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Case SeriesVinca alkaloid induced cranial neuropathy

Aparajita Gupta, Shuvendu Roy, Prateep Paul

Department of Paediatrics, Command Hospital (EC), 17/1E, Alipore Rd, Alipore Police Line, Alipore, Kolkata, West Bengal 700027, 
India 

Effectiveness of Pyridostigmine and Pyridoxine in Vinca  Alkaloid-
Induced Cranial Neuropathy – A Case Series

The neurotoxicity of the vinca alkaloids in the form of peripheral neuropathy is 
well known, however, cranial neuropathy is not widely recognized especially in 
children. We describe here in three children with malignancies who developed 
vinca alkaloid induced cranial nerve palsies during treatment which resolved 
on institution of pyridoxine and pyridostigmine. Vinca-alkaloid-induced cranial 
nerve palsies represent a potentially dangerous but reversible condition.

Abstract

*Corresponding Author
Aparajita Gupta
Classified Specialist (Paediatrics) and 
Paediatric Neurologist
Department of Paediatrics,
Command Hospital (EC),17/1E, 
Alipore Rd, Alipore Police Line, Alipore, 
Kolkata, West Bengal 700027, India 
Email: aparajitadoc@gmail.com

Article History 
Received On : 05 Feb, 2022
Accepted On : 02 Jan, 2023

Funding Sources: None 

Conflict of Interest: None

Keywords: Neurotoxicity; Oncological 
urgency; Reversible Neuropathy

Online Access

DOI: 
https://doi.org/10.3126/jnps.v42i2.42865

Introduction
Vinca alkaloids include anti microtubule agents like Vincristine, Vinblastine and 
Vinorelbine which act against the tubulin subunit of the microtubules, causing 
interference in its assembly and secretory function ultimately leading to primary 
axonal degeneration.1 Vinca alkaloids based chemotherapeutic regimen is used for 
the treatment of various paediatric haematological and solid organ malignancies. 
However, the use of Vinca alkaloids is restrained by the development of dose related 
slowly progressive peripheral sensorimotor neuropathy which mandates delay or 
change in the treatment protocols as well as dose reductions. Cranial neuropathy in the 
form of oculomotor, facial, trochlear, and recurrent laryngeal nerve paresis is reported 
rarely in patients on Vinca based protocols, however the onset of this condition is life 
threatening and requires prompt identification and urgent management.2 We herein 
describe the development of cranial neuropathy in three children with malignancies 
which was successfully managed.

Case 1

Our first case was a 31/2 years old female toddler with bony lesions in the jaw and 
diabetes insipidus of six months duration with a diagnosis of primary Langerhans 
Cell Histiocytosis. She was started on induction chemotherapy consisting of weekly 
Vinblastine (3 mg / m2) along with daily prednisolone (40 mg / m2). After six weeks 
of induction chemotherapy, she was planned to be maintained on Vinblastine (3 mg / 
m2) every three weeks, prednisolone (40 mg / m2) for the first five days of a 21- day 
cycle and 6 - mercaptopurine (50 mg / m2) daily. After two cycles of maintenance 
chemotherapy, she developed a lower motor neuron facial palsy of the right side with 
deviation of the angle of the mouth, mild ptosis and drooling of saliva. There were 
no other focal neurological deficits or any otological symptoms. There was no history 
of a previous neuropathy or family history of inherited neuropathies. Further doses of 
Vinblastine were withheld, and she was started on pyridoxine at 150 mg / m2 and 
pyridostigmine at 3 mg / kg. Four weeks later the facial palsy had resolved and there 
was no recurrence of the symptoms (Figure1).

Copyrights & Licensing © 2022 by author(s). This is an Open Access article distribut-
ed under Creative Commons Attribution License (CC BY NC )

Case Series

DOI: 103126/JNPS.V4113



J Nepal Paediatr Soc | VOL 42 | ISSUE 02 |MAY-AUG,  202278

Case Series Vinca alkaloid induced cranial neuropathy

Figure 1. Facial palsy after instituting Vinblastine therapy and 
recovery of facial palsy after 4 weeks 

Case 2

The second case was a one year old female infant who presented 
with bleeding per vaginum with a solid mass in the uterus which 
was subsequently diagnosed as Embryonal Rhabdomyosarcoma. 
She was started on induction chemotherapy with Vincristine 
(VCR), Adriamycin, and Cyclophosphamide. VCR was given at 
the dose of 1 mg / m2 weekly for four cycles. Immediately after 
the fourth dose she was noticed to have bilateral ptosis (Left < 
right). Extra ocular eye movements and pupillary reactions were 
normal. There were no other focal neurological deficits. MRI brain 
was done to rule out any metastatic lesion which was normal. 
VCR was withheld and she was started on combination therapy 
of pyridoxine (150 mg / m2) and pyridostigmine (3 mg / kg). Ten 
weeks later her ptosis had resolved and there was no recurrence 
of symptoms on further follow up (Figure 2). 

Figure 2. Right sided III CN palsy after instituting Vincristine and 
recovery of ptosis after 10 weeks

Case 3 

Our third case was a four year old male child with generalised 
lymphadenopathy of six months duration and was subsequently 
diagnosed as Hodgkin’s lymphoma. He was started on the 
Adriamycin, Bleomycin, Vinblastine and Dacarzibine (ABVD) 
regimen. Vinblastine was given at 6 mg / m2 on D1 and D15 every 
28 days. After the first cycle the child initially complained about 
diplopia, and on examination was found to have developed 
complete ophthalmoplegia. Pupillary and corneal reflexes were 
normal. There was no other focal neurological deficits. His 
complete blood count, electrolytes, CSF examination and MRI were 

normal. One week later he developed bilateral ptosis (Left < right) 
with normal pupillary reaction. Further doses of Vinblastine were 
withheld, and the child was started on a neuroprotective regimen 
consisting of pyridostigmine and pyridoxine at appropriate doses. 
Two weeks later his ptosis had completely resolved and there was 
no recurrence of symptoms on further follow up. 

Discussion
The neurotoxicity caused by Vinca alkaloids manifests in the form 
of a peripheral neuropathy, autonomic neuropathy and rarely as 
cranial neuropathy and encephalopathy.1 Although peripheral 
neuropathy is commoner, the onset of cranial neuropathy though 
rare, causes severe life-threatening illness. Neurological deficits 
in the form of external ophthalmoplegia, ptosis, jaw pain, 
facial paralysis, and hoarseness of voice with dysphagia are 
the reported manifestations of cranial neurotoxicity. Recurrent 
laryngeal nerve paralysis manifesting as hoarseness of voice 
and autonomic neuropathy manifesting as cardiac rhythm 
abnormalities with hypotension are the most life-threatening 
manifestations of a toxic neuropathy due to vinca alkaloids.3,4 
Children with these symptoms should be subjected to an urgent 
laryngoscopy to directly visualise the vocal cords and not be just 
labelled as due to an upper respiratory infection, laryngitis or 
due to leukemic infiltrates. None of our patients had features of 
recurrent laryngeal nerve paralysis.

Although there is no defined timeline for the onset of the 
neurotoxicity, symptoms usually occur two to 19 weeks after the 
initiation of Vinca alkaloids-based regimen.5 All three patients 
developed signs of neuropathy between one to nine weeks. 
The various factors presumed to accelerate the development of 
neuropathy are, exceeding the maximum recommended cumulative 
doses, predisposition to hereditary neuropathy or family history 
of peripheral neuropathy, parallel administration of drugs like 
allopurinol, isoniazid, phenytoin, and poor nutritional status.2,6 
None of our patients had poor nutritional status, concomitant 
administration of other drugs other than chemotherapeutic agents 
nor did they have any family history of inherited neuropathies. 
The cumulative doses of vincristine and vinblastine did not exceed 
the recommended doses of 2 mg / m2 / week and 6 mg / m2 / 
week respectively in any of the patients. 

Diagnosis of Vinca alkaloid induced neuropathy in children 
with malignancies requires exclusion of other aetiologies most 
importantly CNS disease. The time course of onset of the cranial 
neuropathies in relation to the initiation of Vinca alkaloid therapy, 
normal CSF and MRI brain, complete resolution of the symptoms 
with pyridoxine and pyridostigmine and absence of recurrence 
of symptoms on withholding further Vinca alkaloid-based therapy 
lends credence to the diagnosis of a pure drug induced toxic 
neuropathy in all our cases. Why some children develop toxic 
neuropathy while others do not is not understood. Further there 
is a wide range of duration of timeline for the recovery of the 
symptoms as was seen in our patients (Minimum two weeks and 
maximum 10 weeks) which is also unexplainable. Currently there 
are no objective predictive methods to determine the neurotoxic 
effects of Vinca alkaloid-based therapy and therefore the key to 
minimise the toxicity is to keep a close watch on development of 
the symptoms, some of which may begin in the form of generalised 
weakness, paraesthesia, abdominal pain, constipation, and 
urinary retention. In the absence of a pathophysiological model 



J Nepal Paediatr Soc | VOL 42 | ISSUE 02 |MAY-AUG,  2022 79

Case SeriesVinca alkaloid induced cranial neuropathy

for the drug induced toxicity, management especially in children 
is either by omitting further doses of the vinca alkaloids, reducing 
the dose and at the same time instituting drugs like pyridoxine and 
pyridostigmine which are reportedly used effectively to reverse 
the toxicity.7 Although there are isolated reports on the use of 
folinic acid, glutamate, and lithium for reversing the neurotoxicity 
associated with Vinca alkaloids, no recommended regimen for 
these drugs is available as of now.8-10 At our centre, children 
developing neurotoxicity due to Vinca alkaloids are promptly 
started on pyridoxine (150 mg / m2 BD) and pyridostigmine (3 
mg / kg BD) along with withdrawal of Vinca alkaloids. All children 
in our series were symptom free with this regimen. It is unclear 
whether Vinca alkaloids can be re-started once neuropathy has 
been demonstrated. 

Conclusions
To conclude children receiving Vinca alkaloid-based therapy 
need to be monitored closely for development of neurotoxicity 
especially cranial neuropathy, some of which may be innocuous 
and life threatening. At the same time the symptomatology may 
easily be ascribed to the secondary effects of the malignancies 
on the CNS. Early initiation of therapy with pyridoxine and 
pyridostigmine hastens recovery.

References
1. Windebank AJ, Grisold W. Chemotherapy-induced 

neuropathy. J Peripher Nerv Syst. 2008 Mar;13(1):27-46. 
DOI: 10.1111/j.1529-8027.2008.00156.x. 

2. Dixit G, Dhingra A, Kaushal D. Vincristine induced cranial 
neuropathy. J Assoc Physicians India. 2012 Mar; 60:56-8. 
PMID: 22799120.

3. Tobias JD, Bozeman PM. Vincristine-induced recurrent 
laryngeal nerve paralysis in children. Intensive Care Med. 
1991;17(5):304-5.      
DOI: 10.1007/BF01713944. 

4. Annino DJ Jr, MacArthur CJ, Friedman EM. Vincristine-
induced recurrent laryngeal nerve paralysis. Laryngoscope. 
1992 Nov;102(11):1260-2.     
DOI:10.1288/00005537-199211000-00011. 

5. Chan JD. Pharmacokinetic drug interactions of vinca 
alkaloids: summary of case reports. Pharmacotherapy. 1998 
Nov-Dec;18(6):1304-7. PMID: 9855331. 

6. Müller L, Kramm CM, Tenenbaum T, Wessalowski R, Göbel 
U. Treatment of vincristine-induced bilateral ptosis with 
pyridoxine and pyridostigmine. Pediatr Blood Cancer. 2004 
Mar;42(3):287-8.      
DOI: 10.1002/pbc.10301. 

7. Boyle FM, Wheeler HR, Shenfield GM. Glutamate 
ameliorates experimental vincristine neuropathy. J Pharmacol 
Exp Ther. 1996 Oct;279(1):410-5.     
PMID: 8859020 

8. Petrini M, Vaglini F, Cervetti G, Cavalletti M, Sartucci F, Murri 
L et al. Is lithium able to reverse neurological damage induced 
by vinca alkaloids? J Neural Transm.1999;106(5-6):569-75. 
DOI: 10.1007/s007020050180. 

9. Jackson DV Jr, McMahan RA, Pope EK, Case LD, Cooper 
MR, Kaplon MK et al. Clinical trial of folinic acid to reduce 
vincristine neurotoxicity. Cancer Chemother Pharmacol. 
1986;17(3):281-4.      
DOI: 10.1007/BF00256700.


