Immunological characterization of a neuronal antibody (anti-Tr) associated with paraneoplastic cerebellar degeneration and Hodgkin's disease.

We studied an autoantibody (called anti-Tr), found in the serum and CSF of five patients with paraneoplastic cerebellar degeneration (PCD) and Hodgkin's disease (HD). Anti-Tr antibodies labelled the cytoplasm of Purkinje cells of human and rat cerebellum. The molecular layer of rat cerebellum showed a characteristic dotted pattern suggestive of immunoreactivity of dendritic spines of Purkinje cells. Patients with cerebellar disorders without HD (159) or HD without PCD (30) did not harbor anti-Tr antibodies. Immunoblots of human Purkinje cells or rat and mouse cerebellum were negative. Anti-Tr antibodies, as defined in this study, appear specific for HD-associated PCD. The immunohistochemical pattern described in the rat cerebellum coupled with the absence of reactivity in the immunoblot may be used to identify anti-Tr antibodies.

Pitfalls in the diagnosis of autoantibodies associated with paraneoplastic neurologic disease.

We studied the sera of 15 patients with Sjögren's syndrome using the Western blot technique for the presence of anti-Ro and anti-Hu (type 1 antineuronal nuclear autoantibody [ANNA-1]). All sera reacted with Ro-52 protein. Two of the Sjögren sera reacted with 38-kd bands on Western blots of rat cerebellar homogenate, resembling anti-Hu immunoreactivity. However, when reacted with purified human Purkinje cells or purified recombinant HuD protein, none of the sera immunoreacted with the Hu antigens. We recommend the use of either a recombinant Hu protein or the combination of immunohistochemistry and Western blot of purified human neuronal preparations to identify paraneoplastic antibodies. This approach will prevent the unnecessary workup for suspected lung cancer.

Systemic and anti-neuronal auto-antibodies in patients with paraneoplastic neurological disease.

Sera from 23 patients with paraneoplastic disease of the central nervous system (PNS) were examined for the presence of anti-neuronal (anti-Hu, anti-Yo/PCA) and anti-Ri) and systemic auto-antibodies, including antibodies against DNA, centromeres, nRNP, Sm antigen, Scl-70, Ro(SS-A), La(SS-B), mitochondria, thyroid antigens, parietal calls, brush border antigen and rheumatoid factor. As controls, sera from 33 patients with small cell lung cancer, 33 with ovarian cancer and 7 with breast cancer and from 107 aged-matched healthy persons were used. Systemic auto-antibodies were found in 52% of patients with paraneoplastic neurological syndromes compared with only 16% (P = 0.001) in the control group with cancer only and 15% in the group of healthy controls. The relatively high percentage of systemic auto-antibodies in patients with PNS indicates that there is a genetic susceptibility to the development of auto-immune phenomena. This may provide an explanation for the relatively rare occurrence of PNS in patients with cancer.

Effect of an ACTH(4-9) analogue on cisplatin neuropathy of longstanding duration: a phase II study.

The efficacy of Org 2766, an ACTH(4-9) analogue, on the recovery of cisplatin neuropathy of longstanding duration was investigated in a phase II study. Twenty-two patients were treated with Org 2766 during a period of 4 months and vibration perception threshold (VPT) and sum scores for neuropathic symptoms and signs were compared with pre-treatment values. No change in VPT could be detected. Although there was a small improvement of clinical measures for neuropathy, no clear evidence for repair could be obtained. These results indicate no beneficial effect of Org 2766 on recovery of a longstanding cisplatin neuropathy.

Immune diagnosis of paraneoplastic neurological disease.

A continuous stream of new information on clinical, pathological and immunological aspects of paraneoplastic neurological syndromes has been published in recent years. In this survey, we will discuss current opinions on the value of anti-neuronal antibody detection for establishing a diagnosis of one of the paraneoplastic syndromes of the central nervous system.

Neurotoxicity is not enhanced by increased dose intensities of cisplatin administration.

It is uncertain whether intensive dosing schedules of cisplatin, intended to attain a higher anti-tumour efficacy, alter the severity of cisplatin-induced neuropathy. We assessed the development of neuropathy in three groups of patients treated with cisplatin in different dosing schedules. The severity of neuropathy was determined by measurement of the vibration perception threshold (VPT) before treatment and during follow-up for 2-12 months after the last cycle. 66 patients were treated with an intensive weekly regimen of doses varying from 70 to 85 mg/m2 in 1 day (trial A), 21 patients with a 3-weekly combination chemotherapy containing cisplatin 75 mg/m2 in 1 day (trial B) and 20 patients with a 3-weekly regimen containing cisplatin 20 mg/m2 for 5 consecutive days (trial C). The mean dose intensity achieved was 59 mg/m2/week in trial A, 21 mg/m2/week in trial B and 33 mg/m2/week in trial C. The maximum post-treatment VPT correlated significantly with pretreatment VPT (P < 0.001) and with the cumulative dose of cisplatin (P < 0.001). Following correction for these two variables, the maximum posttreatment VPT did not show a statistically significant association with dose intensity. These results suggest that neuropathy is not related to dose intensity of cisplatin. This implies that treatment with more intensive dosing schedules, employing equal cumulative doses of cisplatin, does not result in a concomitant increase in neurotoxicity within a cumulative dose range of 280-675 mg/m2.

The effects of an ACTH (4-9) analogue on development of cisplatin neuropathy in testicular cancer: a randomized trial.

The efficacy of the ACTH (4-9) analogue Org 2766 in the prevention of subclinical cisplatin neuropathy was assessed in a double-blind placebo-controlled multi-centre study in patients with testicular cancer or adenocarcinoma of unknown primary. Forty-two patients received at least four cycles of cisplatin (100 mg/m2 per cycle), together with subcutaneous injections of Org 2766 (2 mg/day for 5 consecutive days) or placebo. Vibratory threshold was used as a measure of neuropathy. For each individual patient, the influence of cisplatin on vibratory perception was quantified by the slope of the regression line between the natural logarithm of the vibratory thresholds and the number of cycles. From the slopes, the proportional increase of vibratory threshold per cycle of cisplatin was calculated. On average, vibratory thresholds increased by 42% with each cycle of 100 mg/m2 of cisplatin in the placebo group, and by 19% during treatment with Org 2766. The influence of cisplatin on vibratory thresholds was highly significant in the placebo group (P < 0.0001), and of borderline significance in the group treated with Org 2766 (P = 0.06). The difference in slopes between the two groups was of borderline statistical significance (Wilcoxon's two-sample test: P = 0.06; analysis of variance: P = 0.04). These results show that Org 2766 cannot completely prevent cisplatin neuropathy in young men with testicular cancer, but nerve damage may be ameliorated by the use of this ACTH (4-9) analogue.

Paclitaxel (Taxol) induces cumulative mild neurotoxicity.

Paclitaxel (Taxol), a new antineoplastic drug, has been reported to be neurotoxic at doses above 200 mg/m2 per course. It is uncertain whether neurotoxicity is related to cumulative amounts of paclitaxel. Neuropathy was prospectively assessed in 18 patients with breast cancer, receiving between two and eight courses of 135 or 175 mg/m2 of paclitaxel. Vibratory perception thresholds (VPT) and tendon reflex scores were proportionally related to the corresponding cumulative amounts of paclitaxel (P = 0.002; P = 0.0003). The amounts of paclitaxel administered between the first and last assessments (175-1225 mg/m2) were related to concomitant changes in VPT (P = 0.034). Paclitaxel had no clear neurotoxic threshold; if present, it lies below 540 mg/m2. Rather, VPT appeared to increase 0.1 micron per 400 mg/m2 over the entire range of 175-1225 mg/m2 of paclitaxel. Clinical neuropathy prevailed in 0/8 patients at screening and in 5/10 patients at the final assessment (P = 0.029). Neuropathy never exceeded grade 1. Thus, although neurotoxicity of paclitaxel is frequent and cumulative, it remains mild or subclinical up to at least 1400 mg/m2 administered over eight cycles.

Clinical course and risk factors of neurotoxicity following cisplatin in an intensive dosing schedule.

An intensive weekly regimen of cisplatin was administered to 66 patients with solid cancer in doses varying from 70 to 85 mg/m(2) . The occurrence of sensory neuropathy was prospectively examined by assessment of neuropathic signs and symptoms and measurement of vibration perception threshold (VPT). Evaluation was performed before initiation of therapy and during follow-up until 3-12 months after the last cycle of cisplatin. A mild or moderate neuropathy developed in 47% of patients at 2 weeks after treatment This neuropathy continued to deteriorate until approximately 3 months after cessation of chemotherapy leading to a mild or moderate neuropathy in 71% of patients and a severe neuropathy in 9% of patients. Thereafter we observed a gradual but incomplete recovery. The high incidence of neuropathy we found may be explained by the prolonged observation period compared with earlier reports. The only factor correlated with severity of neuropathy was the cumulative dose of cisplatin, while there was no association with either pre-treatment VPT, age, sex, tumor type or co-treatment with etoposide. The progressing course up to approximately 3 months after the end of treatment underscores the need for prolonged follow-up in future studies on cisplatin neuropathy.-

Antineuronal antibodies in patients with neurologic complications of primary Sjögren's syndrome.

Neurologic complications of both the central and peripheral nervous systems occur frequently in patients with primary Sjögren's syndrome (primary SS), but the underlying cause of these complications is unknown. We studied the presence of antineuronal antibodies in relation to neurologic complications in a consecutive series of 45 patients with primary SS. Twenty-five patients had neurologic complications: 12 patients with polyneuropathy, three with psychiatric disorders, four with carpal tunnel syndrome, seven with migraine, seven with myalgia, and four with other complications (transverse myelitis, stroke, Bell's palsy, and pyramidal signs). Ten patients had more than one neurologic complication. Eleven patients had major and 14 had minor complications according to criteria used for rating neurologic complications in patients with systemic lupus erythematosus. Antineuronal antibodies were present in six of 11 (55%) patients with major neurologic complications and in four of 34 (11%) of patients without major neurologic complications (p = 0.001). This difference could be attributed mainly to the group of patients with polyneuropathy. Three of the 10 sera of patients with positive antineuronal antibodies had antibodies reacting with a 38-kd neuronal protein on immunoblotting, identical to the anti-Hu antibody reactivity in paraneoplastic neurologic disease associated with small-cell lung cancer.

Diagnostic value of anti-neuronal antibodies for paraneoplastic disorders of the nervous system.

The diagnostic value of the presence of anti-neuronal antibodies in serum was examined in 21 patients suspected of paraneoplastic disorders of the nervous system (NS) (group 1) and was compared to three control groups; group 2: 25 patients with a neurological disease, without cancer and no sign of paraneoplastic disorder; group 3: 27 patients with neurological disease and cancer and no signs of a paraneoplastic disorder; group 4: 94 patients with cancer and without neurological disease. In group 1, anti-neuronal nuclear antibodies were detected in eight patients (38%), in titres from 1:1000 to 1:32,000. A small cell lung cancer was present in six patients, ovarian cancer in one patient and in one patient no tumour could be detected. The neurological symptoms preceded a diagnosis of cancer in five out of eight patients. Anti-neuronal antibodies were found in the serum of two out of 94 patients (2%) from control group 3 but not in serum from any of the other control groups. These data indicate a moderate sensitivity of 38%, but a high specificity of 98.6% (95% confidence interval 95.5-99.8%) for the presence of anti-neuronal nuclear antibodies if a paraneoplastic NS disorder is suspected.

Frequent hypoxemia and apnea after sedation with midazolam and fentanyl.

More than 80 deaths have occurred after the use of midazolam (Versed), often in combination with opioids, to sedate patients undergoing various medical and surgical procedures. We investigated the respiratory effects of midazolam (0.05 mg.kg-1) and fentanyl (2.0 micrograms.kg-1) in volunteers. The incidence of hypoxemia (oxyhemoglobin saturation less than 90%) and apnea (no spontaneous respiratory effort for 15 s) and the ventilatory response to carbon dioxide were evaluated. Midazolam alone produced no significant respiratory effects. Fentanyl alone produced hypoxemia in half of the subjects and significant depression of the ventilatory response to CO2, but did not produce apnea. Midazolam and fentanyl in combination significantly increased the incidence of hypoxemia (11 of 12 subjects) and apnea (6 of 12 subjects), but did not depress the ventilatory response to CO2 more than did fentanyl alone. Adverse reactions linked to midazolam and reported to the Department of Health and Human Services highlight apnea- and hypoxia-related problems as among the most frequent adverse reactions. Seventy-eight per cent of the deaths associated with midazolam were respiratory in nature, and in 57% an opioid had also been administered. All but three of the deaths associated with the use of midazolam occurred in patients unattended by anesthesia personnel. We conclude that combining midazolam with fentanyl or other opioids produces a potent drug interaction that places patients at a high risk for hypoxemia and apnea. Adequate precautions, including monitoring of patient oxygenation with pulse oximetry, the administration of supplemental oxygen, and the availability of persons skilled in airway management are recommended when benzodiazepines are administered in combination with opioids.

Anti-neuronal antibodies in paraneoplastic neurological disorders with small-cell lung carcinoma.

Auto-antibodies of the neuronal anti-nuclear antibody (anti-Hu) type were found in serum of three patients suspected of a paraneoplastic syndrome of the central nervous system. In all three a small cell carcinoma of the lung was detected. The sera showed bright staining of neuronal nuclei sparing the nucleolus. In two patients the antibody was of the IgG class (titers 1:1600 and 1:4000). In one patient only an IgM class antibody was present (titer 1:1000). The presence of the anti-Hu antibody strongly supports a diagnosis of a paraneoplastic neurological syndrome associated with small cell carcinoma of the lung.

Treatment of ischaemic heart disease complications.

After myocardial infarction, 20% of all patients suffer from left heart aneurysm, the papillary muscle rupture and ischaemic septal perforation. Symptoms, diagnostic methods and surgical treatment are described. Special attention is paid to aneurysm of the posterior wall which, though relatively rare, presents special therapeutic problems.

Long-term evaluation of allograft aorta and valve replacement.

A technique for the management of dissecting aortic aneurysm with aortic valve insufficiency, using allograft replacement and coronary artery reimplantation is presented. The author's experience is based in 56 allograft valve implantations. The softness of the biological material facilitates the coaptation between the valve and an often irregular, calcified bed, as well as reimplantation of coronary arteries. Allograft transplantation produces an immunological response, but this has no notable clinical significance. Long-term results are very satisfactory. Cases of endocarditis, cusp rupture and severe calcification have not been observed.