Taxol produces a predominantly sensory neuropathy

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Taxol was supplied by the National Cancer Institute as a ..... the sensory ganglia or myelin sheath.26 Sensory neuro- .... (sensory neuronopathy) in the dog.
patients with Alzheimer’s disease. Neurosurgery 1984;15:514-518. 8. Damasio AR. The frontal lobes. In: Heilman KM, Valenstein E, eds.Clinical neuropsychology,2nd ed. New York Oxford University Press, 1985:339-376. 9. Porteus SD. The maze test and clinical psychology. Palo Alto, C A Pacific Books, 1959. 10. Wechsler D, Stone CP. Manual, Wechsler memory scale. New York Psychological Corp, 1973. 11. Osborne D, Davis LJ. Standard scores for Wechsler Memory scale subtests. J Clin Psychol 1978;34115-116. 12. Lezak M. Neuropsychological assessment. New York Oxford University Press, 1976:266-269. 13. Lezak M. Neuropsychological assessment, 2nd ed. New York Oxford University Press, 1983:332-333,556-557. 14. Wechsler D. Wechsler adult intelligence scale manual. New York Psychological Corp, 1955. 15. Folstein MF, Folstein SE, McHugh PR. Mini-Mental State. J Psychiatr Res 1975;12:189-198. 16. Kaplan E, Goodglass H, Weintraub S. Boston Naming Test. Boston: 1978. 17. Munoz-Garcia D, Ludwin SK. Classic and generalizedvariants of Pick’s disease: a clinicopathological,ultrastructural and immunocytochemical comparative study. Ann Neurol1984;16467-480. 18. Kamo H, McGeer PL, Harrop R, et al. Positron emission tomography and histopathology in Pick’s disease. Neurology 1987;37:439-445. 19. Groen JJ, Hekster REM. Computed tomography in Pick’s disease: findings in a family affected in three consecutive generations. J Comput AssistTomogr 1982;6907-111. 20. McGeachie RE, Fleming JO, Sharer LR, et al. Diagnosis of Pick’s disease by computed tomography. J Comput Assist Tomogr 1979;3:113-115. 21. Constantinidis J, Richard J, Tissot R. Pick’s disease: histological and clinical correlations. Eur Neurol 1974;11:208-217. 22. Mastri AR, Frey WH, Rustan TD, Sung JH. Dementia with nonspecific degeneration. J Neuropathol Exp Neurol1987;46339. 23. Kim RC, Collins GH, Parisi JE, Wright AW, Chu YB. Familial

dementia of adult onset with pathological findings of a ‘nonspecific nature.’ Brain 1981;10461-78. 24. Knopman DS, Mastn AR, Frey W. Multisystem degeneration presenting with dementia. Neurology 1988;38(suppl1):228. 25. Warrington EK. Selective impairment of semantic memory. Q J EXPPsycho1 1975;27:635-657. 26. Kittner SJ,White LR, Farmer ME, et al. Methodologicalissues in screening for dementia: the problem of education adjustment. J Chronic Dis 1986,39:163-170. 27. McCarty SM, Siegler IC, Logue PE. Cross-sectional and longitudinalpatterns of three Wechsler Memory Scale subtesta. J Geronto1 1982;37:169-175. 28. Anthony JC, LeResche L, Niaz U, Von Korff MR, Folstein MF. Limits of the ‘Mini-Mental State’ as a screening test for dementia a n d delirium among hospita l pa tie nts. Psychol Med 1982;12:397-408. 29. Cutler NR, Haxby JV, Duara R, et al. Brain metabolism as measured with positron emission tomography: serial assessment in a pa tie nt with familial Alzheimer’s disease. Neurology 1985;35:1556-1561. 30. Berent S, Foster NL, Gilman S, Hichwa R, Lehtinen S. Patterns of cortical 1aF-FDG metabolism in Alzheimer’s and progressive supranuclear palsy patients are related to the types of cognitive impairments. Neurology1987;37(suppl1):172. 31. Pillon B, Dubois B, Lhermitte F, Agid Y. Heterogeneity of cognitive impairment in progressive supranuclear palsy, Parkinson’s disease, and Alzheimer’s disease. Neurology 1986;36:1179-1185. 32. Pogacar S, Williams RS. Alzheimer’s disease presenting as slowly progressive aphasia. RI Med J 1984;67:181-185. 33. Kirshner HS, Tanridago, Thurman L, Whetsell WO. Progressive aphasia without dementia: two cases with focal spongiformdegeneration. Ann Neurol 1987;22:527-532. 34. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan E. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34939-944.

Taxol produces a predominantly sensory neuropathy R.B. Lipton, MD; S.C. Apfel, MD; J.P. Dutcher, MD; R. Rosenberg, MD; J. Kaplan, MD; A. Berger, MD; A.I. Einzig, MD; P. Wiernik, MD; and H.H. Schaumburg, MD

Article abstract-Taxol, a plant alkaloid with promise as an antineoplastic agent, produced a predominantly sensory neuropathy in 16 of 60patients treated in two phase I trials. This neuropathy occurred only at taxol doses greater than 200 mg/m2. Symptoms typically started 1 to 3 days following treatment, beginning in the hands and feet simultaneously in most patients. Electrophysiologicdata suggestsboth axonal degeneration and demyelination. This previously undefined neurotoxic neuropathy most likely results from taxol’s unique ability to produce microtubule aggregation in dorsal root ganglion cells, axons, and Schwann cells. NEUROLOGY 1989;39:368-373

Taxol is a plant alkaloid with great promise as an antineoplastic agent.l The drug has a unique mechanism of action; it binds to tubulin and promotes microtubule

as~embly.~J Microtubules formed in the presence of taxol are stable in conditions which ordinarily depolymerize them, including the presence of calcium (4

From the Departments of Neurology (Drs. Lipton, Apfel, Rosenberg,Kaplan,Berger, and Schaunburg) and Oncology (Drs. Dutcher, Einzig, and Wiernik), The Albert Einstein College of Medicine, Bronx, NY. Received July 25, 1988. Accepted for publication in final form September 21, 1988. Address correspondence and reprint requesta to Dr. Lipton, Department of Neurology,Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.

368 NEUROLOGY 39 March 1989

mmol/l) and cold (4 O C)? Taxol also alters the kinetics of microtubule assembly,eliminating the 3- to 4-minute lag time normally observed prior to the initiation of assembly.5 This mechanism contrasts with that of the vinca alkaloids which inhibit microtubule assembly? In tissue culture, taxol causes abnormal bundles of microtubules to form throughout the cytoplasm, thereby disrupting normal cell functions including mitosis, cell proliferation, neurite initiation, and neurite branching.'-12 When taxol is injected directly into rat sciatic nerve, microtubules aggregate into unusual arrangements in both axons and Schwann cells, leading to acute demyelination and chronic loss of axoplasmic transport.13-15 These effects on peripheral nerve and neurites suggested that taxol may produce clinicallysignificantneuropathy. Dose-limitingneurotoxicityhas been observed in two of seven phase I trials of taxol as a chemotherapeutic agent against solid tumors.16-lsThis report describes the clinical features of this previously undefined neurotoxic neuropathy. Subjects and methods. Patients from two phase I trials conducted at the Albert Einstein Cancer Center using 6-hour and 24-hour constant infusion of taxol were included. In addition, we describe a well-studied patient with taxol neuropathy treated in a subsequent phase I1 study of melanoma (case 9). Patients had pathologically documented malignant disease other than leukemia, lymphoma, or myeloma, and had either failed radiation therapy or conventionalchemotherapy,or had a tumor for which no conventional therapy exists. None had evidence of a preexisting paraneoplastic neurologic problem. Taxol was supplied by the National Cancer Institute as a concentrated sterile solution, 6 mg/ml in polyoxyethylated castor oil (cremophor EL) 50% and dehydrated alcohol USP 50%. For the 6-hour trial, the taxol was further diluted in a liter of 5%dextrose and given as an intravenous infusion over 6 hours. Treatment was repeated every 3 weeks based on clinical response. For each patient in the 24-hour trial, onethird of the appropriate dose of taxol was diluted in 500 ml of 5% dextrose in water. Three 8-hour infusions were administered intravenously. Treatment was repeated every 3 weeks depending upon clinical response. The starting dose for the study was 15 mg/m2. Doses were escalated according to a modified Fibonacci scale. At least three patients were treated at each dosage level until toxicity (not necessarily neurologic toxicity) was identified; then four to six patients were treated at each subsequent dosage level. Patients who received more than one dose were maintained at their initial taxol dose on subsequent cycles. Prior to each cycle, clinical status was assessed; if tumor progression was demonstrated while receiving taxol, treatment was discontinued. All patients were screened for neuropathic symptoms using the Eastern Cooperative Oncology Group rating scales.lgNeurologic evaluations were performed on patients who developed neuropathic symptoms following treatment. As it became clear that neurotoxicity was a frequent complication of taxol administration, neurologic evaluations were performed on some patients prior to treatment, to establish a baseline. Neurologic evaluations were performed by a single neurologist (R.B.L.). Patients were examined by the neurologist after treatment only if they developed neurologic complaints such as tingling, numbness, or dysesthesias. Three symptomatic patients from the clinical trials, and the additional patient

reported as case 9, had electromyography and nerve conduction studies (EMG/NCV). Patients with neuropathic symptoms and signs were considered to have a clinically definite neuropathy. Patients who developed typical symptoms but did not receive a neurologic examination were considered to have a clinically probable neuropathy. Clinically definite cases are used to describe the features of the neuropathy; the probable cases are included to estimate its incidence at each dose of taxol.

Results. In total,65 courses of taxol were administered to 26 patients in the 24-hour trial, and 83 courses were administeredto 34 patients in the 6-hour trial. Eighteen patients had baseline examinations prior to initiating taxol therapy. Eight patients developed clinically definite neuropathy. Eight additional patients with symptoms strongly suggestive of neuropathy were classified as having a clinically probable neuropathy. The remaining 44 patients did not have complaints suggestive of neuropathy.A representative case history is presented in detail and all eight clinically definite cases are summarized in table 1.The eight cases of probable neuropathy are summarized in the text. Case 9, included as a case report, is an additional well-studied patient. Case reports. Case 1. A 52-year-old woman presented in 6/83 with well-differentiated adenocarcinoma of colon and metastases to the pelvic floor, small bowel, and vagina. Initial treatment consisted of surgical resection, radiation therapy, and 5-fluorouracil, without subsequent improvement. In 10/85 she was enrolled in the 6-hour taxol trial, at a dose of 275 mg/m2.Her baseline neurologic examination was entirely normal includingpreserved deep tendon reflexes. Three days after her first dose, she noted numbness and dysesthesias in her finger tips bilaterally. Two days later she complained of similar symptoms in her feet up to her ankles and found it painful to walk barefoot. Three weeks after treatment her symptoms were somewhat improved. Neurologic exam at that time revealed hyperalgesias in the distal park of her feet, decreased proprioception in her fingers and toes, and complete loss of deep tendon reflexes throughout. With the second cycle of taxol at the same dose, her original neuropathic symptoms were exacerbated. Neurologic examination 2 weeks later demonstrated loss of pain and temperature sensation in the hands and feet, with distal to proximal shading, and normal sensation 3 inches above the wrist and at the ankle. Vibration and proprioception were impaired in the hands and feet. Reflexes were absent. Treatment was discontinued because of neurotoxicity. Follow-up examination months after the initial treatment revealed symptomatic improvement with residual foot numbness, hypoactive reflexes at the biceps, triceps, and quadriceps, as well as absent reflexes in the brachioradialis and achilles tendons. Case 9. A 70-year-old man presented in 7/86 with melanoma of the right fifth toe and was treated in a phase I1 trial not elsewhere included in the present report. Following toe amputation in 9/86 he was started on taxol (250 mg/m2)every 3 weeks. He received 16 courses with clinical and radiographic disappearance of adenopathy. A few days after each dose he noted tingling of his feet lasting 2 to 3 days. He gradually developed constant numbness in his legs up to the thighs with continuous tingling and burning of his feet. These symptoms improved somewhat with amitriptyline, 50 mg daily. Because March 1989NEUROLOGY 39 369

Table 1. Summary of patients with taxol neuropathy Pt no./ Age/ Sex

Dose

mg/m* (no.cycles)

Other risk factors for neuropathy

Symptoms Hands Feet

Deep tendon

Signs

Hands

Feet

reflexes

1152~

215 ( 2 )

None

Dysesthesias in fingers (first symptom)

Painful dysesthesias in feet

Decreased prop, vib, pain, and temp with shading

Decreased prop, vib, pain, and temp with shading

Absent

2/55/47

250 ( 5 )

Diabetes

Asymmetric numbness and painful dysesthesias, weakness

Numbness in feet, painful dysesthesias and sharp joint pain, leg weakness

Decreased vib, distal motor weakness

Decreased sensation to pp, It, prop, and vib, prox and distal weakness

Absent

3/54F

215 ( 2 )

None

Dysesthesias

Dysesthesias

None

Decreased vib and pp, distally symmetrically

Absent ankle jerks

4/83F

250 ( 1 ) 190 (1) 125 ( 5 )

Renal failure

Paresthesias, lancinating pain

Dysesthesias

Shading to pp, decreased prox strength

Shading to pp, decreased prox strength

Absent

5/49F

250 (1)

None

Paresthesias right thumb (first symptom)

Late paresthesias

Decreased vib and prop, PP and It intact

Decreased vib and prop, PP and It intact

Absent

6/48F

215 ( 4 )

Diabetes

Paresthesias, first in hands, later dysesthesias, hyperpathia

Late paresthesias, dysesthesia, and hyperpathia

Shading to pp and It

Shading to pp and I t

Absent ankle jerks

7/40F

215 ( 3 )

Prior &-platinum chemotherapy

Paresthesias of fingers and mouth (first symptoms), numb tongue after last course

Dysesthesias

Shading to pp and It

Shading to pp and It

Absent ankle jerks

8/62/47

215 (2)

None

Paresthesias fingers

Paresthesias toes

Shading to pp

Shading to pp

Absent ankle jerks

No neurologic exam before taxol therapy was initiated. First symptom indicates the initial manifestation of neuropathy. When not specified, symptoms began in hands and feet simultaneously.

(no.cycles) Number of cycles of chemotherapy. prop vib temp pp

Proprioception. Vibration. Temperature. Pinprick. It Light touch. prox Proximal.

of these symptoms the dose of taxol was reduced to 175 mg/m2 and the interval increased to every 4 weeks starting with the 17th course. Fifteen months later he was referred for neurologic evalua-, tion (after 19 courses of taxol) complaining of diminished agility on the tennis court and frequent falls. Neurologic examination revealed moderate distal weakness of the legs and milder intrinsic hand weakness. Deep tendon reflexes were absent throughout. He was unable to stand on toes or heels. There was a glove-and-stockingsensory deficit in the legs up to the knees and in the hands up to the wrists affectingpin and vibration senses equally. Romberg’s sign was present. There was no evidence of diabetes, renal insufficiency,or vitamin B,, or folate deficiency. NCV andneedle EMG examination (table 2) demonstrated severe generalized peripheral neuropathy, predominantly affecting axons. 370 NEUROLOGY 39 March 1989

Following the reduction of the taxol dose the neuropathy has remained clinically stable, so that he is still able to play tennis daily. The clinical response has also been maintained on the current regimen as of 2/88. Summary offindings. In the initial phase I clinical trials, eight patients developed clinically definite neuropathy while an additional eight developed probable neuropathy (table 3). All of these patients received a taxol dose of 200 mg/mz or greater; 16 of 29 patients (55%) who received taxol in these doses developed clinically definite or probable neuropathy. Of the eight patients with definite neuropathy, five presented with symmetric sensory involvement from the outset. Three began with asymmetric features which subsequently became symmetric (cases 2,4, and 5). All patients eventually developed symptoms of both the upper and lower extremities.

Table 2. EMG and nerve conduction studies r

Courses of Sensory nerve taxol Amplitude Conduction (260-276 mg/m* (PV) velocity (m/eec) course) Sur Med Uln Sur Med Uln

Motor nerve Amplitude Conduction (mV) velacity(m/eec) Med Per Med Per

H reflex latency (msec) Tibial

N N N

N N

A N A

- N N D D

N N N

N N

N N N

N N

-

1

A N A

19

A

D

A

A

N

A

N

A

N

A

1

2

3

2

5

I I

EMG

-

Case report

#S

A

profuse

fibrillations and chronic MUP reinnervation in distal muscles Sur Med Uln Per A m/sec

Surd. Median. Ulnar. Peroneal. Absent. Meters per second.

N Normal. I Increased. D Decreased. - Notdone. MUP Motor unit potential. msec Millisecond.

Table 3. Incidence of neuropathy as a function of taxol dose* Neuropathic manifestation Clinically definite sensory neuropathy Clinically definite sensory and motor neuropathy Clinically probable neuropathyS

t200 mg/mz

200 mg/mZ

260 mg/d

276 mg/rnz

0/31

0/9

1/10

5/10

O/3 1t

Q/9

2/10

0/10

0/31

4/9

3/10

1/10

* This table includes all subjects in the 6-hour and 24-hour infusion studies. A/B is the ratio of patients with the neuropathic manifestation specified at left to the total number of patients receiving the dose specified by the column heading. $ This includes patients with symptoms typical of neuropathy who were not evaluated by the study neurologist. Patients with neuropathic symptoms prior to taxol treatment were not included in thia group unless their symptom6 radically changed after taxol treatment.

t

In three patients (cases 1, 5, and 6) the sensory symptoms began in the hands before the feet. In the remaining five, involvement occurred simultaneously in the hands and feet; one of these patients also developed early numbness around the corners of the mouth and in the tongue (case 7). Burning dysesthesias occurred in six of eight patients, most prominently in the feet. Patient 4 also noted lancinating pain in her back, arms, legs, and shoulder. Two patients had evidence of autonomic involvement (cases 2 and 8) with otherwise unexplained symptomatic orthostatic changes in blood pressure acquired during taxol treatment. Two patients developed motor as well as sensory abnormalities. One patient (case 2) was a diabetic who developed symmetric distal weakness of the arms and legs, worse distally than proximally. This weakness progressed with succeeding taxol treatments and eventually prevented ambulation. The other patient (case 4) developed 4/5 symmetric proximal weakness involving the upper and lower extremities, which

Drogressed while receiving seven courses of taxol. %he onset of neurop&hic symptoms was usually rapid. Three patients developed sensory symptoms within a day of receiving taxol. In another three patients symptoms began by the fourth day followingtreatment. In the remaining patients, symptoms began 1and 3 weeks after the initiation of therapy. All patients developed symptoms followingtheir first course of taxol, and in those who had subsequent cycles, the symptoms progressed following each treatment. Some improvement in neuropathic symptoms during the interval prior to the next dose was well described in four patients. The eight patients with probable neuropathy had symptomatology similar to those with definite neuropathy. Four patients received taxol doses of 200 mg/m2, three received doses of 250 mg/m2, and one received 275 mg/mz. Three patients complained of paresthesias of the fingers or palms primarily; one of these patients went on to complain of toe numbness as well but only after the fourth cycle. Pain was noted by three of these patients. Two patients complained of leg weakness in addition to sensory complaints. Three patients from the phase I taxol trials and one additional patient (case 9) underwent EMG/NCV testing after taxol treatment (table 2). Three had absent surd nerve action potentials. One had slowing of median andulnar sensory nerve conduction velocity. Only the patient with repeated longstanding taxol exposure (case 9) demonstrated motor conduction abnormalities.

Discussion. We present a series of patients who developed a predominantly sensory neuropathy following treatment with taxol and a case report of an additional well-studied patient. Neuropathic symptoms were not present in any patient treated with less than 200 mg/m2 of taxol. Fifty-five percent of patients treated with doses greater than or equal to 200 mg/m2 developed neuropathy, with more cases at the higher doses. Although the development of neuropathy is dosedependent, the sample size is too small to conclude that the incidence of neuropathy increases proportionately with doses beyond 200 mg/m2. March 1969 NEUROLOGY 39 371

The neuropathy which developed in these patients is most reasonably attributed to taxol. This conclusion is supported by the rapid onset and dose dependence of the findings we observed. These features, coupled with the high prevalence of neuropathy, make paraneoplastic sensory neuronopathy extremely unlikely. Nor does it seem likely that the vehicle for taxol, polyoxyethylated castor oil (cremophor EL), produced the neuropathy. This agent has been extensively administered to humans at doses that equal or exceed those used in the present study without reports of neurotoxicity.20-22 Given this striking neuropathy, it may at first seem surprising that neurotoxicitywas not a significant finding in five previous report^.*^-^^ In four of these studies,23-25,27 few patients received doses of 200 mg/m2 or greater, the minimum dose required for neurotoxicity in the present study. Though Legha et alZ6administered a total dose of 200 mg/mz to a substantial number of patients, it was distributed in small increments over 5 days. Given its pharmacokinetic~,17J8~~~ taxol plasma levels must have remained well below those achieved in our trials. The precise mechanism of this unusual neuropathy is uncertain. Presumably it results from taxol’s well demonstrated ability to promote microtubule aggregation in neurons, axons, or Schwann c e l l ~ . ~The - l ~ predominance of sensory features and the rapid onset with early symptoms in the hands and feet suggests that this is not a dying-back neuropathy but rather one affecting the sensory ganglia or myelin sheath.26Sensory neuronopathies have been previously reported in certain malignancies, particularly lymphoma and oat cell carc i n ~ m a , ~with ~,~O pyridoxine in humans and experimental animal^,^^,^^ and with Adriamycin in experimental animals.33 The electrophysiologic data support the presence of both axonal degeneration and demyelination. Three patients (including the additional patient presented as case 9) had absent sural nerve action.potentials,consistent with axonal degeneration. In addition, one patient had decreased conduction velocities in the presence of intact amplitudes suggesting demyelination. These findings are consistent with taxol’s ability to aggregate microtubules in axons as well as Schwann cells when injected into rat sciatic nerve.l3-l5One patient (case 3) had a normal study despite clinical symptoms and an abnormal exam. This may reflect the insensitivity of electrophysiologictesting in detecting early neuropathy or involvement of more proximal nerve segments not accessible to routine NCVs. Further clarification of taxol’s site or sites of action requires more detailed electrophysiologic and neuropathologic studies. In these studies, treatment was discontinued in three patients with excellent therapeutic responses because of neurotoxicity. A method that would diminish neurotoxicity might permit the administration of high doses of taxol, thereby extending the usefulness of this promising agent. Crain and P e t e r s ~ nhave ~ ~ shown ~~~ that nerve growth factor (NGF), a neuronotrophic factor normally required for maintenance of sympathetic and dorsal root ganglion (DRG) neurons in tissue culture, attenuates the cytotoxic effects of taxol in DRG ’

372 NEUROLOGY 39 March 1989

explant cultures. Since the gene for human NGF has been cloned, it is possible that administration of a neuronotrophic factor, along with taxol, may limit the neurotoxicity and extend the useful dosage range of the drug. Additional work is required to characterize the mechanism and spectrum of taxol neuropathy. This work will be of great significance if taxol realizes its promise as an antineoplastic agent. In addition, the relationship between taxol toxicity and neuronotrophic factors may yield fundamental insights about the role and regulation of microtubules in neuronal function.

Acknowledgment The authors would like to thank Ms. Donna Platyan for assistance in the preparation of this manuscript.

References 1. Wani MC, Taylor HL, Wall ME, Coggon P, Mcphail AT. Plant

anti-tumor agents. VI. The isolation and structure of taxol, a novel anti-leukemic and anti-tumor agent from Taxus breuifolia.J Am 1971;93:2325-2327. Chem SOC 2. SchiEPB, Faut J , Horowitz SB. Promotion of microtubule assembly in vitro by taxol. Nature 1979;277:665-667. 3. Parnass J, Horowitz SB. Taxol binds to polymerized tubulin in vitro. J Cell Biol 1981;91:479-487. 4. Schiff PB, Horowitz SB. Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci USA 1980;77:1561-1565. 5. Horowitz SB, Lothstein L, Manfredi JJ, et al. Taxol: mechanism of action and resistance. Ann NY Acad Sci 1986;466:733-744. 6. Luduena RF’.Biochemistry of tubulin. In: Roberta K, Hyams JS, eds. Microtubules. New York Academic Press, 1979;65-116. 7. Masurovsky EB, Peterson ER, Crain SM, Horowitz SB. Microtubule arrays in taxol treated mouse doraal root ganglia-spinal cord cultures. Brain Res 1981;217:392-398. 8. Masurovsky EB, Peterson ER, Crain SM, Horowitz SB. Morphologic alterations in dorsal root ganglion neurons and supporting cells of organotypic mouse spinal cord-ganglion cultures exposed to taxol. Neuroscience 1983;10491-509. 9. Mole-Bajar J , Bajar AS. Action of taxol on mitosis: modification of microtubule arrangements and function of the mitotic spindle in Haemanthus endosperm. J Cell Biol1983;96527-540. 10. De Brabander M, Geuens G, Nydens R, Willebrods R, Demay J. Taxol induces the assembly of free microtubules in living cells and blocks the organizing capacity of the centrosomes and kinetochores. Proc Natl Acad Sci USA 1981;78:5608-5612. 11. Letoumeau PC, Ressler AH. Inhibition of neurite initiation and growth by taxol. J Cell Biol1984,98:1355-1362. 12. Letourneau PC, Shattuck T, Ressler AH. Branching of sensory and sympathetic neurites in vitro is inhibited by treatment with taxol. J Neurosci 1986;61912-1917. 13. Roytta M, Horowitz SB, Raine CS. Taxol induced neuropathy: short term affectsof local injection. J Neurocytol1984;13:685-701. 14. Roytta M, Raine CS. Taxol induced neuropathy: further ultrastructural studies of nerve fiber changes in situ. J Neurocytol 1985;14157-175. 15. Roytta M, k i n e CS. Taxol induced neuropathy: chronic effectsof local injection. J Neurocytol1986;15:483-496. 16. Wiernik PH, Strauman J J , Engel SI, et al. Taxol phase I and pharmacokinetic study. Abstract. Proc Am SOCClin Oncol 1985;5:32. 17. Wiemik PH, Schwartz EL, Strauman J J , et al. Phase I clinicaland pharmacokinetic study of taxol. Cancer Res 1987;47:2486-2493. 18. Wiernik PH, Schwartz EL, Einzig A, et al. Phase I trial of taxol given as a 24 hour infusion every 21 days: responses observed in metastatic melanoma. J Clin Oncol 1987;5:1232-1239. 19. O’Ken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol1982;5649-655.

20. Howrie PL, Ptachcinski RJ, Griffith BP, et al. Anaphylactoid reaction associated with parenteral cyclosporineuse: possible role of cremophor EL. Drug Intel1 Clin Pharm 198619425-427. 21. Christmas D. Immune reaction to propranolol. Anesthesia 1984;39:470-473. 22. Friedman L, Dienstag J , Nelsen P, et al. Anaphylactic reaction and cardiopulmonary anesthesia following intravenous cyclosporine. Am J Med 1984;78:343. 23. Longnecker S,Ross D, Grochow L, et al. Phase I and pharmacokinetic study of taxol in patients with advanced cancer. Abstract. Proc Am SOC Clin Oncol 1985;443. 24. Tutsh K, Snominathon D, Alberti D, et al. Phase I clinical trial with pharmacokinetic analysis of taxol given on a daily X 5 schedule. Abstract. Proc Am SOCClin Oncol 1985;4:40. 25. Ohnuma T, Zimest A, Coffrey VA, et al. Phase I study of taxol in a 24 hour infusion schedule. Abstract. Proc Am Assoc Cancer Res 1985;26:167. 26. Legha S, Tenney D, Dimery I, et al. Aphase I study of taxol (NSC 125973). Abstract. Proc Am Assoc Cancer Res 1985;26173. 27. Kris MG, O'Connell JP, Gralla RJ, et al. Phase I trial of taxol given as a 3 hour infusion every 21 days. Cancer Treat Rep 1986;70605-607.

28. Schaumburg HH, Spencer PS. Toxic neuropathies. Neurology 1979;29:429-431. 29. Denny-Brown D. Primary sensory neuropathy with muscular changes associated with carcinoma. J Neurol Neurosurg Psychiatry 194811~73-87. 30. Horwich MS, Cho L, Porro RS, et al. Subacute sensory neuropathy: a remote effect of carcinoma. Ann Neurol 1977;2:7-19. 31. Schaumburg H, Kaplan J, Windebank A. Sensory neuropathy from pyridoxine abuse. N Engl J Med 1983;309:445-448. 32. Krinke G, Schaumburg HH, Spenser PS, et al. Pyridoxine megavitaminosis produces degeneration of peripheral sensory neurons (sensory neuronopathy) in the dog. Neurotoxicology 1980;2:13-24. 33. Cho ES, Spenser PS, Jortner BS, Schaumburg HH. A single intravenous injection of doxorubicin (Adriamycin) induces sensory neuronopathy in rats. Neurotoxicology 1979;1:583-591. 34. Peterson E, Crain S. Nerve growth factor attenuates neurotoxic effects of taxol on spinal cord-ganglion explants from fetal mice. Science 1982;217:377-379. 35. Crain S,Peterson E. Enhanceddependence of fetal mouse neurons on trophic factors after taxol exposure in organotypic cultures. In: Black IB, ed. Cellular and molecular biology of neuronal development. Plenum Publishing, 1984:177-200.

The significance of MRI abnormalities in children with neurofibromatosis Patricia K. Duffner, MD; Michael E. Cohen, MD; F. Glen Seidel, MD; and David W. Shucard, PhD

Article abstract-We prospectively evaluated 47 children with neurofibromatosis to determine whether the previously reported high signals on magnetic resonance imaging (MRI) (prolonged T2)correlated with CT, brainstem auditory evoked responses (BAER),EEG, clinical examinations,cognitive abilities,or seizure disorder. Thirty percent of children had a history of seizures and 70% had either learning disabilities or mental retardation. Overall, 74% had an abnormal MRI examination. Sixtytwo percent had high signals (prolongedT,) on T,-weighted images. Abnormal signals were located primarily in the basal ganglia, brainstem, and cerebellum.Twenty-fivepercent of patients had abnormal EEGs, 28% had abnormal CTs, and 27% had abnormal BAER examinations. The abnormal signals on MRI did not consistently relate to findings on CT, BAER, EEG, school placement, or clinical examination. The abnormal signals presumably reflect areas of abnormal brain parenchyma, either hamartomas, heterotopias, or local areas of brain dysplasia. NEUROLOGY 1989;39:373-378

In 1986, we reported abnormalities on brain magnetic resonance imaging (MRI) examinations in 15 children and adults with neurofibromatosis (NF).' Over 50% of those patients had focal areas of high signal (prolonged T2)primarily in the globus pallidus, brainstem, and cerebellum. The etiology and significance of these lesions remains unknown. We have prospectively evaluated children with NF in an effort to confirm the earlier findings; to determine whether the lesions could be correlated with CT, EEG, clinical neurologic examinations, and brainstem auditory evoked responses (BAER);and to assess whether

the presence of the lesions was associated with abnormalities of cognitive function and epilepsy. Method and materials. Forty-sevenchildren with NF were evaluatedby the Neurology Serviceof Buffalo Children's Hospital. Patients had been referred for reasons including multiple caf6 au lait spots,2 positive family history for NF, macrocephaly,developmental delay, seizures, and/or learning problems. According to the consensus statement: the diagnosis of NF1 is made if two or more of the followingcriteria are met: (1) 1 6 caf6 au lait spots greater than 5 mm in diameter in prepubertal individuals and greater than 15 mm in postpuber-

From the Departments of Neurologyand Pediatrics (Drs. Duffner, Cohen, and Shucard)and Radiology (Dr. Seidel),State University of New York at Buffalo, School of Medicine, Buffalo, NY. Received May 31,1988. Accepted for publication in final form September 26,1988. Address correspondence and reprint requeststo Dr. Duffner, Department of Neurology and Pediatrics, State University of New York at Buffalo, School of Medicine, 219 Bryant Street, Buffalo, NY 14222.

March 1989 NEUROLOGY 39 373