INTRODUCTION
Tumefactive demyelination of the central nervous system (CNS) can mimic central nervous system infections, tumours and other space occupying lesions of the CNS, posing a diagnostic dilemma and frequently leading to either unnecessary resective surgery or the requirement of a brain biopsy to correctly diagnose these lesions. (1)
Tumefactive Demyelinating Multiple Sclerosis (TDMS) is defined as lesions that are acute in onset, more than 2cm in diameter, with accompanying oedema, mass effect and variable degree of enhancement post gadolinium administration(2). The prevalence of TDMS is estimated to be 1-3/1000 cases of MS. Given that only 4.4% of MS cases present in children under the age of 16 and 0.3% under the age of 10 years, the prevalence of TDMS in this population is exceptionally low.
To date the literature on TDMS in children is scanty with only 79 published cases reported in the world literature (3) and as far as we are aware this is the first reported case in South Africa. This small number of cases underscores the need for more awareness of the entity and in particular the awareness of the ability of neuroimaging to accurately diagnose these lesions without the need of histopathological confirmation.
CASE REPORT
A 13-year-old female was referred to our institution with a 3 month history of sudden-onset left sided weakness and mild headache. On clinical examination, the child had grade 3/5 weakness of the arm and leg, with a hemiplegic gait. Other examination was unremarkable.
A Computer Tomography Brain (CTB) done at the referring institution demonstrated a ring- enhancing lesion based in the right parietal lobe, involving the grey and deep white matter, abutting the right lateral ventricle. There was no mass-effect associated with the lesion.
An MRI performed at our institution demonstrated a well-circumscribed 3 cm (TV) x 5 cm (AP) x 3.8 cm (CC) white matter lesion in the right posterior parietal lobe. Post contrast administration, there was incomplete ring enhancement with corresponding peripheral restricted diffusion on DWI. See Figure 1.
Magnetic resonance imaging with contrast. (a) Sagittal T1 weighted image demonstrating a well-circumscribed hypointense lesion in the right parieto-occipital lobe with no significant mass effect. (b) The lesion is hyperintense on T2-weighted sequence with clear involvement of white matter while sparing the cortex. (c.) On Fluid Attenuated (FLAIR) sequence the lesion is centrally hypointense and peripherally hyperintense. (d) There is peripheral restricted diffusion seen on Diffusion Weighted imaging (corresponding hypointensity on ADC map). Post contrast administration (e, f) demonstrated a “leading-edge”of peripheral enhancement
Assuming a CNS tumour and due to the eloquent location of the lesion the patient was offered surgery, which took the form of an awake craniotomy and tumour excision.
Intraoperative histology was in keeping with a low grade astrocytoma, with formal post-operative histopathological examination confirming a Gemistocytic astrocytoma, WHO grade 2, with numerous foamy macrophages, chronic inflammatory cells and perivascular lymphocytic cuffing. No necrosis was noted. The child responded well to surgery and with rehabilitation was able to ambulate independently and made a good clinical recovery with resolution of her left sided weakness. Post-operative MRI demonstrated post-surgical changes with what was thought to be a small residual lesion. A multidisciplinary team decision was made to repeat the MRI 3 months later. However, the patient presented within 2 months with acute worsening of the left side weakness and complaints of urinary incontinence. Repeat MRI demonstrated extensive ipsilateral disease progression, the lesion crossing the midline with callosal involvement. The spine MRI demonstrated an expansile long segment intramedullary T2WI high signal intensity extending from T2 to T8 level with peripheral enhancement post contrast administration. No leptomeningeal enhancement was noted. See Figure 2.
Subsequent imaging pre and post contrast administration. (a) T1-weighted sagittal image demonstrating disease progression with the lesion extending to the occipital lobe with (b)peripheral incomplete ring enhancement. (c, d) Sagittal and axial images where the lesion crosses the midline to involve the corpus callosum. (e) Sagittal T2-weighted image of the thoracic spine shows a long segment expansile intramedullary high signal intensity with peripheral enhancement (f) post contrast administration
Due to the extensive nature of the recurrent lesion, doubt was raised as to the accuracy of the original histological diagnosis. A second opinion was sought regarding the histopathology.
On review the following features were described: (Figure 3) a well circumscribed, non-encapsulated, non-infiltrative lesion was represented in the biopsy, it consisted of sheet-like aggregates of foamy histiocytes (CD 68 positive) replacing normal cerebral parenchyma with adjacent perivascular aggregates of bland lymphocytes (LCA positive), some neovascularization and red blood cell extravasation. The adjacent cerebral parenchyma showed reactive gemistocytic astrocytes (GFAP positive), aligned around the lesion at the interface between lesional tissue and surrounding cerebral parenchyma, with a very low proliferation index (Ki67<1%).
Light miscroscopy findings: (a) H&E Low power (b) H&E High power (400x) (c) H&E (200x) (d) GFAP staining reactive gemistocytic astrocytes (e) CD68 staining histiocytes (f) Tol Blue showing area of demyelination
Special stains (Pas, Ziehl Neelson, Pas-D and Grocott) were negative for infective organisms. A Luxol-fast blue stain confirmed loss of myelin within the lesion with aggregated Luxol fast blue staining in the foamy histiocytes. Myelin oligodendrocyte glycoproteins unfortunately could not be determined for, as the stain was not available at the reviewing histology laboratory. The overall histological features were thus supportive of a demyelinating process resulting in a circumscribed mass-like focus.
Based on this new diagnosis of TDMS, the child was started on high dose prednisone according to the protocol for treatment of MS, and a dramatic response was noted with resolution of the urinary complaints within one week. The child started to mobilize independently again, and at 6 months follow up has had complete resolution of all her neurological deficits. Follow up imaging revealed significant regression of both the spinal and intracranial lesions.
DISCUSSION
Tumefactive demyelinating lesions can mimic intracranial neoplasms both clinically and radiologically. Single dominant TDMS lesions in particular are often misdiagnosed as brain tumours (4) and several instances of patients being subjected to surgery, as was the case in this case report, and even adjuvant radiation and chemotherapy have been reported. (1)
There are no pathognomonic imaging signs to unequivocally diagnose tumefactive multiple sclerosis and as such a combination of a high index of suspicion, clinical features and combined imaging modalities are required to make a presumptive diagnosis and thus potentially prevent unnecessary surgery or diagnostic delays.
A careful history with emphasis on previous transient neurological signs not referable to a specific site in the CNS points to a diagnosis of MS (2). In our case, prior to the onset of her motor deficit, the patient had been previously well, with no prior neurological symptoms. Perez et al (3) found that headaches were the most common presenting complaint which although nonspecific in nature may point to a diagnosis of demyelination rather than neoplasm.
Classic TDMS lesions are often multiple, usually affect the white matter but may involve the cortex, demonstrate enhancement and varying degrees of mass effect and necrosis, (1,4) all of which may be mistaken for neoplasms. As is seen in our case, and highlighted by Algahtani et al, (2) the presence of a solitary mass lesion makes differentiation of neoplasm from TDMS more challenging. In a series of 31 children, solitary lesions were seen in only 16% of cases (5). The administration of contrast does not necessarily reliably differentiate neoplasia from demyelination as in both instances there is breakdown of the blood brain barrier. The pattern of enhancement is however of value, as enhancement on T1W sequences of the lesion typically has a “leading edge” and is predominately on the side of the lesion that is closest to the ventricles: the so called “open ring configuration” (2,3) in cases of TDMS. Additionally, TDMS lesions do not often cause mass effect, being found in only 45% of cases. (1) Perilesional oedema is somewhat less predictive however as up to 77% of TDMS may demonstrate this phenomenon (1).
Dynamic contrast-enhanced T2*-weighted imaging allows the measurement of cerebral blood volume providing accurate information regarding lesion vascularity. Neovascularization and angiogenesis are observed in neoplasms whereas demyelinating lesions have normal vasculature. Cha et al (4) found a statistically significant difference in relative cerebral blood volume in patients with TDSM versus patients harboring neoplastic lesions and concluded that this may be used to differentiate TDMS from neoplasms and “obviate any surgical intervention” to gain a diagnosis.
The addition of CT scan to the MRI scan is of significant value. Kim et al (6) conducted a study in an attempt to distinguish tumefactive demyelination from CNS neoplasms using a combination of uncontrasted CT scan and contrasted MRI. Multiple MRI parameters alone were assessed including signal intensities on different sequences, enhancement pattern, presence of vasogenic oedema, mass effect and location including cortical or white matter involvement. They concluded that MRI alone did not have high accuracy in distinguishing between TDMS from gliomas and lymphomas, as independently or in combination these parameters yielded low specificity. However, when they combined uncontrasted CT and contrasted MRI, the accuracy of diagnosis was statistically significantly improved, with a diagnostic accuracy rate of CT plus MRI vs MRI alone, being 97% vs 73% respectively. In particular the presence of CT hypoattenuation of MRI enhancing lesions was highly specific in distinguishing TDMS from neoplasia (6).
In their systematic literature review Perez et al (3) estimated that by using the features, more or less as we describe above, about one third of patients may not need invasive diagnostic procedures. A substantial number of procedures may thus potentially be avoided, however, as they point out “consensus guidelines for the diagnosis and treatment of tumefactive demyelinating lesions in children” are still required.
CONCLUSION
This case highlights the difficulties of differentiating between demyelination and neoplasm in children. TDMS has a widely different course and outcome when managed appropriately. In conclusion, a high clinical index of suspicion combined with advanced imaging and a multidisciplinary approach cannot be overemphasized. With the above approach, a significant number of children may be spared invasive and treatment-delaying invasive procedures.