Physician-assessed and patient-reported outcome measures in chemotherapy-induced sensory peripheral neurotoxicity: two sides of the same coin.

BACKGROUND: The different perception and assessment of chemotherapy-induced peripheral neurotoxicity (CIPN) between healthcare providers and patients has not yet been fully addressed, although these two approaches might eventually lead to inconsistent, possibly conflicting interpretation, especially regarding sensory impairment. PATIENTS AND METHODS: A cohort of 281 subjects with stable CIPN was evaluated with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC v. 2.0) sensory scale, the clinical Total Neuropathy Score (TNSc©), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sumscore (mISS) and the European Organization for Research and Treatment of Cancer CIPN specific self-report questionnaire (EORTC QOL-CIPN20). RESULTS: Patients' probability estimates showed that the EORTC QLQ-CIPN20 sensory score was overall more highly related to the NCI-CTC sensory score. However, the vibration perception item of the TNSc had a higher probability to be scored 0 for EORTC QLQ-CIPN20 scores lower than 35, as vibration score 2 for EORTC QLQ-CIPN20 scores between 35 and 50 and as grade 3 or 4 for EORTC QLQ-CIPN20 scores higher than 50. The linear models showed a significant trend between each mISS item and increasing EORTC QLQ-CIPN20 sensory scores. CONCLUSION: None of the clinical items had a perfect relationship with patients' perception, and most of the discrepancies stood in the intermediate levels of CIPN severity. Our data indicate that to achieve a comprehensive knowledge of CIPN including a reliable assessment of both the severity and the quality of CIPN-related sensory impairment, clinical and PRO measures should be always combined.

The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting complication of cancer treatment. Thus far, the impact of CIPN has not been studied in a systematic clinimetric manner. The objective of the study was to select outcome measures for CIPN evaluation and to establish their validity and reproducibility in a cross-sectional multicenter study. PATIENTS AND METHODS: After literature review and a consensus meeting among experts, face/content validity were obtained for the following selected scales: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), the Total Neuropathy Score clinical version (TNSc), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory sumscore (mISS), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and CIPN20 quality-of-life measures. A total of 281 patients with stable CIPN were examined. Validity (correlation) and reliability studies were carried out. RESULTS: Good inter-/intra-observer scores were obtained for the TNSc, mISS, and NCI-CTC sensory/motor subscales. Test-retest values were also good for the EORTC QLQ-C30 and CIPN20. Acceptable validity scores were obtained through the correlation among the measures. CONCLUSION: Good validity and reliability scores were demonstrated for the set of selected impairment and quality-of-life outcome measures in CIPN. Future studies are planned to investigate the responsiveness aspects of these measures.

Electrically evoked nociceptive potentials for early detection of diabetic small-fiber neuropathy.

BACKGROUND AND PURPOSE: This study investigated the utility of pain-related evoked potentials (PREP's) elicited by a nociceptive electrical stimulation of the skin (= electrically evoked nociceptive potentials) in early detection of diabetic small-fiber neuropathy. METHODS: We studied 36 'young' (19-35 years) and 24 'older' (36-65 years) healthy subjects as well as 35 patients (35-64 years) with diabetes and neuropathic symptoms and 22 patients (34-64 years) with diabetes without neuropathic symptoms. Only patients with normal standard nerve conduction testing were included. RESULTS: In patients with neuropathic symptoms, we found a significant increase in PREP latencies and decrease of amplitudes elicited from both, upper and lower limbs. In non-symptomatic diabetic patients, we observed PREP abnormalities from lower limbs only. CONCLUSIONS: These data suggest that the method of pain-related evoked potentials elicited by a nociceptive electrical stimulation of the skin may contribute to the early detection of diabetic sensory neuropathy.

Muscle force and fatigue in patients with sepsis and multiorgan failure.

INTRODUCTION: Neuromuscular abnormalities are found frequently in sepsis and multiorgan failure (MOF). Surprisingly, however, there are no data on maximum skeletal muscle force and fatigue in these patients. OBJECTIVES: To test the research hypotheses that adductor pollicis (AP) force would be lower in patients with sepsis, whereas fatigue would not differ between patients and immobilized but not infected volunteers. DESIGN AND SETTING: Prospective study; university intensive care unit and laboratory. PATIENTS: Patients with sepsis and MOF (sequential organ failure assessment (SOFA) score >10) and healthy volunteers. INTERVENTIONS: Fatigue was evoked during 20[Symbol: see text]min of intermittent tetanic ulnar nerve stimulation achieving 50% of maximum AP muscle force. MEASUREMENTS AND RESULTS: We measured evoked AP muscle force and fatigue, and compound muscle action potential (CMAP), and performed standard electrophysiological tests in 13 patients, and in 7 volunteers before and after immobilization. Maximum force (20+/-16 vs 65+/-19N; p<0.01) and CMAP (3.6+/-2.5 vs 10+/-2.5 mV; p<0.05) were markedly decreased in patients; however, fatigue and ulnar nerve conduction velocity did not differ from volunteers, and a decrement of CMAP was not observed with nerve stimulation frequencies up to 40 Hz. All patients with critical illness polyneuropathy, and an additional 50% of those without, had significant muscle weakness. CONCLUSION: Peripheral muscle force is markedly decreased in sepsis, without evidence for an increased fatigability. Muscle weakness was most likely due to a sepsis-induced myopathy and/or axonal neuropathy, and was not the result of an immobilization atrophy.

Ambulatory norepinephrine treatment of severe autonomic orthostatic hypotension.

OBJECTIVES: This study was designed to establish a patient-controlled, ambulatory norepinephrine treatment of refractory orthostatic hypotension due to primary autonomic failure. BACKGROUND: Autonomic dysfunction leads to disabling postural hypotension. Particularly in primary autonomic dysfunction, repeated syncope and immobilization can be the result. Medical treatment of orthostatic hypotension often fails in advanced cases. METHODS: Ambulatory, patient-controlled norepinephrine therapy was initiated in six patients with orthostatic hypotension due to primary autonomic failure that had been refractory to conventional treatment. Before this therapy, three patients were bedridden; one was immobilized in a wheelchair. All had recurrent syncope and tolerated upright tilt-table testing for less than 15 min despite extensive medical treatment. For ambulatory treatment, a port-a-cath system was implanted and, using a CADD ambulatory infusion pump, norepinephrine was infused in individually adjusted dosages. RESULTS: Norepinephrine infusion therapy enabled all patients to sit, stay and walk around for more than 45 min. One patient died after a five-year treatment period, another after nine months because of nonhemorrhagic brain stem infarctions, both in the absence of norepinephrine treatment. The remaining four patients are still mobile after a period of 19, 10, 9 and 7 months, respectively. None of them has suffered complications due to arterial hypo- or hypertension, and there has been no infection of the infusion system. CONCLUSIONS: In these selected patients with refractory orthostatic hypotension due to primary autonomic dysfunction, ambulatory norepinephrine infusion therapy has proved to be a promising new therapeutic option. Further long-term studies including more patients are necessary to assess additional indications, reliability and safety of this new method.

MRI changes associated with partial status epilepticus.

Neurological disorders of different etiology may cause identical clinical symptoms requiring additional diagnostic procedures for a precise differential diagnosis. Focal epileptic seizures have been shown to cause increased signal intensities in T2 and diffusion-weighted magnetic resonance images (MRI), mimicking other neurological disorders or diseases such as viral encephalitis. In some cases even the combination of neuroimaging and cerebrospinal fluid (CSF) analysis is not sufficient to obtain the final diagnosis, since epileptic seizures may cause pleocytosis as well. Some epilepsy centers presented cases of focal status epilepticus with severe but reversible MRI changes. These cases indicate that MRI-changes following focal seizures are reversible over a different time window compared to MRI changes associated with other etiologies, such as viral infection. This data further suggest that in cases where focal seizures can not be ruled out, a follow-up MRI scan within a few days following the onset of symptoms significantly improves the precision of the differential diagnosis. Recently new scientific data were reported in this review.

Lack of neuroprotection by an ACTH (4-9) analogue. A randomized trial in patients treated with vincristine for Hodgkin's or non-Hodgkin's lymphoma.

PURPOSE: This randomized, double-blind, placebo-controlled study evaluates the effect of the corticotropin (4-9) analogue Org 2766 on the neuropathy-free interval in patients receiving vincristine (VCR) containing chemotherapy for Hodgkin's or non-Hodgkin's lymphoma. PATIENTS AND METHODS: In a longitudinal design, 150 patients were evaluated by interview, neurological examination, and neurophysiological techniques. Patients with an expected cumulative VCR dose of at least 8 mg received a single dose of Org 2766 or placebo before and after each intravenous VCR injection and 3-4 weeks after cessation of VCR. The final patient assessment was performed 1 month after discontinuation of study medication. The neuropathy-free interval as the major end point of this study was defined as the first occurrence of bilateral paresthesias and expressed as the administered cumulative VCR dose. This bi-center study represents the largest cohort of patients monitored for the effect of an ACTH-analogue on VCR neurotoxicity. RESULTS: A total of 147 patients were included in the final analysis. No significant differences were observed between the placebo and actively treated group for the major and secondary endpoints. CONCLUSION: Contrary to a single previous pilot study in patients receiving VCR-based chemotherapy, in our study the ACTH (4-9) analogue Org 2766 did not provide protection from VCR-induced neuropathy.

Myopathy in two siblings with nephropathic cystinosis.

Nephropathic cystinosis is a hereditary disorder characterized by a specific defect in the transport of cystine across the lysosomal membrane, leading to an accumulation of protein-free cystine in tissues, including conjunctiva, liver, bone marrow and kidney. Renal transplantation is necessary because of renal failure. With improved life-expectancy, neurological complications have been reported, including cases of distal myopathy diagnosed ante- and post-mortem. We report on two further rare cases of two siblings suffering from cystinosis who developed a predominantly distal myopathy, proven electrophysiologically and on biopsy during life. The reported clinical picture of a distal atrophy resembling a neurogenic disease, confirms a picture apparently typical in cystinosis. Possible effects of cysteamine therapy on the course of the myopathy are discussed. Copyright 1998 Lippincott Williams & Wilkins

Is stereotactic biopsy a reliable method to differentiate tumor from radiation necrosis?

We report a case of a 37-year-old female who suffered from seizures and underwent external beam radiotherapy due to a suspected low-grade astrocytoma in the left hemisphere. After 7 years free of seizures under antiepileptic treatment and no signs of change in the yearly performed control MRI, she developed a progressive right-sided hemiparesis. MRI now showed an enhancing lesion with space occupying perifocal edema in the entire left hemisphere. Stereotactic biopsy revealed only inflammation. Due to further progress of the neurological deficit an open biopsy was performed. Histological examination revealed a middle-graded astrocytoma and a radiation necrosis. This case demonstrates that radiation necrosis and tumor recurrence may develop concurrently and that it may be difficult to distinguish them by clinical or radiological methods.

Rasch-built Overall Disability Scale for patients with chemotherapy-induced peripheral neuropathy (CIPN-R-ODS).

Chemotherapy-induced peripheral neuropathy (CIPN) is a common neurological side-effect of cancer treatment and may lead to declines in patients' daily functioning and quality of life. To date, there are no modern clinimetrically well-evaluated outcome measures available to assess disability in CIPN patients. The objective of the study was to develop an interval-weighted scale to capture activity limitations and participation restrictions in CIPN patients using the Rasch methodology and to determine its validity and reliability properties. A preliminary Rasch-built Overall Disability Scale (pre-R-ODS) comprising 146 items was assessed twice (interval: 2-3 weeks; test-retest reliability) in 281 CIPN patients with a stable clinical condition. The obtained data were subjected to Rasch analyses to determine whether model expectations would be met, and if necessarily, adaptations were made to obtain proper model fit (internal validity). External validity was obtained by correlating the CIPN-R-ODS with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) neuropathy scales and the Pain-Intensity Numeric-Rating-Scale (PI-NRS). The preliminary R-ODS did not meet Rasch model's expectations. Items displaying misfit statistics, disordered thresholds, item bias or local dependency were systematically removed. The final CIPN-R-ODS consisting of 28 items fulfilled all the model's expectations with proper validity and reliability, and was unidimensional. The final CIPN-R-ODS is a Rasch-built disease-specific, interval measure suitable to detect disability in CIPN patients and bypasses the shortcomings of classical test theory ordinal-based measures. Its use is recommended in future clinical trials in CIPN.

Long-term outcome of Guillain-Barré syndrome.

OBJECTIVES: To investigate long-term neurological residua after Guillain-Barré syndrome (GBS) and to evaluate the predictive value of respiratory insufficiency during the acute stage of the disease. METHODS: Thirty-four patients with GBS including 5 patients with Miller-Fisher syndrome admitted to a university hospital between 1994 and 2002 underwent a neurological and electrophysiological follow-up examination 7 - 86 months after onset of GBS. RESULTS: Of the 34 patients, 5 patients had completely recovered, 11 patients demonstrated mild residual symptoms and/or signs, and 18 patients presented with functionally relevant neurological deficits predominantly in the lower extremity, although all patients could walk without assistance and none showed respiratory failure. Nerve conduction studies revealed abnormal findings in 30 patients. Autonomic function testing of the cardiovascular system showed a pathological blood pressure response to standing in 27 of 33 patients. No association was found between the course of the disease and sleep-disordered breathing at follow-up. Age at onset, need for mechanical ventilation, and duration of the plateau phase correlated with severity of neurological residua at follow-up. CONCLUSIONS: There was a high persistence of residual sensorimotor signs and symptoms after GBS in our cohort. In addition, abnormal blood pressure declines not associated with clinically overt orthostatic dysregulation were detected in the majority of our patients at follow-up. This is in contrast to previous reports describing a gradual improvement of autonomic dysfunction after 2 - 18 months. A combined prognostic score based on patient age, duration of the plateau phase, and ventilatory failure in the acute stage of GBS might predict the long-term outcome.

Dose-related vincristine-induced peripheral neuropathy with unexpected off-therapy worsening.

This study describes the natural course of vincristine-induced peripheral neuropathy in patients with lymphoma (n = 114) receiving vincristine in two different dose intensities. Neuropathic changes were observed in both dose intensity groups, but the higher dose intensity group reported significantly more symptoms during therapy, whereas neurologic signs were significantly more prominent after a cumulative dose of 12 mg vincristine. Furthermore, off-therapy worsening of symptoms (24%) and signs (30%) occurred unexpectedly.

Progressive multifocal leukoencephalopathy: neurological findings and evaluation of magnetic resonance imaging and computed tomography.

On the basis of two of our cases we report here on the clinical symptoms and neuroradiological findings in patients with progressive multifocal leukoencephalopathy. Emphasis is put on the value of MRI in early stages of this disease, especially, and on the increased information provided by this method as compared to CT-scanning.

[Neurocysticercosis. Current review of the literature based on a long-term study of 2 clinically distinct German cases]. / Neurozystizerkose. Aktuelle Literaturübersicht anhand einer Langzeitbeobachtung zweier klinisch distinkter deutscher Erkankungsfälle.

Neurocysticercosis, caused by Taenia solium larvae (cysticerci), is the most common parasitic infection of the human CNS Worldwide. In Germany its appearance is rare. Here we report two cases of neurocysticercosis which we followed over a period of 4-6 years. The first patient acquired neurocysticercosis in Germany. On admission he suffered from papilledema, partial seizures and a mild psychotic disorder. MR-tomography showed an internal hydrocephalus and multiple contrast enhancing parenchymal cysts. In the course of the disease a giant cyst within the left temporal pole developed and was exstirpated neurosurgically. The persistent internal hydrocephalus required ventriculoperitoneal shunting. Therapy with Praziquantel led to a clinical improvement, however, repeated analysis of the cerebrospinal fluid documented persistent inflammation. With the aid of a contrast enhanced three-dimensional (3D) ultrasound imaging technique we demonstrated increased cerebral perfusion surrounding one cyst. This may be interpreted as evidence for persistent disease activity. The second patient presented with repeated episodes of cysticercotic encephalitis, which is rarely described in the literature (incidence 1%). Clinical features, laboratory findings, diagnosis, and therapy of neurocysticercosis will be presented together with the pitfalls of the two described cases. Our cases will be compared to previous reports on clinical findings in neurocysticercosis.

[Shy-Drager syndrome: a rare cause of orthostatic hypotension]. / Das Shy-Drager-Syndrom. Seltene Ursache einer orthostatischen Hypotonie.

HISTORY AND ADMISSION FINDINGS: A 71-year-old man was admitted because of treatment-resistant orthostatic hypotension of unknown aetiology. When aged 64 years he developed some impotence and later urinary incontinence and urinary frequency. At 68 years he noted vertigo on physical activity, and a year later he had signs of reversible cerebral ischaemia. At this point the Schellong test demonstrated vasovagal circulatory dysfunction. After his 70th birthday the unsteadiness on walking and standing got worse and he had recurrent syncopes. He was in a wheel-chair when hospitalized and even the unsteady walk he could maintain for only a few seconds. INVESTIGATIONS: Plasma and urinary concentrations of catecholamines were at the lower limit of normal but failed to increase during orthostasis. Hormonal, cardiological and infectious causes of the orthostatic hypotension were excluded. Orthostatic tests after Schellong and with the tilting table showed orthostatic hypotension without increased sympathetic activity but hypertensive blood pressure levels during the recumbent period. Intravenous infusion of norepinephrine produced an excess rise in blood pressure (raised norepinephrine sensitivity). The recurrent urinary infection was shown to be due to a hypotonic bladder detrusor muscle. Neurological examination revealed cerebellar dysfunction, signs of pyramidal tract abnormality and sensory polyneuropathy. A Shy-Drager syndrome was diagnosed on the basis of the history, absent blood pressure rise and lack of catecholamine release during orthostasis with increased epinephrine sensitivity and characteristic neurological signs. TREATMENT AND COURSE: Physiotherapy and elastic stockings with administration of mineralocorticoids as well as of one direct (norfenefrine) and one indirect (amezinium) sympathomimetic drug failed to improve adequately the abnormal orthostatic response. But on additional administration of an alpha 2-receptor antagonist (yohimbine) the patient was able to stand and walk for a few minutes, but the urinary incontinence and the other neurological signs remained treatment-resistant. CONCLUSION: If orthostatic hypotension occurs together with neurological symptoms, a Shy-Drager syndrome should be taken into account.

Ambulatory infusion of noradrenaline for long-term treatment of Shy-Drager syndrome.

A 70-year-old female patient with advanced Shy-Drager syndrome exhibited severe orthostatic hypotension, low serum catecholamine levels, and autonomic dysfunction. She was bedridden despite oral medication with fludrocortisone, etilefrin, dihydroergotamine, L-dopa, yohimbine, and amezinium methyl sulfate. Only intravenous application of noradrenaline (30 ng/kg/min) provided complete mobilization. After implantation of a port-a-cath system, intravenous noradrenaline treatment could be continued on an outpatient basis. Over the following 5 years, the patient was throughout sufficiently mobile and did not show any significant side effects of this treatment. However, during the 5th year she suffered from nonhemorrhagic brain stem infarction due to cerebral hypoperfusion after orthostatic stress in the absence of noradrenaline infusion. We conclude that ambulatory noradrenaline infusion is a new valuable tool for long-term treatment of advanced Shy-Drager syndrome.

Evaluation of long-term toxicity in patients after cisplatin-based chemotherapy for non-seminomatous testicular cancer.

BACKGROUND: Because of the increasing number of long-term survivors of metastatic testicular germ-cell cancer, a general concern has been secondary morbidities, especially cardiovascular risk factors. PATIENTS AND METHODS: Thirty-two patients treated with cisplatin- and doxorubicin-containing chemotherapy > or = 13 years before the time of analyses were evaluated for neuro-, oto-, pulmonary-, vascular- and gonadal toxicity including evaluation of myocardial damage and cardiovascular risk factors and analysis of microcirculation. RESULTS: Thirty percent of the patients showed abnormal left ventricle function. Elevated follicle stimulating hormone (FSH) and luteinising hormone (LH) levels in 75% of patients were often associated with low testosterone levels. Elevated total cholesterol levels were found in 82% and higher triglyceride levels in 44% of patients, most of them were overweight. About 25% of the patients developed diastolic arterial hypertension after chemotherapy. Reduced hearing was confirmed in 23% of patients, especially at frequencies higher than 3000 Hz. Moreover, 53% of patients presented transient evoked otoacoustic emissions. In 38% of patients non-symptomatic neuropathy was detected, in 28% symptomatic neuropathy, and in 6% disabling polyneuropathy. In 80% of patients with neuropathic symptoms additional morphological and functional abnormalities were found by nailfold capillary videomicroscopy, compared to only 57% of the patients without neuropathic symptoms. CONCLUSIONS: Patients cured by cisplatin-based chemotherapy for metastatic testicular cancer have to be cognizant of their unfavorable cardiovascular risk profile, that might be a greater risk than developing a relapse or second malignancy.