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Folia Neuropathologica
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Case report

Lhermitte-Duclos disease with neurofibrillary tangles in heterotopic cerebral grey matter

Daniel Rusiecki, Boleslaw Lach

Folia Neuropathol 2016; 54 (2): 190-196
Online publish date: 2016/06/13
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Introduction

Lhermitte-Duclos disease (LDD), a disorder first described by French physicians Lhermitte and Duclos in 1920 [25], is a benign, slow growing dysplastic gangliocytoma of the cerebellum, characterized by replacement of the granule cell layer by abnormal granule and Purkinje like cells. The most frequent presenting signs and symptoms are megalocephaly, increased intracranial pressure, nausea, hydrocephalus, ataxia, gait abnormalities, and intermittent headaches, all of which are attributed to the mass effect [6,11,25]. Many cases are associated with a mutation in the phosphatase and tensin homolog or PTEN gene which is also involved in numerous otherwise unrelated central nervous system abnormalities, namely Cowden syndrome [1,6,11], autism spectrum disorder [18], cerebral cortical dysplasia [11,30] and Bannayan-Riley-Ruvalcaba syndrome [30]. The presence of cortical heterotopia has been reported in a small number of LDD cases [3,5,17,32]. We describe a unique case of LDD with cerebral cortical heterotopic grey matter containing neurofibrillary tangles.

Clinical history and autopsy findings

This 42-year-old male with a large head and partial left ocular paresis since childhood, presented with headaches, neck pain, ataxia and signs of raised intracranial pressure. Magnetic resonance imaging (MRI) scan showed left cerebellar mass and obstructive hydrocephalus. A ventriculo-peritoneal shunt was inserted. A posterior fossa craniectomy was carried out and multiple biopsies of the diffusely enlarged left cerebellar hemisphere were performed. Postoperatively the patient made a good recovery and returned to full employment until his sudden death from myocardial infarction and right parietal “stroke” four years later. He had no other significant past medical history. He was a university graduate and worked as an accountant. Post-mortem examination confirmed massive myocardial infarction with endocardial thrombi and systemic atherosclerosis.
The brain weighed 2,220 grams after formalin fixation. The combined weight of the cerebellum and brainstem was 250 grams. The left cerebellar hemisphere was enlarged and measured approximately 6.5 × 5.5 × 7.0 cm. The right (grossly normal) hemisphere measured 5.0 × 4 × 5.0 cm. The lateral and inferior aspects of the affected hemisphere displayed coarse, broad, firm and more numerous gyri, measuring from 5 to 10 mm in width. The brainstem was normal.
Coronal sections of the cerebral hemispheres confirmed a recent haemorrhagic infarct in the posterior parietal area. Both frontal lobes contained subcortical foci of heterotopic grey matter, each measuring approximately 2 cm in the largest diameter. Similar, smaller heterotopic nests were also present in the temporal and parietal lobes on each side.

Material and methods

Large hemispherical blocks of the cerebellum and frontal lobes as well as an additional set of brain tissue samples removed from all representative areas of the left cerebral hemisphere, were formalin fixed and routinely processed for paraffin embedding and staining with hematoxylin and eosin (H&E), Luxol Fast blue combined with Periodic Acid Schiff (PAS & LFB) as well as Kluver-Barrera method, and Palmgren stain for axons. Selected sections of the hippocampus, amygdala and frontal cortex with heterotopic foci were immunostained for Tau protein (Tau, rabbit polyclonal antibodies, 1 : 200), neurofilaments (NF, monoclonal antibody, 1 : 400), glial fibrillary acidic protein (GFAP, polyclonal antibody, 1 : 500) and ubiquitin (UBQ, 1 : 300), all from DAKO as previously reported [20,28]. Glutaraldehyde fixed biopsy specimen from the cerebellar tumour was routinely processed for plastic embedding and ultrastructural study as previously reported [28]. Small fragments of heterotopic grey matter tissue in the frontal lobe were carefully removed from the large paraffin block, deparaffinised, washed in several changes of distilled water, post-fixed in 2% glutaraldehyde for 24 hrs, and re-embedded in epoxy-resin. Routinely stained thin sections were examined in a Phillips 200 electron microscope as previously reported [28].

Results

Microscopically, the cerebellar folia showed striking “inverted” architecture with a thickened molecular layer markedly enriched in the myelinated axons (Fig. 1). Normal Purkinje and granule cells were replaced by dysplastic ganglionic cells of various sizes, often reminiscent of abnormal Purkinje cells (Fig. 2A). Intermediate zones between the normal and abnormal cerebellar tissues showed gradual transitions of a steadily increasing number of large dysplastic cells replacing the small granule cells. Dysplastic areas showed rich vascularization and numerous interstitial vacuoles. Subcortical white matter was markedly reduced in volume and displayed loss of axons and myelin. Scattered intraparenchymal and meningeal vessels contained dusty mural calcifications. The dentate nucleus was abnormal in shape but otherwise not remarkable. The right cerebellar hemisphere contained several, small subpial foci of gangliocytoma composed of dysplastic neurons as well as a disorganized network of myelinated axons and glia. Many folia showed dysplastic neurons overlying depleted granule cells and accompanied by dense myelination of the molecular layer (Fig. 2B), a change indistinguishable from that in the contralateral, main tumour mass.
The heterotopic grey matter of the frontal lobes (Fig. 3) contained scattered neurons with neurofibrillary tangles (NFT) as well as neuritic threads, both strongly positive for Tau (Fig. 4) and UBQ. Electron microscopic examination revealed tight collections of paired helical filaments (PHF) in the perikaryon and myelinated axons in the background (Fig 5A). They measured approximately 20 nm and displayed periodic constrictions (Fig. 5B). However, the diameters deviated upwards and downwards of these values, most likely due to suboptimal processing of the tissue. In addition, there was an almost equal number of long straight 15 nm tubules without constrictions (Fig. 5B). The neuropil of the heterotopic foci as well as the adjacent white matter displayed a moderate degree of gliosis. The cortex overlying heterotopia did not demonstrate architectural abnormalities. However, cortical disorganization with marked gliosis was present in the left superior and middle frontal gyri involved by capillary telangiectasia (Fig. 6A). An increased number of telangiectatic capillaries was noticeable in the white matter of both cerebral and cerebellar hemispheres. Meningeal nests of heterotopic, glio-neuronal and glial tissue were very frequent in all cerebral cortical areas (Fig. 6B) as well as in the leptomeninges overlying the non-tumorous cerebellar folia. There was no evidence of NFTs, amyloid angiopathy or senile plaques in any other part of the brain, including hippocampal formations. Reexamination of the surgical specimen of the tumour biopsy revealed no PHFs in the neuronal or glial cells. The tumour tissue was not available for additional molecular or immunohistochemical testing.

Discussion

Lhermitte-Duclos disease is characterized by thick­en­ed cerebellar folia due to replacement of the granule cell layer by enlarged neurons of various sizes, most often reminiscent of Purkinje cells [10,25]. Other key features include the absence or reduction in numbers of Purkinje and granule cells, and myelination of the molecular layer, creating appearance of inverted folia. The lack or very low proliferative activity indicates that LDD may represent a malformation rather than the tumour [25]. However, progression to malignant and other benign tumours such as anaplastic ganglioglioma [36] and DNET [24] has been reported in a few cases. The new tumour is usually discovered many years after the initial LDD diagnosis [24,36].
Most cases of LDD present unilaterally, with no preference of side. However, bilateral LDD has been reported in five patients [5,7,32,34,39]. Four cases exhibited large bilateral lesions [7,32,34,39], the other had foci of LDD-like changes such as inverse myelination and dysplastic changes in the contralateral hemisphere [5]. Our case was similar to the latter, displaying several small nests of gangliocytic tumour and multifocal aberrant myelination of the molecular layer in the contralateral hemisphere.
Lhermitte-Duclos disease is often associated with macrocephaly and other developmental abnormalities such as subcortical grey matter heterotopia, meningeal glial heterotopia and vascular malformations [25]. Macrocephaly is found in approximately half of LDD cases and is usually present in other PTEN-related conditions such as Bannayan-Ruvalcaba-Riley syndrome [14,25]. However, this number may be higher as Mary Ambler suggested that isolated macrocephaly might be a sign of subclinical LDD [3]. Leptomeningeal glial nests result from an over-migration of glia beyond the pia limitans to the subarachnoid space [8,12]. Experimental studies have revealed that these heterotopia occur after damage to the pial basal lamina [23]. Physical injury to the pial basal lamina during the development, or the dysfunctions as well as deficiencies of proteins comprising the basal lamina, such as laminin, can result in an over-migration of glia [23]. To our best knowledge, there is no known link between LDD or PTEN mutations and any of these conditions. However, PTEN mutations are associated with a high rate of vascular malformations [37] and several studies demonstrated cavernous and venous angiomas [22] as well as other developmental vascular abnormalities in LDD [2,27,41]. An association of this mutation with LDD may explain striking hypervascularisation of gangliocytomas observed in one large study [1], and possible contribution to the widespread presence of telangiectasias in our patient. Multifocal, clinically silent cerebral subcortical grey matter heterotopia is the most unique finding among the constellation of brain abnormalities in our patient. Cortical heterotopia is a malformation caused by an arrest in neuronal migration from the ventricular zone in the developing brain [4,38]. Heterotopia are often associated with malformations in the overlying cortex that may display dyslamination and the presence of abnormal neurons [38]. Lhermitte-Duclos disease and other diseases with heterotopic grey matter or other forms of aberrant neuron migration, share many features such as formation of dysplastic and hypertrophic neurons [19,21], as well as predisposition to megalencephaly in carriers [31].
The presence of Tau-positive neuritic threads and neurofibrillary tangles (NFT) with the ultrastructural PHF characteristics has not been reported in association with LDD. Paired helical filaments in this patient were present only in the heterotopic neurons and not detected in the neoplastic cells or glia in the biopsy tissue, or any other part of the post-mortem brain. Although tau-positive neurons have been found in other forms of cortical dysplasia [16], tau immunoreactivity does not infer presence of NFTs or PHFs [9]. Hyperphosphorylated tau NFTs are typically associated with Alzheimer’s disease [40]. They may also develop at any age in other unrelated conditions such as subacute sclerosing panencephalitis, ALS, certain heavy metal poisoning, dementia pugilistica, Down syndrome, tuberous sclerosis [15,40] and gangliogliomas [26]. It is unknown if the etiological factors responsible for the given disease are also responsible for the production of PHF or whether the environment of chronically diseased brain predisposes to NFT formation [40]. It has been suggested that the presence of NFT-like inclusions in neurons in cortical dysplasia could be secondary to pre-existing cytoskeletal abnormalities [16]. Sen et al. [33] reported absence of NFTs in paediatric cases with cortical dysplasia, while older patients with similar cortical anomalies had classical NFTs. Therefore, it is very plausible that abnormal neurons in dysplastic foci are much more prone to degeneration and premature aging than histologically normal neurons [33].
Lhermitte-Duclos disease is genetically linked to a mutation in PTEN, which acts as a tumour suppressor protein for diverse pathways. The defective function of PTEN can cause excessive mTOR activation that can lead to cell proliferation, hypertrophy, and improper migration [19]. Disrupting PTEN in the cerebellum and cortex of murine models created pathology resembling human LDD and cortical dysplasia, respectively [19,21]. This model had all the features of LDD with hypertrophic neurons, loss of Purkinje cells, and symptoms of increased intracranial pressure [19]. The development of NFT in conjunction with LDD can also be traced to the PTEN pathway. However, the mechanisms that cause dysplastic neurons to accumulate NFTs are uncertain [29]. A study by Griffen et al. [13] has revealed a negative correlation between PTEN levels and the severity of tau tangles in AD brains. It has been subsequently confirmed that PTEN accumulates in NFTs, most likely as a consequence of deregulation of downstream signalling and nuclear dysfunction of PTEN in AD neurons [35]. Unfortunately, this is an archival case from the period when molecular studies for detection of this mutation were unavailable and possible relation between occurrence of NFT and PTEN gene mutation in our patient remains unknown.

Disclosure

Authors report no conflict of interest.

References

1. Abel TW, Bake SJ, Fraser MM, Tihan T, Nelson JS, Yachnis AT, Bouffard JP, Mena H, Burger PC, Eberhart CG. Lhermitte-Duclos disease: a report of 31 cases with immunohistochemical analysis of the PTEN/AKT/mTOR pathway. J Neuropathol Exp Neurol 2005; 64: 341-349.
2. Akiyama Y, Ikeda J, Ibayashi Y, Nonaka T, Asai Y, Houkin K. Lhermitte-Duclos disease with cervical paraspinal arteriovenous fistula. Case report. Neurol Med Chir 2006; 46: 446-449.
3. Ambler M, Pogocar S, Sidman R. Lhermitte-Duclos disease (granule cell hypertrophy of the cerebellum) pathological analysis of the first familial cases. J Neuropathol Exper Neurol 1969; 28: 622-647.
4. Barkovich JA, Kuzniecky RI. Gray matter heterotopia. Neurology 2000; 55: 1603-1608.
5. Beuche W, Wickboldt J, Friede RL. Lhermitte-Duclos disease – it’s minimal lesions in electron microscope data and CT findings. Clin Neuropathol 1983; 2: 163-170.
6. Boonpipattanapong T, Phuenpathom N, Mitarnun W. Cowden’s syndrome with Lhermitte-Duclos disease. Br J Neurosurg 2005; 19: 361-365.
7. Bozbuga M, Gulec I, Suslu HT, Bayindir C. Bilateral Lhermitte- Duclos disease. Neurol India 2010; 58: 309-311.
8. Choi BH, Matthias SC. Cortical dysplasia associated with massive ectopia of neurons and glial cells within the subarachnoid space. Acta Neuropathol 1987; 73: 105-109.
9. Duong T, De Rosa M, Poukens V, Vinters H, Fisher R. Neuronal cytoskeletal abnormalities in human cerebral cortical dysplasia. Acta Neuropathol 1994; 87: 493-503.
10. Eberhart C, Wiestler O, Eng C. Cowden disease and dysplastic gangliocytoma of the cerebellum/Lhermitte-Duclos disease. In: WHO Classification of Tumours of the Central Nervous System. Louis D, Ohgaki H, Wiestler O, Cavenee W (eds.). 1st ed. IARC, Lyon 2007; pp. 226-228.
11. Elia M, Amato C, Bottitta M, Grillo L, Calabrese G, Esposito M, Carotenuto M. An atypical patient with Cowden syndrome and PTEN gene mutation presenting with cortical malformation and focal epilepsy. Brain Dev 2012; 34: 873-876.
12. Golden J. Lissencephaly, Type II (Cobblestone). In: Pathology and Genetics: Developmental Neuropathology. Golden J, Harding B (eds.). 1st ed. ISN Press, Basel 2004; pp. 42-46.
13. Griffin R, Moloney A, Kelliher M, Johnston J, Ravid R, Dockery P, O’Connor R, O’Neill C. Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer’s disease pathology. J Neurochem 2005; 93: 105-117.
14. Haskins Olney A. Macrocephaly syndromes. Sem Pediatr Neurol 2007; 14: 128-135.
15. Hirano A, Tuazon R, Zimmerman HM. Neurofibrillary changes, granulovacuolar bodies and argentophilic globules observed in tuberous sclerosis. Acta Neuropathol 1968; 1: 257-261.
16. Kakita A, Kameyama S, Hayashi S, Masuda H, Takahashi H. Pathologic features of dysplasia and accompanying alterations observed in surgical specimens from patients with intractable epilepsy. J Child Neurol 2005; 20: 341-350.
17. Klisch J, Juengling F, Spreer J, Koch D, Thiel T, Buchert M, Arnold S, Feuerhake F, Schumacher M. Lhermitte-Duclos disease: assessment with MR imaging, positron emission tomography, single-photon emission CT, and MR spectroscopy. AJNR Am J Neuroradiol 2001; 22: 824-830.
18. Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W, Li Y, Baker SJ, Parada LF. PTEN regulates neuronal arborisation and social interaction in mice. Neuron 2006; 50: 377-388.
19. Kwon CH, Zhu X, Zhang J, Knoop LL, Tharp R, Smeyne RJ, Eberhart CG, Burger PC, Baker SJ. Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease. Nat Genet 2001; 29: 404-411.
20. Lach B, Joshi SS, Murty N, Huq N. Transformation of Merkel cell carcinoma to ganglioneuroblastoma in intracranial metastasis. Human Pathol 2014; 45: 1978-1981.
21. Ljungberg MC, Sunnen CN, Lugo JN, Anderson AE, D’Arcangelo G. Rapamycin suppresses seizures and neuronal hypertrophy in a mouse model of cortical dysplasia. Dis Model Mech 2009; 2: 389-398.
22. Lok C, Viseux V, Avril MF, Richard MA, Gondry-Jouet C, Deramond H, Desfossez-Tribout C, Courtade S, Delaunay M, Piette F, Legars D, Dreno B, Saïag P, Longy M, Lorette G, Laroche L, Caux F. Brain magnetic resonance imaging in patients with Cowden syndrome. Medicine 2005; 84: 129-136.
23. Mooney SM, Siegenthaler JA, Miller MW. Ethanol induces heterotopias in organotypic cultures of rat cerebral cortex. Cer Cortex 2004; 14: 1071-1080.
24. Nair P, Pal L, Jaiswal AK. Lhermitte-Duclos disease associated with dysembryoplastic neuroepithelial tumor differentiation with characteristic magnetic resonance appearance of “tiger striping”. World Neurosurg 2011; 75: 699-703.
25. Nowak DA, Trost HA. Lhermitte-Duclos disease (dysplastic cerebellar gangliocytoma): a malformation, hamartoma or neoplasm? Acta Neurol Scand 2002; 105: 137-145.
26. Oberc-Greenwood MA, McKeever PE, Kornblith PL, Smith BH. A human ganglioglioma containing paired helical filaments. Hum Pathol 1984; 15: 834-838.
27. Okunaga T, Takahata H, Nakamura M, Iwasaki K. A case report of Lhermitte-Duclos disease with systematic AVMs. No To Shinkei 2003; 55: 251-255.
28. Omulecka A, Lach B, Alwasiak J, Gregor A. Immunohistochemical and ultrastructural studies of stromal cells in haemangioblastoma. Folia Neuropathol 1995; 33: 41-45.
29. Ortiz O, Bloomfield S, Schochet S. Vascular contrast enhancement in Lhermitte-Duclos disease: case report. Neuroradiology 1995; 37: 545-548.
30. O’Rourke DJ, Twomey E, Lynch S-A, King MD. Cortical dysplasia associated with the PTEN mutation in Bannayan Riley Ruvalcaba syndrome: a rare finding. Clin Dysmorphol 2012; 21: 91-92.
31. Pang T, Atefy R, Sheen V. Malformations of cortical development. Neurologist 2008; 14: 181-191.
32. Perez-Nunez A, Lagares A, Benitez J, Urioste M, Lobato RD, Ricoy JR, Ramos A, González P. Lhermitte-Duclos disease and Cowden disease: clinical and genetic study in five patients with Lhermitte-Duclos disease and literature review. Acta Neurochir 2004; 146: 679-690.
33. Sen A, Thom M, Martinian L, Harding B, Cross JH, Nikolic M, Sisodiya SM. Pathological tau tangles localize to focal cortical dysplasia in older patients. Epilepsia 2007; 48: 1447-1454.
34. Shanley DJ, Vassallo CJ. Atypical presentation of Lhermitte-Duclos disease: preoperative diagnosis with MRI. Neuroradiol 1992; 34: 103-104.
35. Sonoda Y, Mukai H, Matsuo K, Takahashi M, Ono Y, Maeda K, Aki­yama H, Kawamata T. Accumulation of tumor-suppressor PTEN in Alzheimer neurofibrillary tangles. Neurosci Lett 2010; 471: 20-24.
36. Takei H, Dauser R, Su J, Chintagumpala M, Bhattacharjee MB, Jones J, Adesina AM. Anaplastic ganglioglioma arising from a Lhermitte-Duclos-like lesion. J Neurosurg 2007; 107: 137-142.
37. Tan W-H, Baris HN, Burrows PE, Robson CD, Alomari AI, Mulliken JB, Fishman SJ, Irons MB. The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management. J Med Genet 2007; 44: 594-602.
38. Thom M. Epilepsy Part I: Cortical Dysplasia. In: Pathology and Genetics: Developmental Neuropathology. Golden J, Harding B (eds.). 1st ed. ISN Press, Basel 2004; pp. 61-66.
39. Tuli S, Provias JP, Bernstein M. Lhermitte-Duclos disease: literature review and novel treatment strategy. Can J Neurol Sci 1997; 24: 155-160.
40. Wisniewski K, Jervis GA, Moretz RC, Wisniewski HM. Alzheimer neurofibrillary tangles in diseases other than senile and presenile dementia. Ann Neurol 1979; 5: 288-294.
41. Wolansky LJ, Malantic GP, Heary R, Maniker AH, Lee HJ, Sharer LR, Patel UJ. Preoperative MRI diagnosis of Lhermitte-Duclos disease: case report with associated enlarged vessel and syrinx. Surg Neurol 1996; 45: 470-476.
Copyright: © 2016 Mossakowski Medical Research Centre Polish Academy of Sciences and the Polish Association of Neuropathologists. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
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