[Off-label therapy: current problems from the perspective of the Pharmaceutical Commission of the German Medical Profession]. / Off-Label-Therapie: aktuelle Probleme aus Sicht der Arzneimittelkommission der deutschen Ärzteschaft.

The off-label use of approved pharmaceuticals outside the authorized status is implemented in pharmacotherapy of many diseases, especially for rare diseases and in cases of therapy resistance. The German regulations are presented and analyzed and the relative literature is discussed.

[Long-term treatment of refractory myasthenia gravis with immunoadsorption]. / Langzeitbehandlung der therapierefraktären Myasthenia gravis mittels Immunadsorption.

BACKGROUND AND OBJECTIVE: Myasthenia gravis in the majority of patients is a well treatable neurological autoimmune disorder with a prevalence of 60-150 per million. For the treatment of myasthenic crisis in the intensive care unit the use of therapeutic apheresis, e. g. immunoadsorption or plasma exchange, is well established due to its rapid therapeutic effect, whereas the necessity in long term treatment is still questioned. Aim of this retrospective cohort-study was the assessment of patients with refractory myasthenia gravis in Germany treated by regular immunoadsorption, the characterization of previous therapies and the efficacy of long-term treatment. PATIENT AND METHODS: In total 14 patients (9 women, 5 men, mean age: 40.5 years) were identified in Germany using regular therapeutic apheresis. 13 were treated with different modes of immunoadsorption (10 yen l-tryptophan-adsorption, 2 yen epitope-specific adsorption, 1 yen polyclonal sheep antibody on sepharose) and 1 with plasma exchange. Mean duration of standard treatment of myasthenia gravis before initiation of regular apheresis was 7.8 years. RESULTS: Average duration of analyzed apheresis treatment was 6.4 years, with a mean treatment-interval of 1.1 per week. Mean reduction rate of autoantibodies against acetylcholine-receptor-protein was 50-60 % per session. After initiation of immunoadsorption the mean time of hospitalisation decreased significantly by app. 60 %. In particular the number of myasthenic crises could be reduced by 89 % per year. Tolerability of immunoadsorption was very good, no severe adverse events occurred. CONCLUSION: In conclusion, for the treatment of the subgroup of myasthenia gravis patients becoming refractory to standard treatment immunoadsorption should be regarded as integral part of the therapeutic armamentarium to stabilize and optimize the state of neurologic rehabilitation. This evaluation should be also carefully considered by carriers of health care cost as currently best available evidence to decide on appropriate treatment regimens for these rare patients.

Mini-infarct encephalopathy associated with uncommon microvessel convolute formation presenting with presenile dementia.

A female patient started to suffer from transient ischemic attacks when she was 47 years of age, followed by increasing predominantly left-side spastic tetraparesis, generalized seizures and progressive dementia over a period of 11 years. She died when she was 58 years of age. On gross examination the brain showed enlarged ventricles and arteriosclerotic changes of large extracerebral vessels of the circulus arteriosus. Microscopic examination of the atrophic brain showed innumerable incomplete microinfarcts in the white and gray matter throughout all parts of the brain. In the white matter these lesions were characterized by small foci of demyelination and loss of oligodendrocytes while occasionally some scavenger cells were seen. Axons seemed to be unaffected or displayed irregular axonal regeneratory growth. Any inflammatory reaction failed. In the cerebral cortex and subcortical nuclei the lesions showed loss of neurons and decrease in synaptophysin expression. Intracerebral arteries showed fibrosis or fibrohyalinosis of the entire intracerebral small-vessel network. In addition, numerous uncommon clusters of angioma-like telangiectatic vessels were observed. Medium-sized ischemic infarcts were found in the right putamen and adjacent internal capsule region, left-side dorsolateral brain stem and cerebellar hemisphere as well as a left-side pyramidal tract degeneration. Contralateral pseudohypertrophy of the inferior olivary nucleus was seen. The clinical and the neuropathologic observations made in this patient are compatible with small vessel disease characterized by a multicentric special and not yet described type of incomplete mini-infarcts in cerebral cortex and white matter accompanied by some larger ischemic infarcts of the common type in brain stem and cerebellum.

Hashimoto's encephalitis as a differential diagnosis of Creutzfeldt-Jakob disease.

OBJECTIVES: During an epidemiological study of Creutzfeldt-Jakob disease in Germany, Hashimoto's encephalitis was encountered as a differential diagnosis, which has not yet been described in this context. METHODS: The symptoms and findings of seven patients who fulfilled the criteria for "possible" Creutzfeldt-Jakob disease are presented. RESULTS: A Hashimoto's thyroiditis with antibodies against thyroglobulin or thyroid peroxidase, or both and a hypoechoic thyroid ultrasonogram were found in all cases. Analysis of CSF disclosed an increased leucocyte count in three patients, and a raised CSF:serum concentration ratio of albumin (QA1b) in four patients. The 14-3-3 protein, typical of Creutzfeldt-Jakob disease, could not be detected in any of our patients. No periodic sharp wave complexes, which are typical of Creutzfeldt-Jakob disease, were detected on EEG in any of the cases. By contrast with Creutzfeldt-Jakob disease, which leads to death within a few months, the patients with Hashimoto's encephalitis often recover quickly when treated adequately. All the patients improved after administration of corticosteroids. CONCLUSION: The clinical symptomatology of both diseases may be very similar: dementia, myoclonus, ataxia, and personality change or psychotic phenomena are characteristic symptoms.

[Long-term treatment with 7S immunoglobulins in myasthenia gravis. Preliminary clinical results]. / Zur Langzeitbehandlung mit 7S-Immunglobulinen bei Myasthenia gravis. Vorläufige klinische Ergebnisse.

After initial high-dose intravenous 7S immunoglobulin therapy, six patients with seropositive myasthenia gravis received intermittent low-dose 7S immunoglobulins for at least 4-12 months. This treatment was started in five cases following an acute exacerbation of myasthenic symptoms (Oosterhuis class 3-4) and in one case because of marked clinical fluctuations (Oosterhuis class 3). In five of the six patients, there was a clinical response to the immunoglobulin therapy within 2 weeks, followed by marked long-standing improvement and stability of the clinical outcome. In four cases a decrease in the titer of acetylcholine receptor antibodies was noted in parallel. Our observations suggest an additional positive therapeutic effect of long-term, low-dose intravenous immunoglobulin therapy following the acute management of myasthenic exacerbations.

Blunt trauma lesions of the extracranial internal carotid artery in patients with head injury.

Blunt trauma lesions of the extracranial internal carotid artery (ICA) are rare. In our hospital 18 patients with such an injury were diagnosed. All patients were involved in traffic accidents. Most of them had sustained head injuries with fractures of the skull, mandible or maxilla. The onset of neurological signs, most frequently hemiparesis, was usually delayed. 50 percent had bilateral ICA lesions but the clinical presentation was similar to those with unilateral lesions. Mortality of patients with ICA lesions was substantial (28%).

Skeletal muscle antibodies in patients with a thymic tumour but without myasthenia gravis.

Sera from 9 patients with a primary thymic tumour but without myasthenia gravis (MG) at the time of thymectomy were examined for skeletal muscle antibodies. Antibodies to a citric acid extract (CA), associated with the presence of a thymic lymphoepithelioma in MG patients, were detected in 3 sera. AChR antibodies were detected in 5 sera, the concentration markedly elevated in 1 of them. Sarcolemmal and cross-striational antibodies were detected in 2 and 3 sera, respectively. Four of the 5 patients with thymic tumours other than a lymphoepithelioma had AChR antibodies, and 3 of them also had CA antibodies.

Thymolipoma in association with myasthenia gravis.

Among 72 thymic tumors that were examined we have found five (7.5%) thymolipomas. Two of these patients have had clinical symptoms. One, a five-year-old boy, has had an erythrocyte hypoplasia as well as a hypogammaglobulinemia. The other patient, a 56-year-old man, has had myasthenia gravis. This case is the second in the world literature in which a thymolipoma is associated with symptoms of myasthenia gravis. The clinical, radiologic, and histopathologic findings and the pathogenesis of thymolipoma are discussed.

[Computed tomography of the mediastinum in myasthenia gravis. Normal findings, thymic hyperplasia, thymomas (author's transl)]. / Computertomographie des Mediastinums bei Myasthenia gravis pseudoparalytica. Normalbefund--Thymushyperplasie--Thymustumoren.

Computed tomography of the mediastinum was performed in 45 patients with myasthenia gravis. Surgery was carried out in fourteen. Amongst these, there were four thymomas, one thymolipoma, eight thymic hyperplasias and one normal thymus gland. A further patient, who did not have surgery, probably also had a thymic tumour. The normal thymus and thymic hyperplasia cannot be distinguished on computed tomography. Differentiation of small thymomas from normal thymus is not always possible. Invasion by thymomas can only be appreciated with large tumours.

[Demonstration of acetylcholine receptor antibodies in the serum of myasthenia gravis patients applying affinity chromatographically purified human acetylcholine receptor preparations (author's transl)]. / Nachweis von Acetylcholin-Rezeptor-Antikörpern im Serum von Myasthenia gravis Patienten unter Verwendung affinitätschromatographisch gereinigter humaner Acetylcholin-Rezeptor-Präparationen.

Sera from 75 patients with Myasthenia gravis were tested for acetylcholine receptor antibodies using acetylcholine receptors from human skeletal muscle. From the crude Triton x-100 extract, which has so far been used for antibody tracing, a pure acetylcholine receptor preparation was obtained by affinity chromatography using alpha-Najatoxin-Sepharose 4B. When the purified 125J-alpha-Bungarotoxin-acetylcholine receptor complex was applied in a radioimmunoassay 80% of the Myasthenia gravis patients had acetylcholine receptor antibodies in contrast to none of the tested control persons. Inspite of using a pure acetylcholine receptor preparation, no clear-cut correlation was found between the amount of serum acetylcholine receptor antibodies and the clinical stage of the disease. When individual antibody titration curves were established, different reaction patterns were observed indicating either different antibody specificities in regard to antigenic determinants on the receptor molecule or differences in the antibody affinity.

[Communicating hydrocephalus due to acustic neurinoma (author's transl)]. / Kommunizierender Hydrocephalus beim acusticusneurinom.

In 3 patients with predominant symptoms of communicating hydrocephalus more investigations led to the diagnosis of neurinoma at the cerebellar-pontine angle. Possible causes of CSF circulatory disturbances will be discussed.

[Problems of postthymectomy-syndromes, e.g. myasthenia gravis (author's transl)]. / Probleme der Postthymektomiesyndrome-am Beispiel der myasthenischen Reaktion.

6 years after resection and postirradiation of an "asymptomatic" thymoma, myasthenia gravis developed in a 46 year old man which improved within 6 months following initiation of immunosuppressive therapy with azathioprine. In a 28 year old man with incomplete operative removal of a metastasizing malignant thymoma, a myasthenia gravis appeared 8 weeks after surgery, i.e. before irradiation of the tumor relics. Myasthenia improved upon irradiation of the tumor relics and was no longer demonstrable one year after onset of its clinical signs. During the whole period of manifestation of the myasthenia, antibodies to skeletal muscle were deomonstrated in the first case, while, in the second case, in which antinuclear factors were present in the serum throughout the course of the myasthenia, muscular antibodies were detected only prefinally, i.e. in a stage without clinical symptoms of myasthenia. A review of the literature indicates that myasthenia gravis is a particularly frequent event in postthymectomy-syndromes (e.g. polymyositis, thyreoiditis, lupus erythematosus, hematological and dermatological syndromes). In postthymectomy-myasthenia, latency of manifestation, clinical distribution and its course may be rather variable. The problems of diagnosis, immunology and therapy of postthymectomy-myasthenia are discussed and general conclusions concerning postthymectomy-syndromes are drawn.

[Penicillamine-induced myasthenia in chronic rheumatoid arthritis (author's transl)]. / Penicillamin-induzierte Myasthenie bei chronischer Polyarthritis

A myasthenic reaction developed after an average latency of seven to eight months in 12 female patients (average age 51 years) treated with penicillamine for chronic rheumatoid arthritis. In most of them only the purely ocular form was noted, but generalisation of various degrees also occurred. When penicillamine had been discontinued the myasthenic signs were almost always fully reversible, recurring once again when treatment with penicillamine was started. In some instances a transitory symptomatic treatment with cholinesterase inhibitors was necessary. The occurrence of the myasthenic signs in these circumstances is probably similar to the anti-basal membrane nephropathy induced by penicillamine.