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How can the mere presence of an antibody in serum predict a tumor when it is only microscopic? This is possible in patients with certain paraneoplastic neurologic syndromes (PNS) as shown by Mathew et al.1 in this issue of Neurology . Since the first description of antineuronal antibodies (anti-Hu) in 1984 by Posner et al., the association of a neurologic syndrome, an antineuronal antibody, and a microscopic or relatively biologically benign tumor have frequently been recognized.2 Mathew et al. describe six patients with anti-Ma2/Ta antibody whose clinical findings predicted a testicular tumor even though diagnostic tests had been negative. In the face of clinical progression, orchiectomy was performed and a microscopic tumor was identified.1 This article highlights several important clinical points. Anti-Ma2/Ta is indeed a highly specific marker for the presence …

Introduction: The effect of a curriculum without compulsory courses in palliative medicine on students’ knowledge, kills and attitudes towards the care of dying patients and decisions at the end of life was investigated. Methods: In a cross sectional, questionnaire based survey at the medical school of Bonn 1st, 3rd and 5th year students had to grade their knowledge and skills in items concerning palliative medicine. Attitudes towards end of life decisions were queried. Results: The return rate was 78%. Significant increase in self estimation of certainty comparing 1st to 5th year students were detected for the items distinction between palliative and curative medicine (p Discussion: A medical curriculum without compulsory course does increase confidence in some of the core competencies in palliative care, but the overall results at the end of the training are poor. The WHO claims that palliative care has to be “compulsory in courses leading to a basic professional qualification” has still to be fulfilled in Germany. This study can serve as a baseline to evaluate the effect of mandatory courses in palliative care.

Immune mediated paraneoplastic neurological syndromes often become manifest before the underlying malignancy is detected. As a rule, these syndromes do not improve with antineoplastic treatment.1 We report on a case of a patient with small cell cancer with peripheral neurological syndromes that responded favourably to combination chemotherapy. At the time of admission the patient, a 66 year old woman, had had a combination of peripheral neurological symptoms for 3 months: ( a ) muscle weakness and muscle pain of the legs so that she could not walk unattended; ( b ) a numbness of both legs from the foot to the middle of the thigh; ( c ) dryness of the eyes and mouth; and ( d ) severe constipation. Clinical examination showed a load dependent, proximally accentuated symmetric muscle weakness and hypoaesthesia of the legs. The patient was unable to stand or walk without support. The deep tendon reflexes of the arms were decreased on both sides and leg reflexes could not be elicited. No pathological reflexes were detectable. Analysis of CSF yielded normal values for protein content, cell number, and glucose. Besides a slightly increased erythrocyte sedimentation rate (35 mm in the first hour), standard laboratory values showed no abnormalities. Abdominal auscultation and CT were unrevealing. Electrophysiological investigation (somatosensory evoked potentials of the tibial and median nerves, EMG, and …

The hospice model of care for patients with advanced diseases exists in almost all industrialized countries. To date, there have been no international or crosscultural comparisons of the organization and patient outcomes associated with hospice services in different parts of the world. This survey evaluated 159 patients in the USA, Germany and Japan. There were differences between countries in the time of first contact, who recommended palliative care first, the underlying diagnoses, the location of patients, and how consent for hospice care was obtained. Across all countries, there were similar levels of comfort and satisfaction with care. We conclude that the hospice philosophy addresses the basic needs of dying patients which are independent of cultural background, but may be adapted to very different cultures.

It has been suggested that antibodies against nonacetylcholine receptor proteins of striated muscle are markers of the presence of a thymic epithelial tumor in patients with myasthenia gravis (MG). These antibodies may be measured using an immunofluorescence assay against striated muscle(anti-STR) or an ELISA with a recombinant 30-kd titin fragment (anti-MGT30). To directly compare anti-STR with anti-MGT30, we examined the sera of 276 consecutive patients with known or suspected MG. Definite diagnoses and thymic histology, if available, were correlated with the antibody assays. Of the 276 patients, 164 had MG. Thymic histology was obtained in 44 patients: 18 had lymphofollicular hyperplasia, 13 thymic epithelial tumors, 8 atrophy, and 5 were normal. When compared with anti-STR, anti-MGT30 showed a sensitivity of 69% (STR 77%), specificity of 100% (STR 56%, p = 0.026), negative predictive value of 82% (STR 77%), and positive predictive value of 100% (STR 56%, p = 0.003) for the identification of a thymic epithelial tumor versus thymic hyperplasia. We conclude that the anti-MGT30 ELISA is better than the anti-STR immunofluorescence assay for the diagnosis of paraneoplastic MG.

Fast fluid-attenuated inversion recovery (fast-FLAIR), fast spin echo (FSE), and turbo-gradient spin echo (TGSE), new pulse sequences for magnetic resonance imaging (MRI), are able to display multiple sclerosis (MS) lesions more conspicuously (fast-FLAIR) and with shorter imaging times (FSE, TGSE) than is conventional spin-echo MRI. In this study, we scanned 7 MS patients, using fast-FLAIR (18 axial brain slices), FSE (27 slices), and TGSE (9 slices) sequences in the same session, to compare the brain MRI lesion loads detected by these different sequences and the intraobserver reproducibility of these measurements. On the subset of slices (n = 9) covered by all three measurements, the mean lesion load was 7.577 mm3 on fast-FLAIR, 5.248 mm3 on FSE, and 3.080 mm3 on TGSE (p = 0.006) sequences. The mean intraobserver coefficients of variation were 2.92% for fast-FLAIR, 2.86% for FSE, and 4.31% for TGSE (not significant). These findings demonstrate that both fast-FLAIR and FSE sequences may be potentially useful for serial MRI studies for monitoring clinical trials, while TGSE might be useful for speeding diagnostic MRI in MS patients. Longitudinal, clinically correlated studies using these new MRI sequences are needed to confirm these preliminary data.

As management of patients with cancer is evolving, an increased focus is being placed on individualized patient-centered care. Early integration of palliative care into the overall management of patients with cancer can help achieve this paradigm shift. Despite recommendations for earlier integration of palliative care by national and international societies, several barriers remain to achieving this goal. Survey studies have indicated a significant need for increased education regarding palliative care for both medical undergraduates and postgraduate physicians. Key issues in the early integration of palliative care include relationship-building across multiple health systems and specialties; development of a standardized definition of palliative care, making clear that it should be fully integrated with cancer-directed therapy; identification of physician and nonphysician champions; standardization of tools for patient assessment; education programs designed to meet the needs of health care professionals; and ongoing evaluation to assess program benefits and limitations.

Intravenous immunoglobulin is increasingly used in the treatment of neuromuscular disorders. Its efficacy has been proven in Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, and Lambert-Eaton myasthenic syndrome. In addition, there is increasing evidence that it has beneficial effects in other neuromuscular disorders.

The possibility of antagonizing tumor necrosis factor-alpha (TNF-alpha) in vivo with antibodies or soluble TNF receptor has focused much interest on the role of this cytokine in the natural course of MS. We studied nine patients prospectively and serially for one year (14 time points, 131 observations). TNF-alpha and the 55 kDa soluble TNF receptor were measured every 4 weeks in the serum and at defined time points in the CSF. Each value was correlated to clinical symptoms and to MRI measurements obtained on the same day. All patients with relapsing-remitting disease showed periodic increases of TNF concentrations. Overall, the association between serum TNF-alpha levels and bursts of Gd-DTPA enhancement on cranial MRI was not sufficiently tight to reach statistical significance. However, serum TNF levels > 50 pg/ml and measurable CSF levels were always associated with Gd-DTPA enhancing MRI lesions. Isolated high serum TNF peaks were noted during episodes of infection, hay fever or psychic stress. After treatment with glucocorticoids, TNF levels were suppressed for several months, whereas new Gd-DTPA enhancing lesions continued to appear. The concentrations of the soluble 55 kDa TNF receptor did not show marked fluctuations. These results are consistent with an active role of TNF-alpha in MS during periods of disease activity and provide further support for the clinical evaluation of anti-TNF therapies.

We studied whether a triple dose of gadolinium-DTPA alone or in combination with delayed scanning increases the sensitivity of brain MRI for detecting enhancing lesions in patients with MS. We obtained T1-weighted brain MRI scans in two sessions for 22 patients with clinically definite MS. In the first session, we obtained one scan 5 to 7 minutes after the injection of 0.1 mmol/kg gadolinium-DTPA (standard dose). In the second session, 6 to 24 hours later, we obtained one scan before the two scans 5 to 7 minutes (for all patients) and one hour (for 11 patients) after the injection of 0.3 mmol/kg gadolinium-DTPA (triple dose). We detected 83 enhancing lesions in 14 patients when the standard dose of gadolinium-DTPA was used. The numbers of enhancing lesions increased to 138 (average increase 66%; p = 0.001) and the numbers of patients with such lesions to 18 (increase 28%) when we used the triple dose of gadolinium-DTPA. In addition, the total area per patient occupied by such lesions was greater (p < 0.0001) and lesion signal intensity higher (p = 0.0001) on the triple-dose scans than the standard-dose scans. There was an increase in the number of large enhancing lesions (p = 0.03) in the scans obtained 1 hour after the injection of the triple dose of gadolinium-DTPA. These data indicate that in patients with MS, a triple dose of gadolinium-DTPA can reveal many more enhancing lesions, which also appear larger. This suggests that the pathologic nature of "active" lesions in MS is heterogeneous, which might have impact on planning clinical trials.

OBJECTIVES: To compare the sensitivity of fast spin echo (FSE) and of fast fluid attenuated inversion recovery (fast FLAIR) in detecting spinal cord lesions in multiple sclerosis. METHODS: With a 1.5 Tesla machine and a multicoil receiver array, FSE images (with two different pixel sizes) and fast FLAIR images of the spinal cord were obtained from 13 patients with multiple sclerosis. RESULTS: Twenty three lesions (10 cervical, 12 thoracic, and one lumbar) were found in seven patients (54%) using FSE with the larger pixel size. Seventeen lesions (seven cervical and 10 thoracic) were detected in the same seven patients using FSE with smaller pixel size. Nine lesions (five cervical and four thoracic) were found using fast FLAIR in six patients (46%). All the lesions found using fast FLAIR were detected using the other two techniques and all the lesions detected by FSE with smaller pixel size were detected using FSE and greater pixel size. CONCLUSION: Fast FLAIR sequences detect substantially fewer cord lesions in patients with multiple sclerosis.

In this study, we performed a post-contrast magnetization-prepared rapid acquisition gradient echo (MP RAGE) sequence with subsequent reconstruction of axial slices with 5-, 3-, and 1-mm thickness in 26 patients with multiple sclerosis (MS) to investigate the disease activity going on below the resolution of conventional scans. One hundred three enhancing lesions were detected using MP RAGE reconstructed with 1-mm-thick slices, 93 using MP RAGE reconstructed with 3-mm-thick slices and 82 using MP RAGE reconstructed with 5-mm-thick slices. The detection rate using 1-mm MP RAGE was 25.6% higher compared with 5-mm MP RAGE and 12% higher compared with 3-mm MP RAGE. Using 1-mm MP RAGE, we detected five enhancing lesions in 2 of the 12 patients (16.6%) who showed no enhancing lesions on the 5-mm MP RAGE and one enhancing lesion in 1 of the 10 patients (10%) who showed no enhancing lesions on the 3-mm MP RAGE. The increased sensitivity of 1-mm MP RAGE over the other two reconstruction slice thicknesses was due to improved detection of small lesions, located mainly in cortical/subcortical areas. These data indicate that the size of enhancing lesions in MS is highly variable, and that a significant proportion of disease activity goes undetected when performing conventional scans.

Autoimmune T cells play a key role as regulators and effectors of autoimmune disease. In multiple sclerosis (MS), activated T cells specific for myelin components or other locally expressed autoantigens enter the CNS and recognize their antigen(s) on local antigen-presenting cells. After local stimulation, the T cells produce a plethora of cytokines and inflammatory mediators that have profound effects on the local cellular environment, induce and recruit additional inflammatory cells, and contribute to myelin damage. An increasingly detailed knowledge of these processes will greatly facilitate the development of new immunotherapies. This article focuses on the role of T cells in MS. We provide a brief overview of the principles of T-cell immunology, discuss the experimental techniques available for studying T cells, address the role of T cells in the pathogenesis of MS, and highlight modern concepts for immunotherapy.

Background: Paraneoplastic neurological syndromes (PNS) almost invariably predate detection of the malignancy. Screening for tumours is important in PNS as the tumour directly affects prognosis and treatment and should be performed as soon as possible. Objectives: An overview of the screening of tumours related to classical PNS is given. Small cell lung cancer, thymoma, breast cancer, ovarian carcinoma and teratoma and testicular tumours are described in relation to paraneoplastic limbic encephalitis, subacute sensory neuronopathy, subacute autonomic neuropathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert-Eaton myasthenic syndrome (LEMS), myasthenia gravis and paraneoplastic peripheral nerve hyperexcitability. Methods: Many studies with class IV evidence were available; one study reached level III evidence. No evidence-based recommendations grade A–C were possible, but good practice points were agreed by consensus. Recommendations: The nature of antibody, and to a lesser extent the clinical syndrome, determines the risk and type of an underlying malignancy. For screening of the thoracic region, a CT-thorax is recommended, which if negative is followed by fluorodeoxyglucose-positron emission tomography (FDG-PET). Breast cancer is screened for by mammography, followed by MRI. For the pelvic region, ultrasound (US) is the investigation of first choice followed by CT. Dermatomyositis patients should have CT-thorax/abdomen, US of the pelvic region and mammography in women, US of testes in men under 50 years and colonoscopy in men and women over 50. If primary screening is negative, repeat screening after 3–6 months and screen every 6 months up till 4 years. In LEMS, screening for 2 years is sufficient. In syndromes where only a subgroup of patients have a malignancy, tumour markers have additional value to predict a probable malignancy.

Anti-acetylcholine receptor (AChR) antibodies in myasthenia gravis (MG) can be quantitated using AChR extracted from the human rhabdomyosarcoma cell line TE671 (AChRTE671) as a practical alternative to AChR from human amputated limbs (AChRAMP). We compared the two antigen preparations using serum samples from different clinical groups of MG patients (n = 112) and various controls (n = 189). With two exceptions, both tests were positive or negative in the same patients. However, in the generalized MG group, the TE671 assay yielded significantly lower titers than the AChRAMP assay.

Zur Diagnosesicherung der Myasthenia gravis dient die Bestimmung von Autoantikorpern gegen den nikotinischen Acetylcholin-Rezeptor (AChR) des Muskels (Ubersicht bei 6). Dies erfolgt mit Hilfe eines Immunprazipitationstests (1,2). Als Antigen-Quelle wird menschliches Material verwendet (3), hauptsachlich Amputate von Patienten mit Diabetes mellitus. Die Amputate sind oft nur schwer verfugbar und im Hinblick auf die Menge und Art des AChR nicht standardisiert. Bei der partiellen Denervierung durch die diabetische Polyneuropathie steigt der Anteil an extrajunktionalen AChR, der sich auch immunologisch von dem junktionalen Rezeptor der Synapse unterscheidet. Dadurch sind die anti-AChR-Antikorper- Werte zwischen unterschiedlichen Amputatpraparationen nicht exakt vergleichbar.

Article abstract-We report a patient with a reversible multifocal encephalopathy that developed 3 days after completion of treatment with intravenous immunoglobulin for Guillain-Barre syndrome. Magnetic resonance imaging showed reversible bioccipital white matter changes, and transcranial Doppler demonstrated transiently increased flow rates in all major cerebral arteries. We conclude that intravenous immunoglobulin therapy caused cerebral arterial vasospasm and a reversible encephalopathy.NEUROLOGY 1996;46: 250-251

Objectives To review and expand the existing literature of magnetic resonance imaging (MRI) and positron emission tomography (PET) of paraneoplastic limbic encephalitis (PLE). Methods We performed serial MRI and18F-fluoro-2-deoxy-D-glucose (FDG)–PET in a patient with anti-Ma2–positive PLE. In addition, we reviewed the relevant literature by conducting a search in the MEDLINEdatabase. Results We found a total of 7 published patient studies of possible or probable PLE containing both MRI and PET data. In 1 of these reports, the diagnosis of PLE can be regarded as proven. The results of the previous studies are controversial. Epileptic activity and inflammation are assumed to be underlying mechanisms of increased FDG uptake. In our study, we found a focal tracer accumulation in the left medial temporal lobe, which increased during the first 9 months of follow-up and corresponded with an increase of serum anti-Ma2 antibody titers. The MRI findings showed a hyperintense signal change in the left medial temporal lobe without contrast enhancement, which remained unchanged over time. Conclusions The results of functional and structural imaging in PLE may differ substantially. Results of FDG-PET can demonstrate focal hypermetabolism over a long time, which may indicate therapeutic potential. A prospective study with more patients will be needed to clarify the relevance of PET as a possible outcome measure in PLE. Future studies should include scalp or semi-invasive electroencephalographic recordings during PET acquisition.

After the first description of antibodies to titin in patients with thymoma associated myasthenia gravis in 1990, this finding was independently confirmed and the main immunogenic region of titin (mgt30) identified.1 This 30 kDa part of titin is now also commercially available as antigen for detecting anti-titin antibodies. Furthermore, in a series of 276 patients, we could confirm the clinical usefulness of measuring anti-titin antibodies for predicting the presence of a thymic epithelial tumour in patients with myasthenia gravis that was significantly better than the …

Background In Germany, patients severely affected by Multiple Sclerosis (MS) do not routinely come into contact with palliative care, even if possibly beneficial. This study was aimed at investigating how severely affected MS patients and their health professionals perceive palliative care to determine how to better approach these patients in Germany about this topic. Methods 15 patients feeling severely affected by MS and 23 health professionals experienced with MS patients (3 social workers, 7 nurses, and 13 physicians) in both in-/outpatient and rural/ urban settings participated in this qualitative study in Germany. Semi-structured interviews (patients, health professionals) and focus groups (health professionals) were conducted, transcribed verbatim and analyzed via qualitative content analysis. Results MS patients were mostly unfamiliar with the term “palliative care” or were aware of it only in relation to cancer and dying. They did not view it as relevant to themselves. Health professionals predominantly associated palliative care with dying cancer patients, if familiar with it at all. Most physicians doubted its relevance for neurological patients and denied MS as a cause of death. Nevertheless, most felt they already offered their patients sufficient palliative care, or thought that it could not meet MS patients’ complex needs. Most nurses and social workers recognized deficits in existing care structures and regarded palliative care as an opportunity for MS patients. Conclusion MS patients’, and health professionals’ restricted, death-associated awareness of palliative care leads to discomfort, fear or rejection of this idea. Therefore, a defined concept of palliative care emphasizing opportunities for severely affected MS patients and considering early integration should be spread throughout the German MS community as an additional layer of support for this patient group.

Summary Background Gastrostomy feeding is commonly used to support patients with amyotrophic lateral sclerosis who develop severe dysphagia. Although recommended by both the American Academy of Neurology and the European Federation of Neurological Societies, currently little evidence indicates the optimum method and timing for gastrostomy insertion. We aimed to compare gastrostomy insertion approaches in terms of safety and clinical outcomes. Methods In this large, longitudinal, prospective cohort study (ProGas), we enrolled patients with a diagnosis of definite, probable, laboratory supported, or possible amyotrophic lateral sclerosis who had agreed with their treating clinicians to undergo gastrostomy at 24 motor neuron disease care centres or clinics in the UK. The primary outcome was 30-day mortality after gastrostomy. This study was registered on the UK Clinical Research Network database, identification number 9923. Findings Between Nov 2, 2010, and Jan 31, 2014, 345 patients were recruited of whom 330 had gastrostomy. 163 (49%) patients underwent percutaneous endoscopic gastrostomy, 121 (37%) underwent radiologically inserted gastrostomy, 43 (13%) underwent per-oral image-guided gastrostomy, and three (1%) underwent surgical gastrostomy. 12 patients (4%, 95% CI 2·1–6·2) died within the first 30 days after gastrostomy: five (3%) of 163 after percutaneous endoscopic gastrostomy, four (3%) of 121 after radiologically inserted gastrostomy, and three (7%) of 43 after per-oral image-guided gastrostomy (p=0·46). Including repeat attempts in 14 patients, 21 (6%) of 344 gastrostomy procedures could not be completed: 11 (6%) of 171 percutaneous endoscopic gastrostomies, seven (6%) of 121 radiologically inserted gastrostomies, and three (6%) of 45 per-oral image-guided gastrostomies (p=0·947). Interpretation The three methods of gastrostomy seemed to be as safe as each other in relation to survival and procedural complications. In the absence of data from randomised trials, our findings could inform clinicians and patients in reaching decisions about gastrostomy and will stimulate further research into the nutritional management in patients with amyotrophic lateral sclerosis. Funding Motor Neurone Disease Association of Great Britain and Northern Ireland (MNDA) and the Sheffield Institute for Translational Neuroscience (SITraN).

Background In Germany, case management in a palliative care unit was first implemented in 2005 at the Department of Palliative Medicine at the University Hospital Cologne. One of the purposes of this case management is to deal with enquiries from patients and their relatives as well as medical professionals. Using the Case Management Process Model of the Case Management Society of America as a reference, this study analysed (a) how this case management was used by different enquiring groups and (b) how patients were identified for case management and for palliative care services. The first thousand enquiries were analysed considering patient variables, properties of the enquiring persons and the content of the consultations. Results Most enquiries to the case management were made by telephone. The majority of requests regarded patients with oncological disease (84.3 %). The largest enquiring group was composed of patients and relatives (40.8 %), followed by internal professionals of the hospital (36.1 %). Most of the enquiring persons asked for a patient’s admission to the palliative care ward (46.4 %). The second most frequent request was for consultation and advice (30.9 %), followed by requests for the palliative home care service (13.3 %). Frequent reasons for actual admissions were the need for the treatment of pain, the presence of symptoms and the need for nursing care. More than half of the enquiries concerning admission to the palliative care ward were followed by an admission. Conclusions Case management has been made public among the relevant target groups. Case management as described by the Case Management Process Model helps to identify patients likely to benefit from case management and palliative care services. In addition, with the help of case management palliative patients may be allocated to particular health care services.