May 17, 2013 - Rawan Albadareen

Report
NEUROLOGY CASE
PRESENTATION
Rawan Albadareen, MD
PGY-3
5/17/2013
CLINICAL PRESENTATION
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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
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PMHx,
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HTN
HLP
GERD
ALL
Hypothyroidism
PSHx,
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Cholecystectomy
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FHx
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Non contributory
SHx,
Nonsmoker
 Nonalcoholic
 married
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PHYSICAL EXAM
Mental status: alert, oriented to person/place/time
Fluency
Comprehension
Articulation
Repetition
Naming
Normal
x
x
Abnormal
x
x
x
Normal
II
Pupils reactive, visual fields normal
III, IV, VI EOMI, no nystagmus
V
Sensation nml V1-V3
Orbicularis Oculi: 5
VII
Orbicularis Oris: 5
VIII
nml to finger rub
IX, X
+strong cough
XI
Equal shoulder shrug
XII
Tongue midline
Abnormal
Trace facial droop
on the Lt
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Motor:
5-/5 on the Lt side compared to 5/5 on the Rt (improved strength)
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Sensory;
Intact to LT, glove and stocking distribution to pin prick
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Reflexes:
Triceps
Biceps
Brachioradialis
Patella
Ankle
Plantar
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Right
0
1
trace
trace
0
equivocal
Left
0
1
trace
trace
0
equivocal
Coordination:
normal FTN, HTS, rapid alternating (resolved ataxia)
Where
What?
?
DIAGNOSTIC STUDIES..
CSF cytology: -ve for malignant cells,
0 WBC/RBC, Normal Glucose/protein
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Infectious w/u: negative cultures and titers.
MRI Brain 7/2/12 (at the time of initial diagnosis):
 Essentially unremarkable
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MRI BRAIN 12/6/12
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Development of patchy and confluent
areas of FLAIR hyperintinsity
predominantly involving the deep
bifrontal hemispheric white matter
consistent with moderate nonspecific
white matter disease.
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(TIME OF PRESENTATION)
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:
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posterior reversible leukoencephalopathy syndrome,
seizures
subacute focal neurologic deficits
lumbosacral polyradiculopathy
noncardiogenic pulmonary edema
pneumonitis and sudden death
LEUKOENCEPHALOPATHY
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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.
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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.
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• El-Hakam LM, Ramocki MB, Riviello JJ, Illner A.
Baylor College of Medicine
IS IT PREVENTABLE?
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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.
• Ann Acad Med Singapore. 2009 Aug;38(8):743-4.
CYTARABINE (ARA-C)
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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
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peripheral neuropathies,
brachial plexopathy,
encephalopathy,
lateral rectus palsy,
optic neuropathy
extrapyramidal syndrome
THANK YOU!!
MECHANISM OF ACTION
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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
IMPORTANCE OF POLYGLUTAMATION
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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
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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
RESISTANCE TO MTX
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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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