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

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Neurology Case Presentation

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Neurology Case Presentation

Rawan Albadareen, MD

PGY-3

5/17/2013


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


  • PMHx,

    • HTN

    • HLP

    • GERD

    • ALL

    • Hypothyroidism

  • PSHx,

    • Cholecystectomy

  • FHx

    • Non contributory

  • SHx,

    • Nonsmoker

    • Nonalcoholic

    • married


Physical exam

Mental status:alert, oriented to person/place/time


  • 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)


  • Where ?

  • What?


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


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.


  • 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


    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


    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.


    DWI changes.. ADC matching..

    Stroke or not a Stroke…

    That is the question??


    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


    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.


    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


    Thank You!!


    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


    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


    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


    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).


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