Neurology Case Presentation

1. Neurology Case Presentation Rawan Albadareen, MD PGY-3 5/17/2013

2. Clinical presentation • A 58 YO female with pre-B cell acute lymphoblastic leukemia (Philadelphia chromosome positive) w CNS involvement. • She was undergoing CTX high dose MTX-Ara-C . • Three days after last IT MTX, she complained of dysarthria and Lt sided weakness that fluctuated over the course of the day, started at 3 am that morning and by the time of evaluation around 3 pm was almost back to base line. • Worth mentioning this had happened three times in the past and was associated with CTX. The first time this happened the episode was associated with confusion and picture of encephalopathy. • Pt as well has tremors and distal numbness along with dryness of mouth and eyes

3. PMHx, • HTN • HLP • GERD • ALL • Hypothyroidism • PSHx, • Cholecystectomy • FHx • Non contributory • SHx, • Nonsmoker • Nonalcoholic • married

4. Physical exam Mental status:alert, oriented to person/place/time

5. Motor: 5-/5 on the Lt side compared to 5/5 on the Rt (improved strength) • Sensory; Intact to LT, glove and stocking distribution to pin prick • Reflexes: • Coordination: normal FTN, HTS, rapid alternating (resolved ataxia)

6. Where ? • What?

7. Diagnostic studies.. • CSF cytology: -ve for malignant cells, 0 WBC/RBC, Normal Glucose/protein • Infectious w/u: negative cultures and titers. • MRI Brain 7/2/12 (at the time of initial diagnosis): • Essentially unremarkable

9. MRI Brain 12/6/12 (time of presentation) • Development of patchy and confluent areas of FLAIR hyperintinsity predominantly involving the deep bifrontal hemispheric white matter consistent with moderate nonspecific white matter disease. • Leading diagnostic consideration include ADEM, chemotherapy induced necrotizing leukoencephalopathy or viral encephalitis. PML is an additional less likely consideration • No acute or recent infarct.

10. Neurological complications of IT MTX • IT MTX is commonly associated with aseptic meningitis • In addition, IT administration is rarely associated with: • posterior reversible leukoencephalopathy syndrome, • seizures • subacute focal neurologic deficits • lumbosacral polyradiculopathy • noncardiogenic pulmonary edema • pneumonitis and sudden death

11. Leukoencephalopathy • Leukoencephalopathy is a delayed complication of IT MTX, usually occurring after six months of therapy and when the cumulative IT dose of MTX exceeds 140 mg • It is more likely in patients who receive concurrent whole brain radiotherapy or have previously received chemotherapy with intravenous MTX

13. Transient leukoencephalopathy after it mtx mimicking stroke. • Acute neurotoxicity with confusion, disorientation, seizures, and focal deficits may also be seen. • This can clinically mimic stroke with restricted diffusion on MRI. • However, unlike stroke, there is resolution of clinical and imaging findings within 1-4 weeks. • Lesions exceeded the confines of adjacent vascular territories • DWI findings seem to reflect cytotoxic edema within cerebral white matter suggesting a reversible metabolic derangement, rather than ischemia, as the basis for this syndrome.

14. DWI changes.. ADC matching.. Stroke or not a Stroke… That is the question??

15. Hyperperfusion on MRI in acute chemotherapy-related leukoencephalopathy • Magnetic resonance perfusion revealed mildly increased perfusion, a finding inconsistent with ischemic stroke. • Magnetic resonance perfusion imaging proved valuable to rapidly distinguish acute chemotherapy-related leukoencephalopathy from ischemia. • El-HakamLM, Ramocki MB, RivielloJJ,Illner A. Baylor College of Medicine

16. Is it preventable? • Prevention of neurotoxicity by high-dose folinic acid rescue after high-dose methotrexate and intrathecal methotrexate without compromising cure in spite of previous transient leukoencephalopathy after intrathecal methotrexate. • HamidahA, Raja Lope RJ, Abdul Latiff Z, Anuar ZM, Jamal R. • Ann Acad Med Singapore. 2009 Aug;38(8):743-4.

18. Cytarabine (Ara-c) • High doses of Ara-C can cause an acute cerebellar syndrome in 10 to 25% of patients • The pathogenesis of this syndrome is unknown, but there is widespread loss of Purkinje cells in the cerebellum. • Symptoms range in severity from mild ataxia to an inability to sit or walk unassisted. Rarely, seizures develop. • Less frequent complications • peripheral neuropathies, • brachial plexopathy, • encephalopathy, • lateral rectus palsy, • optic neuropathy • extrapyramidal syndrome

20. Thank You!!

21. Mechanism of action • Interference with folate metabolism • Several key enzymes of these synthetic pathways are targets of MTX: • Dihydrofolatereductase (DHFR) • Thymidylatesynthetase (TS) uses a methyl group from the reduced folate (dUMP) to (dTMP). • MTX is considered an S-phase specific cytotoxic drug. • The level of DHFR in any given cell is in great excess of what is needed to provide normal levels of reduced folates • 95% DHFR needs to be blocked, reason behind the need for HDMTX

22. Importance of polyglutamation • Increases the intracellular pool of folates, (not easily transported out of the cell because of their size and charge -continual cellular uptake of folates) • The accumulation of PGMTX metabolites serves to further amplify and prolong the antiproliferative effects of MTX: • Intracellular accumulation and decreased efflux of PGMTX enhances and prolongs inhibition of DHFR, since PGMTX is less readily dissociable from the enzyme than is free MTX • Polyglutamated forms of MTX also bind to other enzymes involved in DNA synthesis such as TS, AICARFT, and GARFT; this further depletes intracellular thymidine and inhibits purine synthesis

23. Rationale for leucovorin rescue • MTX has little selectivity for tumor cells, and its effectiveness is limited by toxicity to normal tissue. • Reduced folate to bypass the metabolic block induced by MTX within 24 to 36 hours. • Folatetransport is deficient in the malignant cells. • In contrast to tumor cells, comparatively little PGMTX synthesis occurs in normal gut epithelium and bone marrow precursors under similar conditions

24. Resistance to MTX • Innate resistance (AML ;no polyglutamination) • Acquired resistance: • Decreased drug transport due to gene mutations or a change in the rate of transcription of the folate carrier • Increased DHFR activity, typically due to gene amplification • Mutations in the DHFR protein, which decrease its affinity for MTX • Decreased cellular polyglutamation of MTX due to increased folylpolyglutamate hydrolase activity or decreased FPGS activity • Decreased TS activity or affinity for the folate antagonists • MTX is not typically used as a single agent for treatment of aggressive malignancy with some exceptions (primary CNS lymphoma, head and neck cancer, and malignant GTD).