SEVERE, DISABLING NEUROLOGIC TOXICITY
FOLLOWING CISPLATIN RETREATMENT
Gerald M. Riga, Tamara C. Wise, and Edward B. Crowell

OBJECTIVE: To describe a severe neurotoxic reaction following the

second cycle of cisplatin-based chemotherapy.
CASE SUMMARY: A patient with unresectable non-small-cell lung
cancer was treated with combined chemotherapy and radiotherapy.
Thirty-six hours after the second course of chemotherapy, the
patient developed severe mental status changes consisting of
aphasia, confusion, and agitation. Complete neurologic workup was
most consistent with an acute vascular event.
DISCUSSION: Reports of acute cisplatin-induced neurologic toxicity

involving the central nervous system are rare. Potential risk factors

are described. Mechanisms of chemotherapy-induced vascular

damage are discussed.
CONCLUSIONS: Total dosage and administration schedule of cisplatin
are associated with an increased incidence of neuropathy. However,
factors predicting the development of early, acute neurotoxicity are
limited by the rarity of these events. It is probable that acute
neurotoxic reactions in cancer patients are caused by an unknown
complex of interactions involving drugs, tumor, and host factors.

Ann Pharmacother 1995;29:134-7.

THE SUCCESS OF A NUMBER of chemotherapy regimens for

genu-cell tumors, ovarian cancer, small-cell lung carcinoma,
and osteosarcoma can be attributed, in part, to cisplatin.
Hence, the drug's broad spectrum of antitumor activity is
now better used. Precautions and improved supportive
therapy with vigorous intravenous hydration and antiemetics can ameliorate cisplatin's potentially severe, doselimiting renal and gastrointestinal toxicity.'> Presently,
polyneuropathy is another treatment-limiting adverse effect of cisplatin.r" Sensory neuropathy has developed in
more than half of the patients treated with this agent, depending on the dose and method of administration.s" Cisplatin neuropathy is a cumulative, dose-related phenomenon, with patients usually becoming symptomatic after receiving more than 300 mg/m'.' However, there is a broad
range of doses (100-600 mg/m') in which neurotoxic effects have occurred."
Rare instances of encephalopathy, cranial neuropathy,
seizures, and cerebrovascular accidents have been described following intravenous or intracarotid cisplatin.P"
These reported cases lacked other significant risk factors
Gerald M. Hlga, PharmD,Assistant Professor,Clinical Pharmacyand Oncology,
Schoolof Pharmacyand the Mary Babb Randolph CancerCenter, West Virginia University, Morgantown, WV
Tamara C. Wise, PA-C,Physician's Assistant, Sectionof Hematology-Oncology,
Department of Medicine
Edward B.Crowell,MD,Associate Professor of Medicine. Section of HematologyOncology,Department of Medicine
Reprints: Gerald M. Higa, PharmD, School of Pharmacy. P.O. Box 9520, West
Virginia University, Morgantown. WV26506,FAX 304/293·5483

for neurologic toxicity, with the exception of a few patients
with brain tumors. We describe a patient who developed a
severe, debilitating central nervous system toxicity following a second course of cisplatin therapy.
CASE REPORT
An unresectableadenocarcinomaof the lung was diagnosed in a
40-year-old woman in January 1994. Except for left hilar and
mediastinal adenopathy, there were no other focal areas of metastaticdisease. Plain film X-rays revealedfindings consistentwith
her history of hypertrophic osteoarthropathy. Computed tomography (CT) of the head was normal. Her neurologicexamination
also was completely normal before she began combined modality therapy in early February with cisplatin(80 m~m2 iv over 2 h
x 1 dose, withoutmannitol),etoposide(80 mg/m /d iv over 2 h x
3 doses), and concomitant radiation to the chest. Approximately
10 days later, her husband reported that the patient began experiencing intermittentepisodes of confusion and partial loss of motor coordination involvingher hands and legs.
The patient was admitted to the hospital on February 28 for a
second cycle of chemotherapy. cr scan of the head on the day of
admission showed several small lesions bilaterally in the parietal-occipital Iobes; these were assessed by the radiologistsand
neurosurgeons to be atypical of metastases. Magnetic resonance
imaging (MR1) of the head performed on March 2 showed focal
areas of increased signal intensity; this was suggestive of either
an embolicvascularaccidentor vasculitis,althoughmetastasesor
infectioncould not be excluded (Figure IA). Chemotherapywas
completed on March 2 without complications. A lumbar puncture was ordered prior to discharge, but could not be performed.
The patient was clinically stable on discharge and had a return
visit scheduledin I week.
Approximately 36 hoursafterthe cisplatin infusion, the patient's
husband found her to be verballyunresponsive, confused,and agitated.The patient was broughtto the emergencydepartmentand
admitted. Initial examination revealed a disorganized and combativemiddle-aged woman.HerT was 37.5'C, HR 120beats/min,
RR 20 breaths/min, and BP 140/80 mm Hg. Physical examination revealedocular movement that did not progress past midline
to the left; there was no nystagmus. The left eye was negativefor
papilledema; fundoscopy could not be performed on the right
eye. Cardiac examination was normal. The lungs were clear to
auscultation except for decreasedbreath sounds at the left base.
On neurologic examination, the patient was disoriented to
time, place, and person, althoughexpressiveaphasia was present.
Her lack of cooperationmade assessment of motor functiondifficult. Sensory examinationfor pain remained intact. Deep tendon
reflexes were 3+ and symmetric. Ankle and patellar clonus was
present.Plantar response was upgoingbilaterally.
The white blood cell count was 11.4 x 109fL with polymorphonuclear cells 0.95 fraction of 1.00. The platelet count,
hemoglobin, and hematocrit were 73 x lO"fL, 120 gIL, and 0.36
fraction of 1.00, respectively. Except for a creatinine of 14/
umol/L, electrolyte concentrations were normal. Laboratory
evaluation also revealed negative findings for both antinuclear
antibodies and rheumatoid factor, an erythrocyte sedimentation

134 • The Annals of Pharmacotherapy • 1995 February, Volume 29

Case Reports

rate of 23 mm/h, fibrinogen of 2.2 gIL (normal 2.0-4.0), which
decreased to 1.2gILa week later,and a prothrombin timeof 14s,
whichpeakedat 16.5s 5 days later.
A transesophageal echocardiogramshowed no vegetation on
the aortic or mitral valves. A repeat MRI scan on March 4 indicated development of bilateral cortical areas with increased signals involving predominantly gray matter(Figure IB). A cerebral
arteriogram demonstrated changes in the right midcerebral artery
consistentwith arteritis,althoughembolic phenomenacould not
be excluded. Electroencephalogram was normal.A lumbarpuncture revealed normal opening and closing pressure. Analysis of
the cerebrospinal fluid (CSF) showed glucose of 4.7 rnmol/L,
proteincontentof 0.39 gIL,many red blood cells (consistent with
a traumatic tap), and 2 whiteblood cells.Cultureof the CSF was
negativefor bacteriaand fungi. A microporemembraneanalysis
was negativefor malignantcells.
Empiricantibiotic therapy was startedto treata possible meningeal infection. A loading dose of phenytoin, with daily doses to
maintain a therapeutic concentration, and dexamethasone 16mg/d
were also initiated.
After reviewing the results of the patient's studies, neurology
consultants believed the patient's condition was the result of an
embolic process, although vasculitis could not be completely
ruled out. The patient's condition improved slowly but steadily.
By hospitalday 7 she had become more orientedand less agitated. However, the patient was still unableto verbalize simplesentences. By hospitalday 10 the patient was ambulating under the
guidanceof a physical therapist.
Phenytoin was discontinued on day 12. Repeat MRI scan on
March 14 showed changes commonly observed in patients with
evolvingischemic lesions(Figure IC).
The patient was hospitalized for 14 days. Although she became oriented, her verbal communication was characterized by
perseveration and receptive aphasia. Laboratory results of electrolyte concentration analysesremainednormal. Dexamethasone
was taperedand discontinued, and the patientwas transferred to a
rehabilitation hospital for continuing supportive and restorative
care. Six months after the development of multiple cerebral infarcts,the patientdied, neverfully recovering her abilityto speak,
eat, or walk.

Discussion
The patient described in this report developed a sudden,
profound, and progressively debilitating neurotoxic reaction that was temporally related to her second course of
cisplatin-based chemotherapy. In view of a negative head
CT preceding the patient's initial course of chemotherapy
and the atypical cerebral processes found just prior to the
second cycle of therapy, it is unlikely that the early signs of
labile confusion and mild motor disturbances in the patient
can be attributed to brain metastases. In addition, the aggregate findings of the MRI scans, angiogram, and echocardiogram support a vascular rather than metastatic etiology.
Radiographic findings suggestive of embolic infarcts
and laboratory parameters indicating disseminated intravascular coagulopathy cannot rule out the possibility that this
complication resulted from a thromboembolic process.
However, bleeding was not evident either peripherally or
centrally.

Figure I. Magnetic resonance images of the head. (A) Focal abnormal areas of signal alteration involving both parietal-occipital lobes, (B) MUltiplenew large areas of
signal alteration along the sulci involving the posterior left temporoparietal lobe and
right posterior frontoparietal lobe. (C) The gyriform distribution of small amounts of
blood on the brain surface or in the surface cortex strongly suggest an evolving ischemic lesion.

TheAnnals of Pharmacotherapy • 1995 February. Volume 29 • 135

Although vasculitis, nonbacterial thrombotic endocarditis, and consumptive coagulopathy contribute to cerebrovascular complications in patients with cancer, anticancer
agents also have been implicated.t-" A number of possible
mechanisms may contribute to the vascular toxicity of cisplatin. Vascular damage from antineoplastic agents has
been shown to cause endothelial retraction and increased
platelet adhesion.l-" Elevated von Willebrand factor antigen (which was not measured in our patient) also has been
found in patients developing acute vascular events. 18 Others have suggested that tumor cell lysis results in a release
of proteins that may disrupt the clotting system. t9 Acute
cerebrovascular accidents occurring after cisplatin therapy
are uncommon. However, it is likely that the development
of such events in patients with cancer is the result of a
complex interaction of drug, tumor, and host factors.
Neurotoxic reactions associated with etoposide are rare
and difficult to assess because many studies use etoposide
in combination with other agents, including cisplatin.20,21 It
is therefore postulated that cisplatin was the responsible
factor because of the temporal relationship between its administration and the neurotoxic complication and the absence of other deftnitive causes.
Dose-dependent peripheral neuropathy, generally seen
after 300 mg/rn-, is one treatment-limiting toxicity of cisplatin." However, acute central neuropathy, presumably
vascular in origin, also has occurred at much lower doses
even in the absence of hyperosmolar mannitol which can
modify the integrity of the blood-brain barrier. l o-13 In contrast to the patient described herein, it is unclear from previous reports whether the patients had signs or symptoms
of mild neurotoxicity prior to cisplatin administration. In
these earlier reported cases, central neurotoxic reactions
also could have been attributed to fluid overload, electrolyte
disturbances, or intracarotid administration of cisplatin,
none of which were associated with our patient. J().13
Cisplatin-based chemotherapy has had a dramatic impact on the prognosis of patients with germ-cell and ovarian carcinomas. Nevertheless, rare and often severe central
neurotoxic reactions can limit further administration of
cisplatin.
Summary

Radiologic tests are invaluable diagnostic tools; however, even the most sophisticated procedures contain flaws. It
is important to note that clinically overt cisplatin neurotoxicity could masquerade initially as mild central nervous
system abnormalities. Clinical signs of difficulty with ftne
motor coordination, diminished (or loss of) vibratory sensation, or confusion may be indicators of impending, severe central neurotoxic reactions. Because the progression
of neuropathy is often unpredictable, a complete neurologic assessment prior to further cisplatin administration is
recommended given the uncompromising nature of cisplatin neurotoxicity.c-

References
I. Hayes OM. Cvitkovic E, Golbey RB, Scheiner E, Helson L, Krakoff IH.
High-dosecis-platindiamminedichloride:ameliorationof renal toxicity by mannitoldiuresis.Cancer 1977;39:1372-81.

136 •

2. Hesketh PJ. Comparativetrialsof ondansetronversus metoclopramide in
the prevention of acute cisplatin-induced emesis. Semin Oncol 1992;
19(suppl 10):33-40.
3. Mollman JE. Cisplatinneurotoxicity. N Engl J Med 1990;322: 126-7.
4. Roelofs RI, Hrushesky W, Rogin J, Rosenberg L. Peripheral sensory
neuropathy and cisplatinchemotherapy. Neurology 1984;34:934-8.
5. Lambert HE, Berry RJ. High-dosecisplatincompared with high dose cyclophosphamide in the management of advanced epithelial ovarian
cancer (FIGO stages III and IV): report from the North Thames CooperativeGroup. Br Med J 1985;290:889-93.
6. GershensonOM. Wharton JT, HersonJ, EdwardsCL, Rutledge FN. Single-agentcis-platinum therapy for advancedovariancancer. ObstetGynecol 1981 :58:487-96.
7. Ozols RF, Ostchega Y. Myers CE, Young RC. High-dose cisplatin in
hypertonic saline in refractory ovarian cancer. J Clin Oncol 1985;3:
1246-50.
8. Legha SS, Dimery IW. High-dose cisplatin administration without hypertonic saline: observation of disabling neuropathy. J ClinOncol
1985;3: 1373-8.
9. Mollman JE, Glover OJ, Hogan WM, Furman RE. Cisplatinneuropathy:
risk factors, prognosis, and protection by WR-272\. Cancer 1988;61:
2192-5.
10. Walker RW, Caimcross JG, Posner 18. Cerebral herniation in patients
receivingcisplatin.J Neurooncol 1988;6:61-5.
II. Newton HB, Page MA, Junek L, Greenberg HS. Intra-arteria) cisplatin
for the treatmentof malignantgliomas.J Neurooncol 1989;7:39-45.
12. Berman 11, Mann MP. Seizures and transientcortical blindnessassociated with cis-platinum (II) diamminedichloride (POD) therapy in a thirtyyear-oldman. Cancer 1980;45:764-6.
13. Kukla U, McGuire WP, Lad T, Saltiel M. Acute vascularepisodesassociated with therapy for carcinoma of the upper aerodigestive tract with
bleomycin,vincristine and cisplatin.CancerTreat Rep 1982;66:369-70.
14. Doll DC, List AF, Greco FA, Hainsworth JD, Hande KR, Johnson DH.
Acute arterial ischemic events following cisplatin-based combination
chemotherapyfor germ cell tumors of the testis. Ann Intern Med 1986;
105:48-51.
15. Graus F, Rogers LR, Posner JB. Cerebrovascular complications in patients with cancer. Medicine 1985;64:16-35.
16. Nicolson GL, Custead SE. Effects of chemotherapeutic drugs on platelet
and metastatic tumour cell-endothelialcell interactionsas a model for
assessingvascularintegrity. Cancer Res 1985;45:331-6.
17. BurkhardtA, Holtje WJ, Gebbens JO. Vascular lesions followingperfusion with bleomycin. Electron microscopic observations. Virchows
Arch A Pathot Anat HistopathoI1976;372:227-36.
18. Licciardello JT, Moake JL. Rudy CK, Karp DD, Hong WK. Elevated
plasma von Willebrand factor levels and arterial occlusive complications associated with cisplatin-based chemotherapy. Oncology 1985;
42:296-300.
19. Donati MB, Gambacorti-Passerini C, Casali B, Falanga A, Vannotti P,
Fossati G, et al. Cancer procoagulant in human tumor cells: evidence
from melanomapatients.Cancer Res 1986;46:6471-4.
20. O'Dwyer PJ, Leyland-Jones B, Alonso MT, Marsoni S, Willes RE.
Etoposide (VP-16-213).Current status of an active anticancerdrug. N
Engl J Med 1985;312:692-700.
21. Goldhirsch A, Joss RA, Cavalli F, Sonntag RW, Brunner KW. Cisdichlorodiammineplatinum (II) and VP-16-2J3combination chemotherapy
for non-smallcell lung cancer. Med PediatrOncol 1981 ;9:205-8.

EXTRACfO
OBJETIVO: Describir un caso clinico de un paciente con cancer que

desarrollo una reacci6n neurot6xica severa luego de haber recibir un
segundo ciclo de quimioterapia con cisplatino. Se revisa la literatura
medica y se examinan aquellos factores que pueden predisponer a un
paciente a desarrollar este tipo de toxicidad temprano en el tratamiento.
RESUMEN DEL CASO: Un paciente con un rumor de pulm6n no resectable
fue tratado con una combinaci6n de quimioterapia y radioterapia.
Treinta y seis horas luego de haber recibido un segundo curso de
quimioterapia, el paciente experiment6 cambios mentales severos tales
como afasia, confusi6n mental, y agitaci6n. Un examen neurologfco
extenso determino que el paciente habia experimontado un evento
vascular agudo.

The Annals cfPharmacotherapy • 1995 February, Volume 29

Case Reports
DISCUSION: La cantidadde reportesque describenla toxicidad
neurologica causada por cisplatinoson escasos. Los factoresque
predisponena un pacientea desarrollaresta toxicidadson discutidosen
este articulo. EI mecanismopor el que ocurre el dariovascularinducido
por quimioterapia tambienson discutidos.
CONCLUSIONES: La dosis total y el horariode administracion del
cisplatinoestan asociadoscon una incidenciaaumento de neurotoxicida.
Sin embargo aquellosfactoresque predicenel desarrollotempranode
esta neurotoxicidad agunda no estan claramentedeterminados debido a
la baja incidenciade esta reacci6n. Se posibleque estas reacciones
neurot6xicas agundasen pacientescon canceresten causadas por unas
interacciones complejasdesconocidas que envuelvenel tumor, los
farmacos, y los factoresde defansadel inmunologica del paciente.

MAGALY RODRiGUEZ DE Bl1TNER

OB.JECTIF: Decrire une reactionde neurotoxicite severe chez un patient
ayant recu un second cycle de chirniotherapie incluantIe cisplatine.
Reviser la litterature et identifierles facteurspredisposantun patient a
cette toxiciteprecoce.

REsuME: Un patient atteintd'un cancer du poumon inoperable recoit un
traitementcombine de chimio et de radiotherapie, Trente-six heures
apres Ie deuxieme cycle de chimiotherapie, Iepatient presenteune
modification severe de son etat mental incluantde l'aphasie, de la
confusion,et de l'agitation. Un examen neurologique completest
compatibleavec un problemevasculaire aigu.
DISCUSSION: Les cas rapportesde toxiciteneurologique induite par Ie
cisplatine, impliquantIe systeme nerveuxcentral,sont rares. Des
facteursde risquespotentiels sont decrits. Les rnecanismes impliques
dans I'inductionde dommagesvasculaires par les agents
chimiotherapeutiques sont discutes,
CONCLUSIONS: La dose totaleet l'horaire d'administrationsont des
facteursassociesaux phenomenes de neuropathie. Toutefoisla rarete
des cas de neurotoxicite aigue rapportesdans la litterature permet
difficilement d' identifierles facteurspredisposants, II est probableque
les reactionsneurotoxiques aigues chez les patientscancereuxsont dus a
des interactions inconnuescomplexesimpliquantles medicaments, la
tumeur,et Ie patient.
CLAUDE MAILHOT

TheAnnals ofPharmacotherapy • 1995 February, Volume 29 • 137