Neuronal involvement in cisplatin neuropathy: prospective clinical and neurophysiological studies.

Although it is well known that cisplatin causes a sensory neuropathy, the primary site of involvement is not established. The clinical symptoms localized in a stocking-glove distribution may be explained by a length dependent neuronopathy or by a distal axonopathy. To study whether the whole neuron or the distal axon was primarily affected, we have carried out serial clinical and electrophysiological studies in 16 males with testicular cancer before or early and late during and after treatment with cisplatin, etoposide and bleomycin at limited (<400 mg/m2 cisplatin), conventional (approximately 400 mg/m2 cisplatin) or high (>400 mg/m2 cisplatin) doses. At cumulative doses of cisplatin higher than 300 mg/m2 the patients lost distal tendon and H-reflexes and displayed reduced vibration sense in the feet and the fingers. The amplitudes of sensory nerve action potentials (SNAP) from the fingers innervated by the median nerve and the dorsolateral side of the foot innervated by the sural nerve were 50-60% reduced, whereas no definite changes occurred at lower doses. The SNAP conduction velocities were reduced by 10-15% at cumulative doses of 400-700 mg/m2 consistent with loss of large myelinated fibres. SNAPs from primarily Pacinian corpuscles in digit 3 and the dorsolateral side of the foot evoked by a tactile probe showed similar changes to those observed in SNAPs evoked by electrical stimulation. At these doses, somatosensory evoked potentials (SEPs) from the tibial nerve had increased latencies of peripheral, spinal and central responses suggesting loss of central processes of large dorsal root ganglion cells. Motor conduction studies, autonomic function and warm and cold temperature sensation remained unchanged at all doses of cisplatin treatment. The results of these studies are consistent with degeneration of large sensory neurons whereas there was no evidence of distal axonal degeneration even at the lowest toxic doses of cisplatin.

Prognostic factors in metastatic spinal cord compression: a prospective study using multivariate analysis of variables influencing survival and gait function in 153 patients.

PURPOSE: Based on a very large patient cohort followed prospectively for at least a year or until death, we analyzed the prognostic significance of various clinical and radiological variables on posttreatment ambulatory function and survival. METHODS AND MATERIALS: During a 312-year period we prospectively included 153 consecutive patients with a diagnosis of spinal cord compression due to metastatic disease. The patients were followed with regular neurological examinations by the same neurologist for a minimum period of 11 months or until death. The prognostic significance of five variables on gait function and survival time after treatment was analyzed. RESULTS: The type of the primary tumor had a direct influence on the interval between the diagnosis of the primary malignancy and the occurrence of spinal cord compression (p < 0. 0005), and on the ambulatory function at time of diagnosis (p = 0. 016). There was a clear correlation between the degree of myelographic blockage and gait function (p = 0.000) and between gait function and sensory disturbances (p = 0.000). The final gait was dependent on the gait function at time of diagnosis (p < 0.0005). Survival time after diagnosis depended directly on the time from primary tumor diagnosis until spinal cord compression (p = 0.002), on the ambulatory function at the time of diagnosis (p = 0.018), and on the ambulatory function after treatment. CONCLUSIONS: The pretreatment ambulatory function is the main determinant for posttreatment gait function. Survival time is rather short, especially in nonambulatory patients, and can only be improved by restoration of gait function in nonambulatory patients by immediate treatment.

[Multiple epidural metastases and development of secondary metastatic spinal cord compression]. / Multiple epidurale metastaser og udvikling af sekundaert metastatisk tvaersnitssyndrom.

The purpose was to examine the frequency of initial multiple epidural metastases, and the occurrence of secondary spinal cord compression (SCC). One hundred and seven patients with SCC from a histologically verified solid tumour were followed prospectively with regular neurological examinations until death. Multiple metastases were demonstrated in 37 (35%). Eight (7.5%) patients developed a second occurrence of SCC all in a new location within the spinal canal. The second occurrence of SCC was found with the same frequency in patients with single metastases (7.1%) compared to patients with multiple metastases (8.1%). The median survival time after the diagnosis of spinal cord compression was 3.4 months, while in the group of patients who developed a second occurrence of SCC the median survival time was 9.2 months. We concluded that only symptomatic epidural metastases should be irradiated, and that all patients treated for SCC should be followed regularly and observed for development of a second SCC.

Clinical and autopsy findings in spinal cord compression due to metastatic disease.

Clinical and autopsy findings are described in 14 patients who had suffered from spinal cord compression due to metastatic disease. All patients were clinically examined at the time of diagnosis of spinal cord compression, and followed until death. Autopsy studies of the cord revealed microscopic tumors similar to the primary tumor in seven cases. There were white matter lesions varying from slight to severe loss of myelin in seven cases. A correlation between the myelin damage and the patients ambulation just before death was found. Copyright 1998 Lippincott Williams & Wilkins

Radiologic features compared to clinical findings in a prospective study of 153 patients with metastatic spinal cord compression treated by radiotherapy.

Plain radiography, myelography and post-myelographic CT-scan are described and related to clinical findings in a prospective study of 153 consecutive patients with myelographic signs of spinal cord compression. The majority of the metastatic tumours arise in the vertebral body or the pedicles. In 80% of the patients with total blockage to the contrast medium on myelography the post-myelographic-CT showed passage of the contrast medium. Ambulatory function at time of diagnosis was correlated to the degree and the localization of the epidural block. In 64 patients who underwent a second myelography, the post-treatment findings of sensory function were correlated to radiological regression.

Clinical outcome in metastatic spinal cord compression. A prospective study of 153 patients.

BACKGROUND: Despite many reports on metastatic spinal cord compression, only very few prospective studies of the clinical outcome of spinal cord compression have been carried out. METHODS: 153 consecutive patients with a known malignant solid tumor and a myelographically verified diagnosis of spinal cord compression were followed with regular neurological examination. RESULTS: At time of diagnosis 79 patients were walking, while the remaining were bedridden. In total 21 of the 74 initially non-walking patients began walking after therapy. There was a need for urinary catheter in 57 (37%) patients at the time of diagnosis. During follow-up, 10 of 57 patients (18%) dispensed with the catheter. A total of 116 patients experienced radicular pain at the time of diagnosis, while in 95 of 116 patients (83%) the pain disappeared after therapy. CONCLUSION: the present study confirms, that early diagnosis, i.e., while the patients are still ambulatory, is most important, but the prognosis for recovery of ambulatory function is not as pessimistic as earlier described. In addition the results indicate that supplementary systemic therapy, when available, may have a positive influence on recovery.

Second occurrence of symptomatic metastatic spinal cord compression and findings of multiple spinal epidural metastases.

PURPOSE: To examine the frequency of initial multiple epidural metastases, and the occurrence of secondary spinal cord compression (SCC). METHODS AND MATERIALS: To evaluate the frequency of a recurrent SCC after radiotherapy, and to compare among patients with single and multiple intraspinal metastases the risk of having a second SCC, we followed 107 patients with SCC from a histologically verified solid tumor prospectively with regular neurological examinations until death. RESULTS: Multiple metastases were demonstrated in 37 (35%). Eight (7.5%) patients developed a second occurrence of SCC all in a new location within the spinal canal. The second occurrence of SCC was found with the same frequency in patients with single metastases (7.1%) compared to patients with multiple metastases (8.1%). The median survival time after the diagnosis of spinal cord compression was 3.4 months, while in the group of patients who developed a second occurrence of SCC the median survival time was 9.2 months. CONCLUSION: Only symptomatic epidural metastases should be irradiated, and that all patients treated for SCC should be followed regularly and observed for development of a second SCC.

Diagnosis of acute aortic occlusion by computer tomography.

We present a case of acute aortic occlusion, which was diagnosed immediately with CT. Since a prompt diagnosis is essential we recommend contrast enhanced CT as a quick procedure to confirm diagnosis and to exclude dissecting thoracic aneurysm and genuine abdominal aneurysm.

[Magnetic resonance imaging compared to myelography and CT. Diagnostic value in patients with suspected medullary spinal compression syndrome]. / Magnetisk resonans-billeddannelse sammenlignet med myelografi og CT. Diagnostisk vaerdi hos patienter mistoenkt for medulloert tvoersnitssyndrom.

Comparison between myelography (MY) and magnetic resonance imaging (MRI) was carried out in 36 patients with clinical suspicion of spinal cord or root compression due to metastatic disease in the spinal canal. In three patients metastatic lesions were visualized on MY but not on MRI, while there were no cases with a negative MY and a positive MRI. In 44% of the cases MY alone or combined with postmyelographic CT (pm-CT) showed a larger tumour extension than did MRI, while the opposite occurred in 25%. As for detection of bony metastases and tumour masses localized outside the spine there was no difference between MRI and MY + pm-CT. The results indicate that the choice between MRI and MY + pm-CT still can be based on the availability and quality of the procedure at a given institution.

Symptoms and signs in metastatic spinal cord compression: a study of progression from first symptom until diagnosis in 153 patients.

The symptoms in metastatic compression of the spinal cord or cauda equine are described after a systematic recording of the sequence of symptoms in 153 patients. Radicular pain was predominant in patients with metastases located in the lumbar area, while the severity of motor symptoms was positively correlated with thoracic metastases. The most common initial symptom was radicular pain, followed, with decreasing frequency, by motor weakness, sensory complaints and bladder dysfunction. The progression of motor weakness influenced the probability of establishing the diagnosis of spinal cord compression by stepwise marked increased probability when patients lost gait function or progressed into total paralysis.

Effect of high-dose dexamethasone in carcinomatous metastatic spinal cord compression treated with radiotherapy: a randomised trial.

We performed a randomised single blind trial of high-dose dexamethasone as an adjunct to radiotherapy in patients with metastatic spinal cord compression from solid tumours. After stratification for primary tumour and gait function, 57 patients were allocated randomly to treatment with either high-dose dexamethasone or no steroidal treatment. Dexamethasone was administered as a bolus of 96 mg intravenously, followed by 96 mg orally for 3 days and then tapered in 10 days. A successful treatment result defined as gait function after treatment was obtained in 81% of the patients treated with dexamethasone compared to 63% of the patients receiving no dexamethasone therapy. Six months after treatment, 59% of the patients in the dexamethasone group were still ambulatory compared to 33% in the no dexamethasone group. Life table analysis of patients surviving with gait function showed a significantly better course in patients treated with dexamethasone (P < 0.05). Median survival was identical in the two treatment groups. Similar results were found in subgroup analysis of 34 patients with breast cancer as the primary malignancy. Significant side-effects were reported in 3 (11%) of the patients receiving glucocorticoids, 2 of whom discontinued the treatment. We conclude that high-dose glucocorticoid therapy should be given as adjunct treatment in patients with metastatic epidural spinal cord compression.

Examination of distal involvement in cisplatin-induced neuropathy in man. An electrophysiological and histological study with particular reference to touch receptor function.

Cisplatin is a widely used anti-neoplastic agent with dose-dependent sensory neuropathy as a major side-effect. The mechanism for the neuropathy is poorly understood; it may be caused by a lesion of the dorsal root ganglion cells or by a distal axonopathy. This distinction is important since regeneration in a neuronopathy is impossible, whereas recovery may occur if the axon is affected only distally. The most distal part of the sensory nerve fibre is, however, not accessible for conventional electrophysiological examination. To ascertain whether the distal receptor-associated part of the fibre is involved, we have used a method previously untested in patients with neuropathy. In 26 males treated with cisplatin for testicular cancer 3-6.5 years previously, and in 22 normal males, the compound sensory action potentials evoked by a tactile probe were recorded through needle electrodes placed close to the sural and median nerves. The responses were compared with action potentials evoked by electrical stimulation of the same nerves. Biopsies from the distal sural nerve at the dorsolateral aspect of the foot were obtained in three patients and in four subjects not treated with cisplatin. Sixteen patients had received a conventional dose (307-435 mg/m2) of cisplatin and 10 patients had received a high dose (553-1197 mg/m2). Two-thirds of the conventional dose patients and all the high dose patients had mild to severe sensory loss and reduced or absent tendon reflexes. The amplitude of the electrically evoked sensory action potential decreased with increasing dose of cisplatin and was correlated with the reduction of vibration sense. Tactile responses, probably originating mainly from Pacinian corpuscles, were, with the exception of two high dose patients, recorded from all sural and median nerves. The two high dose patients without a tactile response had a severely reduced or no electrically evoked response at the sural nerve. The sural nerve biopsies from high dose patients showed loss of large fibres; Pacinian corpuscles were obtained in two of these patients and contained normal axons. Our findings do not suggest that cisplatin causes a primarily distal lesion with sparing of more proximal parts of the peripheral nerve. We interpret the results as being consistent with a neuronopathy affecting primarily large sensory neurons. Brainstem and somatosensory evoked potentials and H-reflexes suggested that the spinal cord and brainstem were affected as well.

McGill Pain Questionnaire translated into Danish: experimental and clinical findings.

OBJECTIVE: To develop a methodology for translating the McGill Pain Questionnaire (MPQ) into a Danish version, and to make comparisons to studies of patients speaking other languages. DESIGN: Finding suitable Danish adjectives using the same methodology as that in the original MPQ. Comparison of Danish descriptors to the words in the English version of MPQ. Survey in healthy subjects and patients with rheumatoid arthritis (RA) and fibromyalgia (F). SETTING: The general public and hospital outpatients. PATIENTS: A random sample of 186 healthy volunteers, 20 patients with rheumatoid arthritis and 41 patients with fibromyalgia. MAIN OUTCOME MEASURES: Danish words translated as closely as possible to the descriptors in the original McGill Pain Questionnaire. A pain-assessment instrument making international pain description possible. RESULTS: A Danish version of the McGill Pain Questionnaire was developed with scale values of Danish descriptors not differing more than 5 x SEM from the 'patient' words in the English version. The subdivision into classes and subclasses was respected. In the reliability experiment, the same rank values were found in 85% of subclasses. In a study using two experimental pain stimulus intensities, seven of 10 subjects obtained higher MPQ scores following the high-intensity stimulus. In the clinical study, the pain profiles of patients with RA and F in English, Italian, and Danish patients were almost the same. CONCLUSION: The present methodology of translating the McGill Pain Questionnaire permits comparison of studies from English-speaking and non-English-speaking populations, thus facilitating international research exchange.

Comparison of myelography combined with postmyelographic spinal CT and MRI in suspected metastatic disease of the spinal canal.

Comparison between myelography (MY) and magnetic resonance imaging (MRI) was carried out in 36 patients with clinical suspicion of spinal cord or root compression due to metastatic disease in the spinal canal. In 3 patients metastatic lesions were visualized on MY but not on MRI, while there were no cases with a negative MY and a positive MRI. In 44% of the cases MY alone or combined with postmyelographic CT (pm-CT) showed a larger tumor extension than did MRI, while the opposite occurred in 25%. As for detection of bony metastases and tumor masses localized outside the spine there was no difference between MRI and MY + pm-CT. The results indicate that the choice between MRI and MY + pm-CT still can be based on the availability and quality of the procedure at a given institution.

Diagnostic value of spinal computer tomography in patients with intraspinal metastases causing complete block on myelography.

The value of post-myelographic spinal computer tomography (CT) was evaluated in cancer patients with spinal metastases causing complete myelographic block. In 22 out of 25 lumbar myelographies (88%) showing complete blockade, sufficient contrast medium had leaked proximally to allow determination of the cranial limit of the metastasis on the CT-scan. It is concluded that the post-myelographic spinal CT can replace a supplementary cervical myelography in the majority of patients with epidural metastasis, causing a complete myelographic block.

Recovery of gait after radiotherapy in paralytic patients with metastatic epidural spinal cord compression.

We report on 15 patients with paralysis of the legs caused by metastatic epidural spinal cord compression. After radiation therapy 6 patients regained motor function, 5 of whom recovered ambulatory function, but the recovery was delayed for 3 months or more. The duration of the paralysis prior to treatment varied from 20 hours to 10 days with no significant difference between the group with and the group without recovery. The median time from the initial motor symptoms to total paralysis was longer (45 days) in the patients who recovered compared with those permanently paralyzed (9 days). The response to radiation therapy seems to depend on the rate of loss of spinal cord function rather than the length of total paralysis. We recommend active treatment of patients with paraplegia due to metastatic epidural spinal cord compression, even when the paralysis has been present for over a week.

Risk factors for thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study.

As previously reported, 1007 patients with chronic atrial fibrillation participated in the Copenhagen AFASAK study. Before inclusion to trial, they all had a physical examination, chest roentgenogram, and echocardiogram with determination of left atrial size. This study evaluated the importance of cardiovascular risk factors for development of thromboembolic complications. To exclude any treatment effects on occurrence of thromboembolic complications, we included only the 336 patients from the placebo group. Using Cox's regression model, previous myocardial infarction was a significant risk factor for development of thromboembolic complications. Age, gender, heart failure, chest pain, hypertensive heart disease, diabetes, systolic and diastolic blood pressure, smoking, relative heart volume, and left atrial size were all without statistical importance.

Long-term neurotoxicity in patients treated with cisplatin, vinblastine, and bleomycin for metastatic germ cell cancer.

Thirty patients treated for germ cell cancer with six cycles of cisplatin, vinblastine, and bleomycin participated in a follow-up examination of neurotoxicity 49 to 106 months after treatment. Of these, 22 patients (73%) had sensory loss; half of them complained of paresthesias. The vibration perception threshold was increased in 24 patients (80%). Auditory stimulation revealed a normal latency of the first component of the brain stem-evoked potentials Pl but an increased interpeak interval between this and Pv; reflecting a central conduction defect. Motor conduction velocity (CV) along the peroneal nerve was normal. The average sural nerve CV was decreased (P less than .01) and the sensory action potential amplitude was reduced (P less than .01). Warm perception threshold was increased in 10 patients (33%). Cortical-evoked potentials after tibial nerve stimulation had increased latencies in 29 patients (97%). The peripheral CV along the tibial nerve was slowed (P less than .01) in 19 patients, and the central conduction time from Th12 to cortex was prolonged in 15 patients (P less than .01). The changes in conduction along peripheral and central pathways after tibial nerve stimulation are compatible with a toxic effect on the sensory root ganglia causing a "dying back" axonal degeneration of central and peripheral nerve fibers.

Progressive neurological dysfunction during latent HIV infection.

OBJECTIVE--To determine whether the delayed conduction through the spinal cord and peripheral nerves seen in patients with AIDS is related to infection with HIV or to the presence of an immunodeficient state. DESIGN--Two year prospective follow up study of electrophysiological measurements in subjects positive for HIV antibody but without AIDS. SETTING--HIV screening clinic and clinical departments in a university hospital in Copenhagen, Denmark. SUBJECTS--Twelve homosexual men positive for HIV antibody who had not developed AIDS. RESULTS--Eight latencies were measured: from the ankle to T12, the wrist to C7, T12 to the cerebral cortex, C7 to the cerebral cortex, the ankle to the gluteal crease (tibial nerve), the gluteal crease to T12, the wrist to Erb's point (median nerve), and Erb's point to C7. Spinal latencies increased in all subjects at C7 by a mean of 4.2% (SE 0.9%) and in all except one at T12 by a mean of 5.5% (1.0%). The conduction time from the gluteal crease to T12 was increased by a mean of 32.0% (5.0%) whereas that in the median and tibial nerves by only 5.6% (1.0%) and 2.2% (2.2%) respectively. CONCLUSIONS--A mild and slowly progressive peripheral neuropathy of the axonal type and a more severe progressive myelopathy or myeloradiculopathy occur concomitantly with early HIV infection, possibly as the result of a direct neurotropic action of HIV.

Cerebral ventricular enlargement relates to neuropsychological measures in unselected AIDS patients.

In a cross-sectional study of unselected Danish AIDS patients various linear measures of cerebral ventricular size obtained by computed tomography were compared with results of neuropsychological test performances. Third ventricular width as well as right and left septum-caudate distances were enlarged in the patients (P less than 0.01). Of 20 patients 15 had at least one abnormal ventricular measurement. Although only one patient was demented, ventricular size correlated inversely with neuropsychological function (r = -0.61, P less than 0.02). The correlation between ventricular size and variation of the reaction time was even closer (r = 0.74, P less than 0.01). It is concluded that neuroradiological signs of central atrophy often occur in AIDS patients.