Chemotherapy-related trigeminal and glossopharyngeal nerves neurotoxicity: a cohort study.

BACKGROUND AND OBJECTIVES: The association between orofacial neurotoxicity and chemotherapy treatment is still unclear. In this context, the purpose of this study is to relate the orofacial alterations that manifest during antineoplastic pharmacological treatment, highlighting the drugs commonly related to orofacial neuropathy and the adequate instrument to verify the alterations at clinical levels. METHODS: This prospective cohort study, addressed patients who would start therapy with taxanes, platinum, or related therapy. The collection of signs and symptoms was divided into 3 different times (baseline, second or third cycle of antineoplastic chemotherapy treatment, and sixth cycle). A total of 40 patients were submitted to the application of the Short McGill pain questionnaire and Neutoxicity Induced by Antineoplastics questionnaire (QNIA). To verify sensory alterations in the face, a clinical evaluation was performed with the help of Semmes-Weinstein monofilaments. RESULTS: Taxanes show greater orofacial neurotoxic potential, being associated with sensory alterations assessed by monofilaments (P = .003) and the presence of orofacial pain analyzed by the Short McGill pain questionnaire (P = .001). These medications related to neuropathy in the orofacial region measured through the QNIA, demonstrating a predominantly acute nature (P < .001). CONCLUSION: It is suggested that chemotherapy may induce neurotoxicity in the orofacial region.

REVERSIBLE NEUROTROPHIC KERATOPATHY ASSOCIATED WITH ROSUVASTATIN THERAPY: A CASE REPORT.

BACKGROUND: Rosuvastatin is a 3-hydroxy-3-methyl-glutaryl-CoA reductase enzyme inhibitor that is in wide use with few reported ocular adverse events. OBJECTIVES: To report a case of bilateral neurotrophic keratopathy associated with rosuvastatin therapy that dramatically improved following drug discontinuation. CASE PRESENTATION: A 65-year-old female presented with painless diminution of vision in both eyes of gradual onset and progressive course for 1 month. She had recently started rosuvastatin therapy for hyperlipidemia. Examination revealed bilateral stage 2 neurotrophic keratopathy with impaired corneal sensation which was previously resistant to conservative ulcer treatment. Following discontinuation of rosuvastatin therapy, there was dramatic bilateral improvement in corneal sensation, size of the corneal ulcers, and visual acuity. CONCLUSION: Rosuvastatin may result in reversible trigeminal nerve impairment and neurotrophic keratopathy.

The effects of levetiracetam, sumatriptan, and caffeine in a rat model of trigeminal pain: interactions in 2-component combinations.

BACKGROUND: Levetiracetam is an antiepileptic drug with analgesic efficacy shown in pain models and small clinical trials. Sumatriptan is used in acute migraine treatment. Caffeine is widely consumed in some beverages/foods and is also an adjuvant in analgesic formulations. We examined the effects of systemic levetiracetam, sumatriptan, and caffeine and their interactions in 2-component combinations in the rat orofacial formalin test, a model of trigeminal pain. METHODS: Rats received a subcutaneous injection of formalin solution into the perinasal area, and the total time spent in nociceptive behavior (face rubbing) was quantified. The antinociceptive effect of drugs/drug combinations was assessed 1 hour after per os administration. The type of interaction between levetiracetam/sumatriptan and caffeine was examined by comparing the effects of a fixed, effective dose of levetiracetam/sumatriptan alone with the effects of the same dose applied with increasing, subeffective doses of caffeine. The type of interaction between levetiracetam and sumatriptan was determined by isobolographic analysis. RESULTS: Levetiracetam (1-50 mg/kg) and sumatriptan (0.5-5 mg/kg) produced significant and dose-dependent antinociceptive effects in both phases of the orofacial formalin test (P ≤ 0.001). Caffeine (7.5-100 mg/kg) produced significant antinociception in the second phase of the test (P = 0.04). Caffeine (1-7.5 mg/kg) significantly reduced the antinociceptive effects of levetiracetam (25 mg/kg) (first phase P = 0.002, second phase P < 0.001) and sumatriptan (2.5 mg/kg) (first phase P = 0.014, second phase P = 0.027); dose-dependent inhibition was observed in the second phase. Levetiracetam and sumatriptan exerted an additive interaction in the second phase of the orofacial formalin test. CONCLUSIONS: Results indicate that levetiracetam may be useful for treatment of pain in the trigeminal region. Dietary caffeine might decrease the effects of levetiracetam and sumatriptan; this needs to be considered in clinical settings. A levetiracetam-sumatriptan combination could also be useful in trigeminal pain treatment. Its efficacy and adverse effects should be examined clinically.

Neurotrophic corneal ulcer after retrobulbar injection of chlorpromazine.

An 80-year-old woman with a painful, poorly seeing right eye underwent retrobulbar chlorpromazine injection for pain control. After the injection, the patient's symptoms improved; however, a neurotrophic ulcer developed within 2 weeks after the procedure. It is postulated that chlorpromazine may lead to sensory denervation to the cornea with the subsequent development of neurotrophic keratopathy, as observed in this case. Awareness of this potential adverse effect is important for proper patient safety, education, and postinjection management.

Trigeminal nerve injury associated with injection of local anesthetics: needle lesion or neurotoxicity?

BACKGROUND: The authors used comprehensive national registry and clinical data to conduct a study of adverse drug reactions (ADRs), in particular neurosensory disturbance (NSD), associated with local anesthetics used in dentistry METHODS: The study included data sets of annual sales of local anesthetics (from 1995 through 2007), 292 reports to the Danish Medicines Agency, Copenhagen, Denmark, of adverse reactions to local anesthetic drugs, and a clinical sample of 115 patients with NSD associated with local anesthetics. The authors assessed lidocaine 2 percent, mepivacaine 2 percent and 3 percent, prilocaine 3 percent, and articaine 4 percent sold in cartridges. RESULTS: The study results showed a highly significant overrepresentation of NSDs associated with articaine 4 percent, in particular with mandibular blocks. CONCLUSIONS: The distribution of NSDs was disproportionate to the market share of three of the four drugs in both national registry data and clinical data. These findings indicate that the main cause of injury was neurotoxicity resulting from administration of the local anesthetic rather than the needle penetration. CLINICAL IMPLICATIONS: Clinicians may consider avoiding use of high-concentration (4 percent) anesthetic formulations for block anesthesia in the trigeminal area in cases in which there are viable alternatives.

Ablation of T cell immunity differentially influences tumor risk in inbred BD rat strains.

Inbred rat strains BDIX and BDIV are constitutionally susceptible and resistant, respectively, to the development of malignant peripheral nerve sheath tumors (MPNST) induced by neonatal exposure to N-ethyl-N-nitrosourea (EtNU). They represent a model system for analysis of molecular and cellular processes underlying differential cancer susceptibility. A point mutation in the Neu/ErbB-2 gene is an early marker of Schwann precursor cells at high risk of malignant conversion and is diagnostic of the resulting MPNST predominantly developing in the trigeminal nerves. Initially considerable amounts of Neu/ErbB-2-mutant cells arise in nerve tissue of both rat strains subsequently disappearing in resistant BDIV rats, but persisting and giving rise to MPNST in susceptible BDIX animals. An almost identical cellular immune response-sequentially involving macrophages, T helper- and cytotoxic T lymphocytes-is mounted in the trigeminal nerves of EtNU-treated rats of both strains. In this study, T cell maturation was prevented by neonatal thymectomy following EtNU-exposure. While resistance against MPNST development significantly decreased in BDIV rats MPNST incidence and survival time remained unaltered in thymectomized BDIX rats. Contrary to euthymic animals a number of both thymectomized BDIV and BDIX rats developed MPNST lacking the Neu/ErbB-2-mutation. This suggests that Schwann cells initiated by other genetic alterations can progress to full malignancy in immune-compromised rats only. T cell-dependent resistance against tumorigenesis originating from non-Neu/ErbB-2-mutant Schwann precursors might thus be shared by both strains while BDIV T lymphocytes additionally prevent the development of Neu/ErbB-2-mutant MPNST. Rat strain-specific differences in the interaction of T lymphocytes with (pre)malignant Neu-mutant cells may thus critically contribute to susceptibility and resistance towards EtNU-induced MPNST development.

Cranial neuropathies after intracranial Photofrin-photodynamic therapy for malignant supratentorial gliomas-a report on 3 cases.

BACKGROUND: In an RCT of PDT in the treatment of malignant gliomas, 3 patients developed cranial neuropathies after photoillumination. We are aware of no previous reports on cranial neuropathy after intracranial PDT. METHODS: In a cohort of 80 patients, there were 41 men and 39 women; 47 were newly diagnosed and 33 had recurrent tumors. All patients underwent surgical tumor extirpation. There were 77 malignant gliomas, 2 meningiomas, and 1 metastatic tumor. The tumor locations were as follows: 39 frontal, 25 temporal, 12 parietal, and 4 occipital. Of the 25 patients with temporal lobe tumors, 18 received PDT. RESULTS: Three of the 18 patients with temporal lobe tumors developed cranial neuropathies after PDT. The floor of the middle fossa received photoillumination in all 3 patients. This complication was not seen in any other patient with tumors in the frontal, parietal, or occipital regions, or patients with temporal lobe tumors who did not receive PDT. The first patient developed seventh nerve paresis and hypoesthesia in fifth nerve distribution, which resolved only partially. The second patient developed a seventh nerve paresis that resolved completely. The third patient developed transient neuralgic pain in the trigeminal nerve distribution. CONCLUSIONS: Cranial neuropathies could be the result of photoillumination of fifth and seventh cranial nerves during PDT of the temporal fossa. We recommend shielding of the middle fossa floor during PDT.

Trigeminal nerve palsy and Horner's syndrome following epidural analgesia for labor: a subdural block?

Horner's syndrome is a rare complication of epidural analgesia for labor. Much more uncommon is trigeminal nerve palsy. Both complications may be attributed to a subdural localization of the catheter, as we demonstrated clinically by a repeat injection and patchy sympathetic block and with the typical image on epidurography.

Species and sex differences in susceptibility to olfactory lesions among the mouse, rat and monkey following an intravenous injection of vincristine sulphate.

Species and sex differences in susceptibility to vincristine sulphate (VCR)-induced olfactory epithelial lesions were investigated among the BALB/c mice, Crj: CD(SD) IGS rats and common marmoset monkeys following a single intravenous administration on day 1. As dosage levels, the 0.17-fold LD10, 0.6-fold LD10 and LD10 were used for mice and rats, and a maximum tolerated dose (MTD) was chosen only for monkeys. The order of strength of VCR action on peripheral neuropathic signs, body weight gain, and hematological parameters was mice > rats > monkeys, without clear sex differences. Histopathologically, on day 2, single cell death in the olfactory epithelium and vomeronasal organ was observed only in male mice at LD10, and in female mice at 0.6-fold LD10 or more. On day 5, the olfactory epithelium in these mice showed regenerative proliferation suggesting a sign of recovery. On day 10, axonopathy and demyelination in the sciatic and trigeminal nerves were noted in mice of both sexes at 0.6-fold LD10 or more. In rats and monkeys of either sex, however, no morphological changes were observed at any dose level. In conclusion, mice, particularly females, were shown to be more susceptible to VCR-induced apoptosis in the olfactory epithelium than rats and monkeys.

Adverse drug reactions in the orofacial region.

A wide spectrum of drugs can sometimes give rise to numerous adverse orofacial manifestations, particularly dry mouth, taste disturbances, oral mucosal ulceration, and/or gingival swelling. There are few relevant randomized double-blind controlled studies in this field, and therefore this paper reviews the data from case reports, small series, and non-peer-reviewed reports of adverse drug reactions affecting the orofacial region (available from a MEDLINE search to April, 2003). The more common and significant adverse orofacial consequences of drug therapy are discussed.

Restoration of corneal epithelial barrier function and wound healing by substance P and IGF-1 in rats with capsaicin-induced neurotrophic keratopathy.

PURPOSE: To investigate the effects of topical application of the combination of substance P (SP) and insulin-like growth factor (IGF)-1 on corneal epithelial barrier function and epithelial wound closure in rats with capsaicin-induced neurotrophic keratopathy. METHODS: Neonatal rats were injected subcutaneously with a single dose of capsaicin to induce neurotrophic keratopathy. Corneal epithelial barrier function was evaluated with an anterior fluorophotometer. Tear fluid secretion was measured by the Schirmer test. Corneal epithelial wound healing was determined by measurement of the size of the epithelial defect after debridement of the entire epithelium. The combination of SP (1 mM) and IGF-1 (1 micro g/mL) in phosphate-buffered saline was administered in eye drops six times daily. RESULTS: Corneal epithelial barrier function was impaired and corneal epithelial wound healing was delayed in rats injected with capsaicin. The application of eye drops containing the combination of SP and IGF-1 to capsaicin-injected rats resulted in a significant improvement in corneal epithelial barrier function compared with that apparent in capsaicin-injected animals that received eye drops containing vehicle alone. Such treatment with SP and IGF-1 also significantly increased the rate of corneal epithelial wound closure in capsaicin-injected animals. CONCLUSIONS: Topical application of the combination of SP and IGF-1 improved both corneal epithelial barrier function and epithelial wound healing in an animal model of neurotrophic keratopathy.

Mefloquine-induced trigeminal sensory neuropathy.

Trigeminal sensory neuropathy is an important finding, often indicative of trauma but sometimes related to neoplasia, infections, demyelinating conditions, connective tissue disorders, other disorders, or, occasionally, drugs. This paper reports on a patient with sudden-onset trigeminal sensory neuropathy of the lip that proved to be drug-induced, secondary to the antimalarial drug mefloquine. This appears to be the first report of sensory impairment in the orofacial region from exposure to mefloquine.

Iatrogenic trigeminal sensorimotor neuropathy resulting from local anesthesia: a case report.

Trigeminal neuropathy resulting from local anesthetic injection has not been reported in the literature. We present a 49-year-old man with 8 months of unilateral facial sensorimotor deficits in the distribution of the trigeminal nerve, following a local anesthetic injection. His medical history was significant for resection of an ipsilateral tongue carcinoma 4 years earlier with only postsurgical dysarthria and no other neurologic deficits. Magnetic resonance imaging of the head and face showed postsurgical changes and ipsilateral atrophic muscles of mastication without evidence of infection or tumor recurrence. Electrodiagnostic evaluation revealed prolonged ipsilateral R1, ipsilateral and contralateral R2 responses of the blink reflex, and neurogenic electromyographic changes in ipsilateral masseter and temporalis muscles, consistent with ipsilateral trigeminal nerve injury. Although trigeminal neuropathies from various etiologies have been reported, this unique case offers another etiology to consider: iatrogenic trigeminal neuropathy secondary to local anesthetic injection.

Bupropion-induced isolated impairment of sensory trigeminal nerve function.

Bupropion is increasingly used for nicotine withdrawal and in the treatment of major depression, especially in bipolar patients. We present the case of a 38-year-old female schizoaffective, rapid-cycling patient treated with bupropion for a depressive episode. After 4 weeks of successful treatment (300 mg/day), the patient developed a circumscribed unilateral impairment of sensory trigeminal nerve function. Symptoms completely recovered after discontinuation of bupropion. When re-exposed to bupropion, mild symptoms reappeared, leading to final discontinuation of bupropion. With this natural on-off-on-off design, a causative role of bupropion for trigeminal impairment in this patient can be assumed. To our knowledge, a similar side-effect of bupropion has not been described to date.