phase AP) are provided. No abnormality is evident in the angiographic images.
[Figure - 3]
| Mr|| |
T 1 axial (with and without contrast), T 1 sagittal with contrast, fluid attenuated inversion recovery (FLAIR) axial, T 2 axial and sagittal along with H 1 MR spectra through the enhancing posterior third ventricular lesion and relatively normal brain is provided. Compared to the previous MR studies of August and October '04, the posterior third ventricular lesion has progressed to form a definitive mass. It shows intense contrast enhancement and is iso-signal on FLAIR and T 2 sequences. The leptomeningeal enhancement is now more extensive and at places shows nodularity noticeable in the ambiens cisterns. The right thalamic lesion seen earlier is now more extensive and similar T 2 hyperintensity is also seen in the left thalamus. The thalamic lesions appear hyperintense on FLAIR images also. Hyperintensity on FLAIR is also observed in the right cerebellar hemisphere, callosal cistern. MR spectroscopy shows increase in the Choline peak and reduced NAA peak in the posterior third ventricular mass.
| Mri|| |
Axial T1 (with and without contrast), T2, FLAIR and sagittal T1 and T2 and a MR venogram in lateral view are provided. Evidence of diffuse leptomeningeal enhancement, nodularity and widening of sylvian cisterns suggestive of CSF loculation is seen. There is generalized pachymeningeal enhancement as well. The posterior third ventricular mass has further increased in size and the thalamic abnormality has extended in to the midbrain. The anterior third ventricle and the lateral ventricles are dilated. There is a 2 cm burr hole on the skull vault in the frontal bone with overlying scalp swelling, possibly the site of biopsy. Adjacent brain mater is seen herniating through the burr hole.
| Summary|| |
There appears to be leptomeningeal pathology originating in the posterior third ventricular region spreading progressively to involve the adjacent cisternal and sulcal spaces and later to the entire cranial subarachnoid. Concomitant pachymeningeal disease starting at the tentorium is also evident. A well-defined mass in the posterior third ventricular region with progressive thalamo-mesencephalic signal abnormality is noticeable. Angiography fails to reveal any tumour vascularity in the mass. MR signal characteristic of the mass suggests the mass to be of uniform texture and highly cellular with homogeneous contrast enhancement. Similar is the appearance of the leptomeningeal nodules observed during the later part of follow-up. The likely aetiology of the progressive meningitis seems to be a malignant disease.
Radiological differential diagnosis
Germ cell tumour
Small cell carcinoma
Primary leptomeningeal gliomatosis
| Clinical Discussion Continued|| |
In retrospect, it seems that a lesion in the posterior third ventricle was present from the very beginning but was not prominent enough to be detectable in the first reading of the MRI. By another seven months, the posterior third ventricular lesion had progressed to form a definite mass. The mass further increased in size, the leptomeningeal enhancement displayed nodularity at places; signal abnormality in the thalamus increased to involve the mid-brain and there was pachymeningeal involvement as well. In view of the above, there is no doubt that the patient suffered from a neoplastic disease. The neoplasm most probably started near the posterior third ventricle. The neoplasms in this region in adults are usually pineal region tumors, metastasis or astrocytoma (especially 'anaplastic').
Pineal region tumours are divided into tumours arising from pineal parenchymal cells (pineocytomas and pineoblastomas) and those arising from ectopic germ cells (germinomas, teratomas, embryonal carcinomas, choriocarcinoma and yolk-sac tumours).
Germinomas are the most common of the germ cell tumors in this region and account for upto 50% of all pineal region tumors. Germinomas occur mostly between 10 to 30 years of age, with peak age of presentation in the second decade. There is a strong male preponderance. Pineal gland is one of the preferred sites for occurrence of germinoma. Pineal germinomas often have secondary implant in the interior third ventricular recesses. MR signal characteristics are non-specific but they are usually isointense with cortex of all pulse sequences. They are homogenously hyperintense on T1 weighted image. Although site of the initial tumor and enhancement with contrast in MRI, favors the possibility of pineal germinoma, the patient's sex and age are relative against it. Isointensity of the mass with the brain and intense contrast enhancement favors germinoma.
Pineal teratomas are the second most common pineal region tumour, accounting for upto 15% of all tumours in this area. Like other germ cell neoplasms in this region, they also have a male predilection (2:1 to 8:1). Contrary to the usually well-differentiated gonadal and sacrococcygeal masses, the intracranial teratomas are often poorly differentiated and may be locally invasive or metastasize. Teratoma is likely in this case, because there is no mesodermal evidence of tissues representing mixture of two or three embryological layers (ectoderm, mesoderm and endoderm) in the form of heterogeneity in imaging, presence of fat etc.
Choriocarcinomas account for <5% of pineal region tumours and also have a male predilection. These tumours have elevated levels of b-Hcg in both CSF and plasma (we do not know whether these were done in this patient). They are highly vascular more likely to bleed than other tumours of this region. The operative finding of high vascularity in this case supports this diagnosis but angiogram does not support high vascularity. Apart from blood, CT and MR characteristics are similar to other germ cell tumours.
Yolk sac tumour or embryonal carcinomas have calcification or necrosis / hemorrhage respectively in the imaging and thus are not likely in this case. Pineocytoma is a slow growing tumour with a long clinical course over the years and thus can be easily ruled out in this case.
Pineoblastomas usually occur in patients younger than 20 years of age. On imaging, pineoblastomas often show heterogeneity with areas of cystic degeneration. The age of this patient and the MRI features do not support this diagnosis, but the possibility cannot be ruled out.
Although pineal gland consists mainly of pineocytes, there is a small population of fibrillary astrocytes that give rise to the very rare primary pineal glioma, primarily astrocytomas. More commonly, astrocytomas in this region arise from adjacent structures such as splenium of the corpus callosum, adjacent quadrigeminal plate or third ventricular wall. Involvement of thalamus and midbrain in this case may point to the origin of such a tumour in this case, though the extensive leptomeningeal spread is extremely rare. I could fine only a case report of anaplastic astrocytoma behaving in a similar fashion with leptomeningeal spread.
One finds several case reports of intracranial neoplasms that invade leptomeninges and present with raised intracranial pressure.,,,,,,,,, Also, there are several conditions reported to simulate tuberculous meningitis.,,,,, Any of these conditions are possible in this case, but we have discussed more likely possibilities to avoid an unduly long discussion.
Finally, it seems that the tumor arose near the pineal region and invaded the leptomeninges as well as pachymeninges (to a lesser extent) and in imaging it was isointense with brain parenchyma and had intense contrast enhancement. In view of the above discussion, germinomas appear to be most likely. However, if the posterior third ventricular mass is taken as primarily meningeal pathology, then primary leptomeningeal gliomatosis may be the most likely possibility. Clinically, any of the neoplasms mentioned above cannot be ruled out including sarcoma, glioblastoma multiforme, anaplastic astrocytoma, metastatic carcinoma or pineoblastomas.
| Final Clinical Diagnosis|| |
Neoplastic meningitis due to ?Germinoma/other pineal region tumour or ?Primary leptomeningeal gliomatosis. Less likely ?Leptomeningeal metastasis from a carcinoma.
| Pathology Discussion (V. V. Radhakrishnan)|| |
Partial autopsy restricted to the examination of the brain was only consented in this case and this was performed on this young female subject within three hours following death. There was a recent surgical wound over the right frontal region. The brain was removed through the conventional intermastoid incision. On removing the calvarium, the dura mater over the supero-lateral surfaces of the cerebral hemispheres was tense and this was due to the bulging of the brain. A portion of the right frontal lobe was protruding through the sutured dura mater. On reflecting the dura, the brain was extremely soft in consistency and therefore it was not possible to dissect or examine at the time of autopsy. The brain was immediately fixed in 30% buffered formaline for a period of three weeks.
After fixation the brain weighed 1250 grams. The supero-lateral surfaces of both cerebral hemispheres appeared symmetrically edematous and this is characterized by the obliteration of sulcal grooves and flattening of the gyri. The cortical surfaces of both cerebral hemispheres appeared pale and against which the congested cortical veins stood very prominently. There was no evidence of exudate over the supero-lateral surfaces of both cerebral hemispheres. Examination of the brain from the inferior surface showed a diffuse dark brownish friable material over the basal leptomeninges and these were seen encasing the brain- stem, superior surface of the cerebellum and also cervical segment of spinal cord. The basilar artery and other major blood vessels in the circle of Willis were also embedded in this dark brownish material. Grossly, these features were suggestive of sub-arachnoid hemorrhage and therefore all the major blood vessels in the circle of Willis were carefully dissected by removing the dark brownish material. No vascular lesion in the form of any aneurysm could be demonstrated in the circle of Willis. Besides, there were bilateral uncal herniations and as a result of which there was a distortion and antero-posterior elongation of the pons and midbrain. The brain was sectioned at coronal planes and no parenchymal lesion was demonstrated in the cerebral hemispheres or in the cerebellum. However there were bilateral irregularly and vaguely defined friable lesions in the thalamic region.
Fourteen representative blocks of tissue were selected from different anatomical locations for the histopathological studies. These blocks of tissues were processed routinely using standard protocol and they were embedded in paraffin. Five-micron thick paraffin sections were examined under the microscope using luxol- fast- blue combined with hematoxylin and eosin stains. Representative sections from pons and cerebellum showed a diffusely infiltrating neoplastic lesion essentially confined to the leptomeninges and this is characterized by the presence of densely packed nests of cells showing pleomorphism. Brisk mitotic activity was also a striking feature at several microscopic fields in the sections. These cells are scattered in a dense collagenous matrix. Discrete and confluent foci of necrosis and haemorrhages were also seen at several microscopic in the sections. Some of the neoplastic cells contained brown pigment in their cytoplasm. These pigments stained positively with Masson-Fontana stain and hence they were confirmed to be melanin [Figure - 4]. Some of these cells also gave positive immunostaining for S-100 and neuron specific enolase but stained negatively for desmin and cytokeratin. There were several microscopic foci in the sections showing invasion into the molecular layers of the cerebellum. Owing to the partial nature of this autopsy as well as in the absence of a demonstrable primary neoplastic lesion in the extra- cranial anatomical location, these gross and light microscopic features were regarded as consistent with the diagnosis of primary leptomeningeal melanoma.
Primary leptomeningeal melanoma is an uncommon but very aggressive malignant lesion that originates from the pial melanin bearing cells, characteristically found at the base of the brain. It is regarded that the malignant transformation of the pre- existing precursor melanin cells leads to the diffuse infiltration of the leptomeninges and thus correlates with the onset of neurological manifestations of the disease.
Melanin exists in two distinct forms within the central nervous system. Neuriomelanin is a darkly staining argentophilic intra- cytoplasmic granular protein and these are found predominantly within the neurons in the zona compacta of the substantia nigra, the locus ceruleus, the dorsal root ganglia of the vagus nerve and, sympathetic root ganglia. Very little is known about the biosynthesis of neuromelanin. On the other hand, the true melanin is synthesized within the melanosomes from the tyrosine precursors and these are present within the melonocytes. In general, melonocytes are sparsely distributed in the leptomeninges and they are mostly located over the anterior and lateral segments of the spinal cord, the brain- stem as well as in the base of the brain. It is from these cells that a primary leptomeningeal melanoma is thought to arise.
Primary leptomeningeal melanoma of the central nervous system are broadly classified into two types (1) Diffusely infiltrating carpet- like lesions encasing the leptomeninges and they characteristically spread along the subarachnoid space (2) They may at times manifest as a nodular solitary lesion from the leptomeninges and grossly resemble a meningioma. In either form, the primary leptomeningeal melanoma is a highly malignant neoplasm and histopathologically characterized by the presence of pleomorphism, mitotic figures, necrosis and haemorrhage. Although majority of these tumours contain melanin pigment in their cytoplasm but it is not uncommon to find that some of these tumours may be amelanotic at the light microscopic level. However ultrastructural studies often reveal that these amelanotic neoplastic cells contain mature or immature melanosomes in their cells.
The biological behaviour of the primary leptomeningeal melanomas is usually aggressive in nature. Diffuse infiltration of the basal leptomeninges can cause communicating hydrocephalus. These tumours usually disseminate along the entire cerebrospinal pathway. A diffuse infiltration along the subarachnoid space may grossly mimic with the features of the subarachnoid hemorrhage as seen in this case.
Because of their rarity, the primary leptomeningeal melanomas are difficult to diagnose in its early stagers. The neuroimaging features of these tumours in CT and MRI scans are seldom diagnostic. However careful cytological examination of the CSF specimens in these patients can detect the melanin containing neoplastic cells. The cytological diagnosis can be further supported by the positive immunostaing by the melonocytes cell specific monoclonal antibody HMB-45.
| Conclusion|| |
We wish to emphasize that one of the causes in a patient with chronic meningitis is primary leptomeningeal melanoma. This possibility should be considered in a patient who does respond to the conventional antibiotic treatment. Besides primary leptomeningeal melanomatosis, carcinomatous meningitis and primary leptomeningeal gliomatosis can also manifest as malignant meningitis. Careful and early cytological examination of CSF has a definite role in making an accurate diagnosis in patients with primary leptomeningeal melanoma.
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[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4]
[Table - 1], [Table - 2], [Table - 3], [Table - 4]