Background
Case presentation
1999 | A 12-year-old girl with negative medical history presents with vestibular syndrome lasting three weeks |
1999–2006 | After having experienced several relapses with various symptoms (paresthesias of her left and right upper limbs, paresthesias of her distal limbs, weakness of upper limbs), she fulfilled McDonald criteria for definite relapsing-remitting MS due to demyelinating lesions in MRI (Fig. 1a, b, c), positive oligoclonal bands type 2 in cerebrospinal fluid (CSF) and positive visual evoked potentials (VEP). |
2006 October | Several rounds of intravenous boluses of methylprednisolon were effective and the patient improved. When she started treatment by interferon beta Ia (Rebif® Merck-Serono), her Expanded Disability Status Scale (EDSS) was 2.0. |
2008–2009 | The treatment was interrupted due to her pregnancy in February 2008. In January 2009 she gave birth. During the early postpartum period the patient’s neurological status was unstable. |
2009 January to April | The patient suffered three relapses (sensitive symptoms, left-sided hemiparesis, paraparesis of distal limbs) and her EDSS increased to 4.0 although she obtained several rounds of intravenous methylprednisolon. |
2009 May | She resumed interferon beta Ia (Rebif® Merck-Serono) and reached remission. |
2011 March to May | Her disease progressed again, her EDSS increased to 4.5 and follow-up MRI reflected clinical activity (Fig. 2a, b). Central quadruparesis was more pronounced in her left limbs and spinal ataxia varied over time between a need of assistance when walking longer distances and mild deficit. She responded well to intravenous methylprednisolon rounds. |
2012 August | To stop the disease progression, she was indicated to natalizumab (Tysabri® Biogen Idec), receiving 12 infusions (august 2012 - september 2013). |
2013 September | The follow-up brain 3.0 Tesla MRI showed enlargement of the lesion in the right frontal lobe, evaluated by radiologists as PML (Fig. 3a, b, c, d). We also noticed seroconversion of JCV antibodies, but JCV index was low (0.38) and CSF PCR of DNA revealed no copies of JCV (Focus diagnostics, CYPRESS, California, USA). |
2013 December | Not meeting Slovak indication criteria, the patient ceased taking natalizumab. The patient started treatment with fingolimod (Gilenya® Novartis Pharmaceuticals UK). At that time she was quadruparetic, more prominent on the left side. She needed assistance due to wide-based gait and she had intermittent headaches (mild to moderate congestive-dull or pulsating headache located in bi-temporal areas, partially alleviated by analgesics) EDSS was 5.0. |
2014 February | A follow-up 3.0 Tesla MRI of the brain showed enlargement of the prior frontal lobe lesion (Fig. 4a, b, c), misinterpreted as PML again. A new CSF examination showed normal proteinorhachia (0.22g/l) and cellularity (1lymphocyte), not increased lactate (1.91 mmol/l), positive oligoclonal bands type 2 (14 bands), and increased IgG index 1.44. The PCR test of DNA JCV was negative again (0 copies UNILABS, Denmark). We decided to continue with fingolimod. |
2014 December | Over the following several months she developed new clinical symptoms: headache, sporadic epileptic seizures, disorientation. Immunomodulatory treatment was stopped. Repeated MRI was comparable with the MRI from February 2014, the atypical lesion in the right frontal lobe was in mild progression. |
2015 May |
1H-magnetic resonance spectroscopy (1H-MRS) detected decreased creatin to cholin ratio in several small areas of the frontal lobe, possibly suggesting tumorous mass (Fig. 5) Brain biopsy of the tumefactive lesion from the right frontal lobe. Histopathological findings revealed presence of anaplastic astrocytoma (Fig. 6a, b, c, d, e) |
2015 June | The patient needed anti-oedematous (dexamethason or methylprednisolon, boluses of manitol) and anti-epileptic therapy (valproic acid and levetiracetam) due to repeated secondary generalized epileptic seizures and intracranial hypertension syndrome. |
2015 August | Before starting oncological treatment, 11methyl-methionine positron emission tomography (11C MET PET) showed cortical localization of the brain tumor (Fig. 7). Patient’s condition remained unstable due to frequent epileptic seizures. Three weeks later she suddenly died during status epilepticus (23/Aug/2015). |
Discussion and conclusions
TDL | malignant GT | PML | PML-IRIS | References | |
---|---|---|---|---|---|
Clinical sy | motor, cognitive (aphasia, apraxia, agnosia, Gerstman, coma) sensitive, cerebellar, brain stem. Visual field defects, Epileptic seizures | epileptic seizures, cognitive and memory deficit, motor, sensitive. |
altered mental status (aphasia), motor, limb and gait ataxia, visual symptoms: homonymous hemianopia, cortical blindness, diplopia. Epileptic seizures. No optic nerve and spinal cord involvement.
|
altered mental status (aphasia), motor, limb and gait ataxia, visual symptoms: hemianopia, cortical blindness, diplopia. Epileptic seizures. No optic nerve and spinal cord involvement
| |
MRI T2w/
FLAIR
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Unilateral or bilateral. Frontal, parietal. Periventricular, juxta cortical. 2 cm, large lesion with little mass effect and edema
Variable rate of hyper-intensity.
Central dilated vessel.
Irregular border. Supra-tentorial WM, partially GM involvement.
|
Unilateral. Supra-tentorial.
Hyper or hypo intense.
Irregular border. Central necrosis.
Intensive vascular edema and mass effect
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Bilateral. Supra-Intra-tentorial. Cortex, deep gray matter. (Frontal, parietal, occipital. Subcortical location, U-fibers, cortex, basal ganglia). 3 cm.
Early new lesions. Hyper-intense. Ill-defined to WM, sharp to GM.
No mass effect. Punctuate perilesional lesions.
|
Bilateral, spreading. Cortex and subcortical WM. Edema
| |
MRI T1w
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Hypo-intense.
CT- hypo-intensity
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Hypo-intense. CT-hypo-intensity
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Hypo-intense.
CT-hypo intensity
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Hypo-intense
with hyper- intense rim
| |
MRI Gd +
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incomplete rim enhancement
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complete rim enhancement
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negative or variable, punctuate and rim like
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positive or variable, punctate and rim like
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MRI - PWI, DWI
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decreased PWI in lesions, increased DWI in active demyelination
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increased PWI, increased DWI in central necrosis
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DWI always hyper-intense, with peripheral rim.
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+/− restricted DWI
| |
1H- MRS
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increased Cho, lipids, lactate, mildly decreased NAA and NAA/Cr (differ from malignant GT)
elevation of the β,γ-Glx peaks
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increased Cho and Cho/Cr, lipids, lactate, decreased NAA, lack of β,γ-Glx elevation
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A decrease of NAA/Cr ratio, NAA and Cr. An increase of Lac/Cr, Cho/Cr, Cho, lipids/Cr, mIns, Lac, Lip.
|
increased Cho, decreased NAA, the presence of Lac/lipids at 1.3 ppm, and the presence of mIns, Higher Cho/Cr, mIns/Cr, Lip1/Cr, and Lip2/Cr in PML-IRIS than PML .
Lower NAA/Cr than PML.
| |
CSF native
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normal or mild increased proteinorhachia and white blood count.
Positive oligoclonal bands, elevated IgG index
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GFAP+ cells
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mildly increased cellularity, normal proteinorhachia
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mild to moderate increase of lymphocytes and protein levels
| |
CSF JCV DNA
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negative, infrequently low positivity (less than 25)
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negative? unknown
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JCV-specific IgG, DNA copies, infrequently negative
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JCV-specific IgG, DNA copies. Sometimes negative
| |
Response to corticoids
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very good
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only partial
|
none
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good
| |
Histology
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Hyper-cellularity, myelin protein-laden macrophages, variable lymphocytic inflammation, reactive gliosis and relative axonal preservation.
| moderate cellularity, bizarre cells with hyperchromatic nuclei, moderate pleomorphic, gemistocytes, perivascular lymphocytes, rare areas of necrosis, neo-vascularization GFAP + cells: immature,
reactive, and neoplastic astrocytes and ependymal cells
| swelling of oligodendrocyte and multi-lobular astrocytes, basophilic nuclei, eosinophilic inclusion bodies, 2/3 of number of T cells in PML-IRIS.
Positive DNA JCV staining in all types of cells. Active gene copies in high numbers of virally infected cells, as well as a low inflam- matory infiltrate.
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Hyper-cellularity, CD8+ positive T cells dominate - their number the same as in active MS lesions, fewer CD4+ and CD20+ T cells in perivascular cuffs.
High plasma and B cells in PML-IRIS-lesions.
No or low number JCV-infected cells.
| |
Outcome
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as typical MS
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progressive worsening
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progressive worsening
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worsening, regression possible
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Immunological markers in peripheral blood | upregulation of transcription factors of Th1 (pSTAT1 and T-bet) and Th17 (pSTAT3) in circulating CD4+, CD8 + T-cells and monocytes. CD4+ T-cells with a proinflammatory Th1 and Th17 phenotype, |
lower T-bet, pSTAT1, and pSTAT3 in CD4+, CD8 + T-cells, and monocytes. Lower CD4 Th1 and Th17. Increased IL-10, TGF-β, PGE2, down modulation of co-stimulation molecules by APCs. Tumor angiogenesis, expression of CD34+ progenitor cells.
Deficit of NK cells
|
variable data: stable CD4+ and CD8+, non-significant decrease or increased T cells but unchanged CD4/CD8 ratio. Decrease expression of CD49d, CD29 (VLA-4), CD11a, CD62L, CXCR3 on T cells. Decreased expression of VLA4 on myeloid dendritic cells, decreased count of dendritic cells. Production of CD34+ cells, increase of memory B cells. Increased IL-10.
| Increased IFN-γ, IL-12p70, IL-4, IL-10, IL-5, IL-13. CD4+,T1 + PSTAT3+, CD8+, PSTAT1+,T-bet + . Decreased CD4+, CD25+ FoxP3+ |