No	Study/Author	Year	Age – Gender	Diagnosis	Route of administration	Signs and symptoms of neurotoxicity	Imaging findings	Onset – timing	Management	Outcome
1	Ayalon I et al.[14]	2019	14-M	Osteosarcoma of the Rt tibia	IV -HDMTX	-status epilepticus/ tonic-clonic seizure -altered mental status -fever	MRI: subtle diffusion restriction in the posterior subcortical white matter, more prominent on the Lt periventricular white matter, extending to the parietotemporal and centrum semiovale area - apparent diffusion coefficient map	5 days after 2^nd dose	-aminophylline (2.5 mg/kg/dose per day for 4 days) -high-dose steroids (dexamethasone).	Minimal residual neurological deficits (anisocoria, facial asymmetry, and instability on tandemk gait)
2	Cruz-Carreras MT et al.[20]	2017	2nd patient 17-F	osteosarcoma of the Rt femur	IV -HDMTX & calcium leucovorin rescue	-slurred speech -weakness -numbness on the Rt side of the face and Rt arm -flattening of the Rt nasolabial fold -absent gag reflex -Rt facial paralysis	MRI brain: area of restricted diffusion in the Lt corona radiate and centrum semiovale without any associated FLAIR signal abnormality or enhancement	5 days after a course of IV MTX	-aminophylline -DM (30 mg po) -leucovorin after the episode	-Symptoms resolved in 4 h but recurred after an MRI was performed, with Rt facial paralysis -Symptoms resolved completely 2 days after treatment
3	Afshar M et al.[29]	2014	14-F	Osteogenic sarcoma	IV HDMTX	-Waxing and waning sensorium and mild dysmetria	N/R	2 days after the last dose of MTX	-DM 2.5 mg/kg q.d. for 2 days	-Symptoms resolved in 24 h
4	Dropcho EJ.[12]	2011	12-M	osteosarcoma of the Rt femur	IV HDMTX	-confused and agitated -Lt arm and leg weakness -Rt arm weakness -mild lethargy -slurred speech	- CT scan: unremarkable - Brain MRI scan: 1. T2-weighted and FLAIR images: several areas of hyperintense signal in the centrum semiovale bilaterally, worse on the Rt side. The lesions did not enhance with gadolinium. 2. Diffusion-weighted and ADC images: consistent with acute cytotoxic edema	4^th day after the 3^rd cycle	- leucovorin -aminophylline IV	-Symptoms resolved completely in 7 days of onset
5	Müller J et al.[30]	2008	10-M	Osteosarcoma of the Lt fibula	HDMTX infusion	-somnolent -urinary incontinency -decreased reflexes -mild nystagmus -narrow pupils, but reactive to light	N/R	20 minutes after the end of the 1^st HDMTX infusion	-Parenteral dexamethasone - Forced diuresis with 4000ml/m² infusion with furosemide every 6 hours -Calcium folinate	-Neurological symptoms resolved in 24h
6	Inaba H et al.[31]	2007	Patient 1: 14-M	Patient 1: Osteosarcoma	Patient 1: IV HDMTX	Patient 1: -hemiparesis -bilateral weakness -dysphasia -confusion /emotionality	Patient 1: MRI (2 days after the onset): 1. Restricted diffusion on DWI 2. Increased T2 and/or FLAIR signal Anatomic locations: 1. Unilateral cerebral white matter (focal) 2. Bilateral corticospinal tracts in the internal capsule and midbrain (focal)	Patient 1: 8 days after the 5th course of HDMTX	Patient 1: -aminophylline -lorazepam	Patient 1: -Symptoms resolved in 3 days
7	Mittal R et al.[4]	2005	10-M	Osteosarcoma of the Lt proximal tibia	HDMTX & calcium leucovorine	-diplopia -one episode of seizures -disorientation -semiconscious -ophthalmological examinations: mild abnormality in the conjugate movements of the eyes, with essentially normal fundi	-CT brain: normal -MRI brain (14 days after the 5th dose of HDMTX): normal	3 days after the 5th dose of HDMTX	-oropharyngeal suction -oxygen was givenby face mask -moved to the ICU for supportive care	-Symptoms resolved completely in 48h
8	Drachtman RA et al.[15]	2002	Patient 1: 16-M Patient 2: 13-M	Osteogenic sarcoma both patients	IV HDMTX	Patient 1: -Dysarthria -CN VII palsy Patient 2: -Rt CN VII palsy -Lt hemiparesis -dysarthria -impaired gag	Patient 1: -MRI: normal -CT: normal Patient 2: -MRI: normal -CT: normal -MRA: normal	Patient 1: 7 days after last MTX Patient 2: 7 days after last MTX	Patient 1: DM 1 mg/kg x 1 Patient 2: DM 1 mg/kg TID	Patient 1: -Symptoms resolved in 30 minutes Patient 2: -Symptoms resolved in 3 days
9	Kiu MC et al.[21]	1994	16-M	Osteogenic sarcoma of the Lt femur	HDMTX infusion & leucovorin rescue	-alternative hemiparesis -dysarthria -intermittently stuporous, agitated, confused	CT brain: normal	5 days after the 2^nd course of HDMTX	-IV leucovorin 100mg (every 6h for 3 days)	-Symptoms resolved completely in 72h
10	Walker RW et al.[17]	1986	19 patients Age range: 13-42 14M/5F	osteogenic sarcoma (8 patients with lung metastases)	IV HDMTX & leucovorin rescue -8 patients: IV vincristine 1 day following the HDMTX -6 patients: were treated with bleomycin, cyclophosphamide, and dactinomycin	-behavioral abnormalities (inappropriate laughter, lethargy, unresponsiveness) -focal sensorimotor or reflex signs (mono- or hemiparesis with aphasia +/- paresthesia or numbness) -generalized seizures -signs alternated from one side to the other	CT brain: normal	-1-13 days after treatment -after 1 dose: 1 patient -after 2 doses: 9 patients -after 3 doses: 3 patients -after 4 doses: 4 patients -after 5 doses: 1 patient -after 6 doses: 1 patient	No specific treatment	-Usually lasted from 15 minutes to 72 hours -Resolved abruptly
11	Jaffe N et al.[19]	1985	9 patients average age 12 years (3F/6M)	Osteosarcoma	HDMTX-CFR *Patient 2: concurrently with cisplatin	Patient 1: a) -Lt Facial weakness -Lt upper limb paresis -sleepy -uncooperative -no response to painful stimuli b) -Rt Facial weakness -speech impediment-Broca-type aphasia -Rt hemiparesis Patient 2: a) -Speech impediment -Lt upper extremity weakness b) -Rt Facial weakness -Rt upper limb paralysis -dystonic movements -speech impediment -emotional disturbances Patient 3: a) Focal facial seizure, loss of consciousness b) Generalized seizure Patient 4: a) -twitching of hand and eyebrow -nystagmus -convulsion and loss of consciousness -status epilepticus with Lt frontal cerebral predominance b) Convulsion Patient 5: a) Generalized seizure lasting approximately 1h b) Status epilepticus lasting 1-2 days Patient 6: Rapidly progressive ascending neuromuscular paralysis extending to bulbar area Patient 7: Generalized seizure, loss of consciousness Patient 8: Grand mal seizure, intermittent loss of consciousness for 24 hr Patient 9: -bitemporal headache -weakness Lt arm -slurring of speech	Patient 1: CT scan: normal Patient 2: CT scan: normal Patient 3: CT scan: normal Patient 4: CT scan: Slight enlargement of ventricles Patient 5: CT scan: normal Patient 6: CT scan: normal Patient 7: CT scan: normal Patient 8: CT scan: normal Patient 9: CT scan: normal	Patient 1: a) day 5 (2) * b) day 4-5 (7) Patient 2: a) day 16 (4) b) day 9 (5) Patient 3: a) day 6 (39) b) day 1 (40) Patient 4: a) day 2 (2) b) day 26 (6) Patient 5: a) day 6 (9) b) day 4 (11) Patient 6: day 7 (N/R) Patient 7: day 50 (20) Patient 8: day 4 (15) Patient 9: day 8 (6)	N/R	-Symptoms resolved in all patients -HDMTX-CF treatment was reinstituted in all patients -Recurrent neurologic dysfunction in 5 of the 9 patients. -Complete resolution in all patients again. -No permanent neurologic deficit
12	Fritsch G et al.[32]	1984	12-F	Osteogenic sarcoma of the Rt humerus metastatic to the Rt lung	HDMTX infusion	-slurred speech -unable to swallow -bilateral paresis of the external rectus eye muscles -ataxia -Rt hemiparesis	CT scan: -16 days after the HDMTX infusion: periventricular hypodensity, particularly around the frontal horns -14 months after the HDMTX infusion: areas of decreased attenuation around the frontal horns, and a hypodense lesion in the left temporal lobe	9h after the completion of the 11th HDMTX infusion	-calcium leucovorin I00 mg every 3 hours -forced diuresis	-Symptoms resolved completely after 30 hours -Five years after the episode: absent deep tendon reflexes, no other sign of neurologic dysfunction
13	Packer RJ et al.[22]	1983	Patient 1: 6-F Patient 2: 18-F	Patient 1: osteogenic sarcoma of the Lt femur Patient 2: osteogenic sarcoma of the Lt distal femur metastatic in the lung	Patient 1: HDMTX-CFR Patient 2: HDMTX-CFR	Patient 1: -brief trance-like episodes without loss of postural tone or associated motor movements and intermittent episodes of visual loss - unconsciousness followed by Lt body tonic-clonic seizure -Examination: Lt hemiparesis involving face and arm greater than leg without sensory loss. Patient 2: -Lt sided weakness of the face, arm, and leg and decreased sensation of the Lt arm. -Examination: slurred speech without aphasic difficulties and Lt hemiparesis involving face, arm, and leg equally	Patient 1: -CT brain: a large noncontrast enhancing hypodense lesion in the Rt posterior frontal lobe - Contrast-enhanced CT and a brain scan (10 days later): normal Patient 2: -Contrast-enhanced CT: normal -Brain scan (4 days later): normal - Contrast-enhanced CT (10 days later): normal	Patient 1: 5 days after the 3^rd course of HDMTX-CF Patient 2: 6 days after the 2^nd dose of HDMTX-CF	Patient 1: -Valium -phenobarbital -phenytoin Patient 2: N/R	Patient 1: -Symptoms resolved completely -Within one hour: fully alert, oriented and seizure free. -Cleared her hemiparesis over 72 hours. Patient 2: -Symptoms resolved in 5 days
14	Allen JC et al.[18]	1978	Patient 1: 22-M Patient 2: 21-M Patient 3: 13-F Patient 4:18-M	Patient 1: osteogenic sarcoma of the Rt femur Patient 2: osteogenic sarcoma of the Rt pelvis Patient 3: osteogenic sarcoma of the Lt humerus Patient 4: osteogenic sarcoma of the Rt femur	Patient 1: VCR HDMTX CFR Patient 2: VCR HDMTX CFR Patient 3: BCD 4 bi-weekly HDMTX CFR VCR Patient 4: BCD VCR HDMTX CFR	Patient 1: -Rt hemiparesis and aphasia -Lt hemiparesis with Lt sided focal seizures Patient 2: -Lt gaze palsy -Lt hemiparesis -dysarthria -bilateral Babinski signs -intermittently stuporous, agitated, and confused Patient 3: -headache, dizziness, photophobia, and fever -Lt hemiparesis -Rt hemiparesis -dysarthria -extreme emotional agitation Patient 4: -dysarthria -dysphasia -palsies of the Lt 9^th, 10^th,11^th, and 12^th cranial nerves -Lt hemiplegia, and Lt hemianesthesia	Patient 1: -Contrast-enhanced CT head: normal. -Bilateral carotid angiogram: normal Patient 2: -Contrast-enhanced CT head: normal. -CAT scan (10 months later): area of decreased density in the Rt frontal lobe, consistent with old ischemic infarction. Patient 3: Contrast-enhanced CT head: normal CT scan (3 months later): normal Patient 4: -Contrast-enhanced CT head: normal -CT scan (6 months later): normal -Bilateral carotid angiography: normal	Patient 1: 13 days after the 2^nd course of CMT Patient 2: 32 days after the 1^st course of BCD/ 10 days after the 3^rd course of HDMTX Patient 3: 2 months after the last BCD/8 days after the 4^th course of HDMTX Patient 4: 14 days after the 1^st BCD / 9 days after the 1^st course of VCR/HD MTX	Patient 1: N/R Patient 2: heparinization for 72 hours Patient 3: N/R Patient 4: N/R	Patient 1: -Gradually improved -Residual mild Rt hemiparesis Patient 2: -Symptoms resolved completely in 3 days -Died of metastatic disease 18 months later -Autopsy: no gross or microscopic abnormalities of the brain Patient 3: 3 months later: mild Rt hemiparesis Patient 4: Symptoms resolved completely