Early next month I am planning to have Cyberknife hypo-fractionated stereotactic radiotherapy (5 x 5 Gy) for my AN/VS. Perioperative IV administration of nimodipine has been recommended by the Congress of Neurological Surgeons to improve post-op facial nerve outcomes following AN/VS surgery.* The authors write: “... there appears to be a consistent positive effect of treatment with vasoactive agents, specifically nimodipine, on the outcome of the facial nerve over the long term and potentially on hearing preservation. Although IV therapy is likely more efficacious, oral therapy may be of use as well ... Further research is needed to ascertain the true effect of vasoactive treatments for perioperative improvement in long-term facial nerve and cochlear nerve outcomes; however, treatment may be considered to attempt to achieve this effect in one’s individual practice currently.”
I've reviewed several nimodipine articles in the medical literature. My question is does it makes sense for me to take nimodipine in relation to my upcoming radiotherapy? The dosing I am considering is oral nimodipine 60 mg q4h during treatment and beginning 24 hours before I commence treatment.
Nimodipine has not been FDA approved for this use and, apparently, all of the literature on its use in conjunction with AN/VS treatment is in relation to surgery, not radiosurgery or radiotherapy. However, one of articles I considered, by Tong et al., found “Delayed cognitive deficits can be alleviated by calcium antagonist nimodipine by downregulation of apoptosis following whole brain radiotherapy” The investigators used a rat model where the rats received “a single dose of 30 Gy of WBRT followed by nimodipine injection intraperitoneally” at 2.5 ml/kg daily for seven days. (There is another study by Wang et al. (Cytotherapy. 2016 Jan;18(1):53-64. doi: 10.1016/j.jcyt.2015.10.006. PMID: 26719199) that looked at the "Neuroprotective effects of human umbilical cord-derived mesenchymal stromal cells combined with nimodipine against radiation-induced brain injury through inhibition of apoptosis." One arm of the study included nimodipine alone but the abstract doesn't report their findings on that arm and I don't have access to the full text article but they did find that mesenchymal stromal cells plus nimodipine was effective in mice in treating radiation-induced brain injury following whole brain irradiation.)
In any case, my understanding is that brain irradiation induces some analogous types of trauma that are possibly mitigated by nimodipine. On that basis and the strength of evidence for surgical trauma and the relatively mild side effects profile I am inclined to give nimodipine a try. However, I would like more information to make the best decision.
* See Van Gompel, JJ et al. below.
Excerpts from Select Nimodipine Studies- Sin, JH et al. “Nimodipine for the treatment of otolaryngic indications”, Am J Health Syst Pharm. 2018 Sep 15;75(18):1369-1377. doi: 10.2146/ajhp170677. PMID: 30190294 (abstract only).
“Three prospective randomized studies have investigated nimodipine for hearing and/or nerve preservation in patients undergoing VS resection, the results of which have suggested a potential benefit of initiating nimodipine during the perioperative period … One small pilot study found that nimodipine improved facial nerve function after maxillofacial surgery … Due to its proposed vasoactive and neuroprotective effects, nimodipine may play a role in the treatment of a number of otolaryngic pathologies including VS… Since all of the aforementioned indications are still considered off label, clinicians and patients should collaboratively assess the risks and benefits before initiating treatment." - Tong, Jing et al. “Delayed cognitive deficits can be alleviated by calcium antagonist nimodipine by downregulation of apoptosis following whole brain radiotherapy” Oncology Letters vol. 16(2) (Aug 2018): 2525-2532, PMID: 30013647.
The investigators used a rat model where the rats received “a single dose of 30 Gy of WBRT followed by nimodipine injection intraperitoneally” at 2.5 ml/kg daily for seven days. - Van Gompel, JJ et al.; “Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on Emerging Therapies for the Treatment of Patients With Vestibular Schwannomas”, Neurosurgery, Volume 82, Issue 2, 01 February 2018, Pages E52–E54, PMID: 29309638. The full text is at https://www.cns.org/guidelines/guidelines-management-patients-vestibular-schwannoma/chapter_9 .
- Scheller, C et al. “Prophylactic nimodipine treatment and improvement in hearing outcome after vestibular schwannoma surgery: a combined analysis of a randomized, multicenter, Phase III trial and its pilot study”, J Neurosurg. 2017 Dec;127(6):1376-1383. doi: 10.3171/2016.8.JNS16626. Epub 2017 Feb 24. PMID: 28298021 (abstract only).
“A pilot study (n = 30) and an analogously performed Phase III trial (n = 112) pointed to a beneficial effect of prophylactic nimodipine and hydroxyethyl starch (HES) in vestibular schwannoma (VS) surgery … the data from both studies were pooled … Logistic regression analysis adjusted for tumor size showed a 4 times lower risk for hearing loss in the treatment group compared with the control group (OR 0.25, 95% CI 0.09-0.63; p = 0.003). Facial nerve function was not significantly improved with treatment. Apart from dose-dependent hypotension (p < 0.001), the study medication was well tolerated ... Prophylactic nimodipine is safe and may be recommended in VS surgery to preserve hearing.” - Kunert, P et al., "Surgery for sporadic vestibular schwannoma. Part IV. Predictive factors influencing facial nerve function after surgery", Neurol Neurochir Pol. 2016;50(1):36-44. doi: 10.1016/j.pjnns.2015.11.006. Epub 2015 Nov 26. PMID: 26851688 (abstract only).
In correlation studies and multivariate regression analyses of 212 post-operative sporadic VS patients, nimodipine use correlated significantly (p=0.016) with very good CNVII-LTF (long-term function). Nimodipine use also had "an independent impact on very good CNVII-LTF" (p=0.0349). - Monzani, D et al., "Nimodipine in otolaryngology: from past evidence to clinical perspectives", Acta Otorhinolaryngol Ital. 2015 Jun; 35(3): 135–145. PMCID: PMC4510937.
“prophylactic treatment with NMDP [nimodipine] is definitively shown to be effective in reducing both facial and cochlear nerve damage in humans due to vestibular schwannoma surgery by improving axon regeneration and collateral sprouting. One study showed that all patients who had received NMDP and hydroxyethyl starch-based prophylaxis had a significant recovery of facial nerve function (House-Brackmann Grade I-II) compared with preoperative staging (House-Brackmann Grade III or worse) ... In addition, in more than 50% of patients undergoing surgical removal of vestibular schwannoma without prophylactic medication, intraoperative brainstem auditory evoked potentials monitoring showed a sudden or slowly progressive loss of potentials. Despite prompt initiation of intraoperative vasoactive treatment, preservation of hearing function could not be obtained, suggesting that prophylaxis is superior to intraoperative vasoactive treatment.” - Herzfeld, Eva et al. “Investigation of the neuroprotective impact of nimodipine on Neuro2a cells by means of a surgery-like stress model” International journal of molecular sciences vol. 15,10 18453-65. 14 Oct. 2014, doi:10.3390/ijms151018453. PMCID: PMC4227225.
“In rat experiments, enhanced axonal sprouting and higher survival of motoneurons was demonstrated after cutting or crushing the facial nerve by nimodipine. These results were confirmed in clinical trials following vestibular Schwannoma surgery ... in this study, we established an in vitro model to examine the survival of Neuro2a cells after different stress stimuli occurring during surgery with or without nimodipine. Nimodipine significantly decreased ethanol-induced cell death of cells up to approximately 9% in all tested concentrations. Heat-induced cell death was diminished by approximately 2.5% by nimodipine. Cell death induced by mechanical treatment was reduced up to 15% by nimodipine.” - Scheller, C et al. “Neuroprotective efficacy of prophylactic enteral and parenteral nimodipine treatment in vestibular schwannoma surgery: a comparative study”, J Neurol Surg A Cent Eur Neurosurg. 2014 Jul;75(4):251-8. doi: 10.1055/s-0033-1355164. Epub 2013 Oct 10. PMID: 24114058 (abstract only).
“Oral nimodipine improves neurologic outcome after aneurysmal subarachnoid hemorrhage. In addition, the neuroprotective efficacy of nimodipine has been revealed following skull base, laryngeal, and maxillofacial surgery … A consecutive series of 37 patients with vestibular schwannoma treated with nimodipine from the day before surgery until the seventh postoperative day was analyzed retrospectively ... Facial nerve outcome was significantly better in the group with parenteral nimodipine medication (p = 0.038). Logistical regression analysis revealed a seven times smaller risk for a deterioration of facial nerve function in the group with parenteral treatment … These results support a dependency of nimodipine's neuroprotective efficacy on its serum levels. Parenteral nimodipine treatment produces higher serum levels and has a higher neuroprotective potency ..." - Scheller, C et al. “Prophylactic intravenous nimodipine treatment in skull base surgery: pharmacokinetic aspects,” J Neurol Surg A Cent Eur Neurosurg. 2012 May;73(3):153-9. doi: 10.1055/s-0032-1313724. Epub 2012 May 3. PMID: 22241592 (abstract only).
“Nimodipine is primarily used in subarachnoid hemorrhage (SAH). Clinical trials revealed also a beneficial effect of prophylactic nimodipine treatment on cranial nerve functions following vestibular schwannoma surgery … Interindividually, continously administered intravenous nimodipine produces considerably variable serum levels. Controls of nimodipine serum concentrations may be useful to optimize nimodipine medication in skull base surgery and in the management of SAH. The serum nimodipine level is a useful marker for CSF and intracranial nerve tissue concentrations of nimodipine.”
