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N EUROLOGY C ASE P RESENTATION Rawan Albadareen, MD PGY-3 5/17/2013.

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Presentation on theme: "N EUROLOGY C ASE P RESENTATION Rawan Albadareen, MD PGY-3 5/17/2013."— Presentation transcript:

1 N EUROLOGY C ASE P RESENTATION Rawan Albadareen, MD PGY-3 5/17/2013

2 C LINICAL 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 P HYSICAL EXAM NormalAbnormal Fluencyx Comprehensionx Articulation x Repetitionx Namingx NormalAbnormal IIPupils reactive, visual fields normal III, IV, VIEOMI, no nystagmus VSensation nml V1-V3 VII Orbicularis Oculi: 5 Orbicularis Oris: 5 Trace facial droop on the Lt VIIInml to finger rub IX, X+strong cough XIEqual shoulder shrug XIITongue midline 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) RightLeft Triceps00 Biceps11 Brachioradialistrace Patellatrace Ankle00 Plantarequivocal

6 Where ? What?

7 D IAGNOSTIC 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 B RAIN 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 N EUROLOGICAL 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 L EUKOENCEPHALOPATHY 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 T RANSIENT 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 H YPERPERFUSION 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-Hakam LM, Ramocki MB, Riviello JJ, Illner A.El-Hakam LMRamocki MBRiviello JJIllner A Baylor College of Medicine

16 I S 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.  Hamidah A, Raja Lope RJ, Abdul Latiff Z, Anuar ZM, Jamal R. Hamidah ARaja Lope RJAbdul Latiff ZAnuar ZMJamal R Ann Acad Med Singapore. 2009 Aug;38(8):743-4.Ann Acad Med Singapore.


18 C YTARABINE (A RA - 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 T HANK Y OU !!

21 M ECHANISM OF ACTION Interference with folate metabolism Several key enzymes of these synthetic pathways are targets of MTX: Dihydrofolate reductase (DHFR) Thymidylate synthetase (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 I MPORTANCE 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 R ATIONALE 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. Folate transport 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 R ESISTANCE 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 folyl polyglutamate 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).

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