Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028738 (nystagmus)
 7,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carboplatin, a second-generation platinum drug used in the treatment of cancer, can damage the hair cells in the vestibular system; however, little is known about the time course of its vestibulotoxic effects. The present study examined the acute vestibulotoxic effects of carboplatin (50 mg/kg) in the chinchilla. The duration of the nystagmus response evoked by cold caloric stimulation was significantly reduced 6 h following carboplatin treatment and showed a maximum, permanent reduction of approximately 50% by 24 h after injection. Light-microscopic observations at 6 h subsequent to injection revealed swollen afferent dendrites beneath type-I hair cells and the appearance of small vacuoles within the type-I hair cells; these changes were most pronounced in the crista ampullaris of the semicircular canals compared to the maculae of the utricle and saccule. Many mitochondria were swollen and partially depleted of their membranous infoldings. The mitochondrial abnormalities tended to be somewhat more severe in the hair cells than in their afferent terminals. The structural abnormalities in the mitochondria were more severe at 24 h following injection resulting in the appearance of larger and more numerous vacuoles in the hair cells. By 3 days after injection, many type-I hair cells were filled with large vacuoles which often caused severe distortion of the nucleus and disruption of the plasma membrane. Small vacuoles were occasionally observed in type-II hair cells, mainly in the crista ampullaris. These results indicate that the vestibulotoxic effects of carboplatin occur quite rapidly and cause significant disruption of the mitochondria in hair cells and their afferent terminals.
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PMID:Early damage in the chinchilla vestibular sensory epithelium from carboplatin. 939 Aug 29

Carboplatin preferentially destroys inner hair cells (IHCs) and type-I spiral ganglion neurons while sparing outer hair cells (OHCs). Loss of IHCs and type-I ganglion cells is associated with a significant reduction of the compound action potential (CAP). However, the cochlear microphonic (CM) potential and distortion product otoacoustic emissions (DPOAEs) remain normal, indicating that the OHCs are functionally intact. In the vestibular system, carboplatin selectively destroys type-I hair cells and their afferent neurons. Damage of type-I vestibular hair cells and their afferent terminals is associated with significant depression of nystagmus induced by cold, caloric stimulation. Histochemical studies revealed a rapid decrease in succinate dehydrogenase (SDH) staining in IHCs soon after carboplatin treatment, and staining intensity remained depressed in surviving IHCs for at least 1 month after carboplatin treatment. These results suggest that carboplatin depresses the metabolic function in surviving IHCs. Several lines of evidence suggest that free radicals may contribute to carboplatin-induced sensory cell damage. Intracochlear infusion of L-buthionine-[S,R]-sulfoximine (BSO), which depletes intracellular glutathione (GSH), increases IHC and OHC loss. Previous in vitro studies have shown that neurotrophin 4/5 (NT-4/5) promotes the survival of spiral ganglion neurons from cisplatin ototoxicity. In vivo perfusion of NT-4/5 promoted the survival of spiral ganglion neurons, but did not protect the hair cells.
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PMID:Selective loss of inner hair cells and type-I ganglion neurons in carboplatin-treated chinchillas. Mechanisms of damage and protection. 1084 92

Paraneoplastic cerebellar degeneration (PCD) is a rare syndrome associated with systemic malignancies, most in lung and ovarian cancer. Cerebellar ataxia has previously been associated with the presence of anti-Purkinje cell antibodies (anti-Yo) in the serum and cerebrospinal fluid and responses to therapy are uncommon. We reported two patients were identified with delayed onset of PCD associated with high titer of CSF anti-Yo (1:30,000, 1:320 U/ml) and a marked elevation of tumor markers for ovarian cancer (CA-125 17,700 ng/ml, 43 ng/ml) titer 1 year and 6 months prior to discovery of the carcinoma. Both developed subacute onset of severe ataxia, dysarthria, tremor, nystagmus with progression to severe debilitation (wheelchair bound or bedridden status). One of these patients also developed dysphagia that required PEG tube feeding. They were treated with six cycles of intravenous immunoglobulin (IVIG) 0.4 gm/kg/day x 5 days, every 4-6 weeks in conjunction with combination chemotherapy of Taxol and Carboplatin after the surgical resection of ovarian cancer. In each case, a significant improvement of neurological deficits were seen after the third cycle of IVIG, approximately 4 months after initiation of treatment. This type of delayed response is contrary to the previous reports. Both patients could ambulate without assistance in correlation with dramatic decrease in anti-Yo titer (1:80, 1:320 U/ml) and CA-125 (11 ng/ml, 8 ng/ml). This is a first report of benefit from IVIG in patients with late onset of PCD, which showed a delayed response with significant neurological improvement.
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PMID:Neurologic improvement after high-dose intravenous immunoglobulin therapy in patients with paraneoplastic cerebellar degeneration associated with anti-Purkinje cell antibody. 1677 14