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Paraneoplastic neurological syndromes (PNS) are remote effects of cancer on the nervous system. An overview of the management of classical PNS, i.e. paraneoplastic limbic encephalitis, subacute sensory neuronopathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert-Eaton myasthenic syndrome and paraneoplastic peripheral nerve hyperexcitability is given. Myasthenia gravis and paraproteinemic neuropathies are not included in this report. No evidence-based recommendations were possible, but good practice points were agreed by consensus. Urgent investigation is indicated, especially in central nervous system (CNS) syndromes, to allow tumour therapy to be started early and prevent progressive neuronal death and irreversible disability. Onconeural antibodies are of great importance in the investigation of PNS and can be used to focus tumour search. PDG-PET is useful if the initial radiological tumour screen is negative. Early detection and treatment of the tumour is the approach that seems to offer the greatest chance for PNS stabilization. Immune therapy usually has no or modest effect on the CNS syndromes, whereas such therapy is beneficial for PNS affecting the neuromuscular junction. Symptomatic therapy should be offered to all patients with PNS.

Neuroimaging is usually unremarkable in paraneoplastic cerebellar degeneration (PCD), at least in the early stages of the disease. A patient with proven PCD is reported in whom it could be shown that cerebellar atrophy evolved very rapidly and was present in early imaging studies. Even with the use of the whole spectrum of modern diagnostic tools, the underlying malignancy can be difficult to diagnose. In addition to mammography, MRI is recommended in these cases and repeat FDG-PET may be necessary.

Objective To compare the mortality of patients in a palliative care unit on working days with that on weekends and public holidays. Design Retrospective database study. Setting Palliative care unit in Germany. Population All admissions to palliative care unit between 1 January 1997 and 31 December 2008. Main outcome measure The impact of day type (working days or weekends and public holidays) on mortality was analysed using Poisson regression models. Results A total of 2565 admitted patients and 1325 deaths were recorded. Of the deaths, 448 (33.8%) occurred on weekends and public holidays. The mortality rate on weekends and public holidays was 18% higher than that on working days (mortality rate ratio 1.18, 95% confidence interval 1.05 to 1.32; P=0.005). Conclusion Patients in the palliative care unit were at higher risk of dying on weekends and public holidays. In the absence of a prospective study, the exact reasons for this correlation are unclear.

Improved methods of imaging the cerebral vascular system have increased the detection of traumatic or spontaneous dissection of the vertebral and carotid arteries. Especially MRI allows direct demonstration of intramural hematomas that are a sign of dissection of the vessel wall. We report on a patient who had an acute onset of dysarthria and monocular blurred vision, which recurred several times. Doppler ultrasound showed stenosis in both internal carotid arteries with reduced velocity of the flow; angiography confirmed the stenosis, showing a long stretch of stenosis (70%) of the right and a short stretch of stenosis (60%) of the left internal carotid arteries. MRI demonstrated a narrowing of the lumen by an intramural mass, whose signal characteristics were typical for blood. The MRI findings were thus consistent with the diagnosis of a spontaneous dissection of the carotid arteries. Since the Doppler ultrasound follow-up showed no change during the following 3 days, we interpreted the MRI findings as an indication of bleeding in an atheroma. The carotid disobliteration, performed first on the left side and later on the right side, confirmed this interpretation. Since stenosis due to a fissuring atheroma or bleeding in an atheroma requires different therapy than a dissection, it is thus important to consider the possible differential diagnosis in interpreting the MRI.

PART 1: DISORDERS PART 2: NEUROLOGIC OUTCOME AND PALLIATIVE CARE PART 3: COMMON SYMPTOMS PART 4: OTHER PROBLEMS WITH ADVANCED ILLNESS PART 5: ETHICAL ISSUES PART 6: GENERAL ASPECTS

Sirs: A 34-year-old previously healthy heterosexual man with a history of alcohol and tobacco abuse was admitted to hospital after a first epileptic seizure. Neurological examination was unremarkable. Lumbar puncture was performed the same day with the following results: 4 cells/mm3, protein 953 mg/l. Non-contrast CT was normal. EEG showed generalized slowing and epileptiform discharges. At first, symptomatic epilepsy in the context of alcoholism was suspected. During the following days, repeated complex partial seizures developed. The patient was disoriented, anterograde and retrograde memory were severely impaired. On the 4th day, MRI showed a contrast-enhancing (T1-) hyperintense signal alteration in the left medial temporal lobe on FLAIR and T2-weighted images (Fig. 1a). Repeat CSF-analysis showed 22 cells/mm3, protein 952 mg/l, and positive oligoclonal bands. Serum/CSF tests for HSV 1/2, VZV, HIV 1/2 were negative. HHV-6-Ab titer in serum was 1:20 (IgG). VDRL in serum was positive, titer 1:8, in CSF 1:4. Quantitative TPPA-test in serum was 1:81920, in CSF 1:524288. Treponema pallidum IgG-Western Blot was positive in serum and CSF. Neurosyphilis (NSP) was diagnosed and IV penicillin treatment at a dose of 3 10 million units/d for 20 days was initiated. (Note: US Centers for Disease Control and Prevention recommended treatment for NSP [18]: penicillin G 18–24 million units/d administered as 3–4 million units IV every 4 hours or continuous infusion for 14 days). Because of the MRI findings suggestive of limbic encephalitis [7, 12], paraneoplastic limbic encephalitis (PLE) was considered as a differential diagnosis. Anti-neuronal antibodies (anti-Amphiphysin, -Hu, -Ri, -CV2, -Ma2) were negative. Whole body F-18FDG-PET showed a focal hypometabolism in the left medial temporal lobe and a circumscribed area of increased tracer uptake in the left upper lung (Fig. 1b). Thoracic CT correspondingly showed a hyperdense lesion of 1.6 cm in the left superior pulmonary lobe, suspicious of carcinoma. Wedge resection of the left superior pulmonary lobe was performed. Histopathological analysis showed a demarcated severe chronic inflammation with fibrosis (non-caseous degeneration). Treponema pallidum PCR was negative. There were no signs of malignancy. Under continuous anticonvulsant therapy no more seizures occurred. The patient’s state subsequently improved. However, after 8 months of follow up the patient still suffered from generalized cognitive slowing, impaired anterograde memoryand executive functions. Repeat MRI showed atrophy of left medial temporal lobe structures. Although NSP has become rare in industrialized countries [9], it has to be considered in a variety of neuropsychiatric disorders. PLE is another infrequent CNS disorder, which manifests itself in the presence of an – initially frequently occult – malignancy. Patients with PLE can harbor anti-neuronal antibodies, most often anti-Hu or antiMa2, which, however, are not obligatory [11]. Because of their unspecific or atypical clinical course, the spectrum of differential diagnoses of both diseases is wide. Particularly NSP has always been considered “the great imitator”. Nevertheless, to our knowledge these entities have never been reported as direct differential diagnoses. Clinical hallmarks of PLE are memory dysfunction, epilepsy, and psychiatric abnormalities [17]. The LETTER TO THE EDITORS

Objectives: To describe a previously healthy patient now suffering from monophasic encephalitis caused by a primary infection with BK virus and to discuss possible risk factors for developing BK virus encephalitis. Design: Case report. Setting: Referral hospital. Patient: The patient was examined on referral. Main Outcome Measures: The main diagnostic tests performed were serology, polymerase chain reaction on cerebrospinal fluid samples, and cranial magnetic resonance imaging. Results: During the course of the patient's encephalitis, an IgM titer developed against polyomavirus, followed by anti—polyomavirus IgG. Wild-type BK virus was demonstrated in cerebrospinal fluid samples. Cranial magnetic resonance imaging showed diffuse reversible white matter changes most prominent on T2-weighted images. Conclusion: We conclude that diagnostic tests for BK, a human polyomavirus, should be included in the screening program for encephalitogenic pathogens.

Background: Paraneoplastic neurological syndromes (PNS) are defined by the presence of cancer and exclusion of other known causes of the neurological symptoms, but this criterion does not separate “true” PNS from neurological syndromes that are coincidental with a cancer. Objective: To provide more rigorous diagnostic criteria for PNS. Methods: An international panel of neurologists interested in PNS identified those defined as “classical” in previous studies. The panel reviewed the existing diagnostic criteria and recommended new criteria for those in whom no clinical consensus was reached in the past. The panel reviewed all reported onconeural antibodies and established the conditions to identify those that would be labelled as “well characterised”. The antibody information was obtained from published work and from unpublished data from the different laboratories involved in the study. Results: The panel suggest two levels of evidence to define a neurological syndrome as paraneoplastic: “definite” and “possible” . Each level can be reached combining a set of criteria based on the presence or absence of cancer and the definitions of “classical” syndrome and “well characterised” onconeural antibody. Conclusions: The proposed criteria should help clinicians in the classification of their patients and the prospective and retrospective analysis of PNS cases.

Publisher Summary This chapter presents a discussion on palliative care in the terminal stage of neurological diseases. Most palliative care specialists believe that the wish for physician-assisted death is strongly associated with the inadequate availabilty of the clinical services and interventions subsumed by the term "palliative care". Indeed, many specialists believe that optimal palliative care can abolish the call for active euthanasia in almost all instances. It is the poor availability of palliative care in most countries that should and could be changed rather than legalization of physician-assisted suicide or active euthanasia. The chapter includes definitions implying palliative care as an interdisciplinary, therapeutic approach that focuses on the comprehensive management of the physical, psychological, social, and spiritual needs of patients with progressive incurable illnesses and their families.Traditionally, palliative care has focused on end-of-life issues in the cancer population. Specialist-level palliative care has been practiced in hospices and palliative care units, where most patients are close to death from malignant neoplasms. The principles that guide palliative care clearly apply to the management of patients with progressive neurological disorders.

Autologous serological screening of a cDNA expression library (SEREX) derived from childhood neuroblastoma led to the identification of 10 different antigens, including 6 novel gene products. The novel antigen 018INX was derived from a small open reading frame in a region of alpha-internexin mRNA that was previously described as 3' untranslated region. 018INX thus represents a novel type of tumor antigen. Five novel gene products were derived from NNP-1 (NNP3) and Hu genes (HuC-L, HuD3, HuDY, HuD1pro(c)). As indicated by sequence analysis, these antigens were generated by alternative splicing and/or alternative promoter usage or allelic polymorphism. mRNA expression analyses revealed different tissue restrictions of novel compared to known HuD and NNP-1 transcripts in normal and malignant tissues. The expressions patterns of distinct transcripts indicated potential clinical meanings as diagnostic and/or prognostic tissue markers. When kinetics of serum antibody titres against SEREX-defined antigens were compared to tumor load over time in our patient with neuroblastoma, we found 100-fold increases of anti-Hu and anti-018INX antibody titres preceding the clinical diagnosis of recurrent tumor growth after 2 years. When sera of pediatric patients with cancer (30) and healthy controls (30) were tested for humoral responses to SEREX-defined neuroblastoma antigens, we detected antibodies against all known antigens and NNP3 with low frequencies and titres in control sera, while anti-018INX and anti-Hu antibodies were found in cancer patients only. Our findings indicate that SEREX-defined tumor antigens might provide novel tools for understanding and treatment of this aggressive childhood malignancy.

Amyotrophic lateral sclerosis (ALS) is the most common degenerative motor neuron disease in adults. The clinical picture consists of generalized fasciculations, progressive atrophy and weakness of the skeletal muscles, spasticity and pyramidal tract signs, dysarthria, dysphagia, and dyspnea. Pseudobulbar affect is common. Disease-specific treatment options are still unsatisfactory. Therapeutic nihilism is not justified as a large array of palliative measures available to enhance the quality of life of patients and their families. Because of its clinical characteristics, ALS represents a paradigm for palliative care in neurological diseases. Numerous projects are being undertaken worldwide in an effort to enlarge the evidence base for palliative interventions in ALS. Palliative care in ALS is a multidisciplinary effort requiring careful coordination. An open and empathic disclosure of the diagnosis is essential. Nutritional deficiency caused by dysphagia can be relieved by a percutaneous endoscopic gastrostomy. Respiratory insufficiency can be effectively treated by non-invasive home mechanical ventilation. The terminal phase of the disease should be discussed at the latest when symptoms of dyspnea appear, in order to prevent unwarranted fears of "choking to death." Psychological and spiritual care of patients and families are important. Collaboration with hospice institutions and completion of advance directives can be of invaluable help in the terminal phase.

founded a hospice residence where she continues to work with the dying. Despite potential stylistic issues with tone, readers interested in the field of medical humanities will find these accounts a valuable contribution to the growing literature exploring care at end of life. These captivating essays remind readers of the necessity to listen deeply if they are to provide culturally congruent, person-centered, and family-focused care. The multitude of concerns faced by the dying demand skilled practitioners with the courage to compassionately embrace the complexities of human life (and death). Selections from this work would provide useful material for medical, nursing, social work, and chaplaincy programs that are seeking to develop a generation of health care professionals with the ability to practice reflectively.

Paraneoplastic limbic encephalitis (PLE) is a rare disorder characterized by personality changes, irritability, depression, seizures, memory loss and sometimes dementia. The diagnosis is difficult because clinical markers are often lacking, and symptoms usually precede the diagnosis of cancer or mimic other complications. The frequency of antineuronal antibodies in patients with PLE has not been investigated. We examined the neurological symptoms and the causal tumours in 50 patients with PLE to determine the utility of paraneoplastic antibodies and other tests. The diagnosis of PLE required neuropathological examination or the presence of the four following criteria: (i) a compatible clinical picture; (ii) an interval of

In patients with cancer, symptoms of limbic and brain-stem dysfunction may result from a paraneoplastic disorder. Paraneoplastic limbic or brain-stem encephalitis occurs more frequently with testicular cancer than with most other cancers. We sought antineuronal antibodies that might be used in a diagnostic test for this syndrome.Immunohistochemical and immunoblotting techniques were used to detect serum and cerebrospinal fluid antibodies. Serologic screening of a complementary DNA library and Northern blotting were used to clone the target antigen and determine which tissues expressed it.Of 13 patients with testicular cancer and paraneoplastic limbic or brain-stem encephalitis (or both), 10 had antibodies in serum and cerebrospinal fluid against a 40-kd neuronal protein. These antibodies were used to clone a gene that we call Ma2, which codes for a protein (Ma2) that was recognized by serum from the 10 patients, but not by serum from 344 control subjects. Ma2 was selectively expressed by normal brain tissue and by the testicular tumors of the patients. Ma2 shares homology with Ma1, a "brain-testis-cancer" gene related to other paraneoplastic syndromes and tumors.The serum of patients with subacute limbic and brain-stem dysfunction and testicular cancer contains antibodies against a protein found in normal brain and in testicular tumors. Detection of these antibodies supports the paraneoplastic origin of the neurologic disorder and could be of diagnostic importance.

The identification of antineuronal antibodies has facilitated the diagnosis of paraneoplastic neurological disorders and the early detection of the associated tumours. It has also led to the cloning of possibly important neuron-specific proteins. In this study we wanted to identify novel antineuronal antibodies in the sera of patients with paraneoplastic neurological disorders and to clone the corresponding antigens. Serological studies of 1705 sera from patients with suspected paraneoplastic neurological disorders resulted in the identification of four patients with antibodies that reacted with 37 and 40 kDa neuronal proteins (anti-Ma antibodies). Three patients had brainstem and cerebellar dysfunction, and one had dysphagia and motor weakness. Autopsy of two patients showed loss of Purkinje cells, Bergmann gliosis and deep cerebellar white matter inflammatory infiltrates. Extensive neuronal degeneration, gliosis and infiltrates mainly composed of CD8 + T cells were also found in the brainstem of one patient. In normal human and rat tissues, the anti-Ma antibodies reacted exclusively with neurons and with testicular germ cells; the reaction was mainly with subnuclear elements (including the nucleoli) and to a lesser degree the cytoplasm. Anti-Ma antibodies also reacted with the cancers (breast, colon and parotid) available from three anti-Ma patients, but not with 66 other tumours of varying histological types. Preincubation of tissues with any of the anti-Ma sera abrogated the reactivity of the other anti-Ma immunoglobulins. Probing of a human complementary DNA library with anti-Ma serum resulted in the cloning of a gene that encodes a novel 37 kDa protein (Ma1). Recombinant Ma1 was specifically recognized by the four anti-Ma sera but not by 337 control sera, including those from 52 normal individuals, 179 cancer patients without paraneoplastic neurological symptoms, 96 patients with paraneoplastic syndromes and 10 patients with non-cancer-related neurological disorders. The expression of Ma1 mRNA is highly restricted to the brain and testis. Subsequent analysis suggested that Ma1 is likely to be a phosphoprotein. Our study demonstrates that some patients with paraneoplastic neurological disorders develop antibodies against Ma1, a new member of an expanding family of 'brain/testis' proteins.

Anti-Ta-associated encephalitis is a paraneoplastic inflammatory brain disorder with immune-mediated neurological symptoms. The well-characterised onconeuronal antibody, anti-Ta, reacts with the paraneoplastic protein PNMA2 (former antibody name: anti-Ma2). 1 Neurological symptoms often include abnormalities in eye movement, short-term memory loss, seizures, irritability, personality change or confusion.2,3 The symptoms tend to precede tumour diagnosis and are often more debilitating than the malignancy itself.2 The first study of anti-Ta-related paraneoplastic encephalitis reported 10 young men with testicular cancer.3 Other tumours occur in females4 and approximately 30 cases have been reported.2,5 Several tumours express the protein that, in healthy adults, is restricted to brain and testicular germ cells.3 In contrast to other paraneoplastic syndromes, a remarkable number of patients show neurological improvement if the underlying tumour allows complete surgical resection.2 We report a patient’s history of anti-Ta-associated neurological syndrome with atypical parkinsonism and massive rigidity due to occult testicular cancer. In 2001, a 66-year-old man suddenly developed disorientation, restlessness, psychomotor agitation and fever. A bradykinetic syndrome with rigidity was noted. Verbal output was reduced and the patient responded only in short sentences. Head CT and lumbar puncture examinations were normal, and EEG demonstrated a right temporal epileptic focus. After 2 weeks, the patient was admitted to the Department of Neurology, Charite, University Medicine Berlin, Berlin, Germany, with further neurological deterioration. He was drowsy, with markedly reduced verbal output, and only occasionally followed simple …

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.