Pyridostigmine kinetics in healthy subjects and patients with myasthenia gravis.

Comparative pyridostigmine kinetics in plasma were measured in 10 healthy subjects given 4 mg iv and 60 mg oral pyridostigmine bromide. As determined from the AUC ratio, oral availability was 11.5% to 18.9% (means = 14.3%). Mean t 1/2 of the plasma level decline after oral dosing was 200 minutes, twice as long as the terminal elimination t1/2 after intravenous infusion (97 minutes). Thus absorption may proceed at a slower rate than elimination. Comparison of intraindividual data revealed strict dependence of the AUC on the infused dose (2, 4, and 8 mg) in one subject and variability in AUC up to a factor of two when two subjects took oral pyridostigmine three times. Patients with myasthenia who were receiving continuous therapy with oral pyridostigmine had AUC values per unit dose corresponding to those in healthy subjects. Storage stability of pyridostigmine in plasma required acidification of samples and storage at -75 degrees C. When native plasma was kept at -20 degrees C, there was appreciable loss of pyridostigmine within 1 to 2 months, the extent of which depended on the initial concentration.

Intrathecal baclofen therapy for stiff-man syndrome and progressive encephalomyelopathy with rigidity and myoclonus.

We report on eight patients with stiff-man syndrome (SMS) or its "plus" variant, progressive encephalomyelopathy with rigidity and myoclonus (PERM) receiving intrathecal baclofen via pump. In six of the patients, follow-ups continued for approximately 2.5 to 6.5 years after pump implantation. Intrathecal baclofen was an effective last-resort alternative for patients who responded poorly to or did not tolerate oral antispasticity medications. General mobility increased, and spasms and rigidity were reduced; however, no complete remissions were observed either before or after pump implantation. PERM patients showed more severe and rapid progression of symptoms and more attacks of autonomic dysregulation than SMS patients. They also required higher doses and more rapid dosage increases. Complications of intrathecal baclofen therapy included spasm-induced rupture of the catheter, catheter dislocation causing radicular symptoms, and pump malfunction resulting in inaccurate dosage administration. Patients suffered fewer side effects with intrathecal baclofen than with oral medication, but overdose resulted in a transient, comalike state in one patient and sudden dosage reduction due to pump failure was fatal in another.

Paraneoplastic myasthenia gravis: detection of anti-MGT30 (titin) antibodies predicts thymic epithelial tumor.

It has been suggested that antibodies against non-acetylcholine 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.

CD45 isoform expression in autoimmune myasthenia gravis.

In myasthenia gravis (MG), humoral and cellular immune mechanisms are involved in the autoimmune pathogenesis. In this study, we investigated the role of the CD45 molecule in MG, having recently reported an association in multiple sclerosis. CD45, a protein-tyrosine phophatase receptor type C (PTPRC), is essential for both thymic selection and peripheral activation of T and B cells. Our aims were to determine (a) the prevalence of a functional mutation in the CD45 gene (exon 4 77C --> G; prevalence analysis), and (b) the distribution of memory (CD45RO+) and naive (CD45RA+) T cells in the peripheral blood (subset analysis). T cells from 78 patients with generalised MG were stained with monoclonal antibodies against CD45RO, CD45RA, CD4 and CD8 and quantified by four-colour flow cytometry. The control panel for the prevalence analysis (a) consisted of 303 healthy individuals. (b) From those, 67 age- and sex-matched probands were randomly selected as controls for the subset analysis. Patients were stratified according to their MG onset age, thymic pathology and immunosuppressive treatment. Statistical analysis was performed by Fisher's exact test, asymptotic chi2 test, the two-sided Mann-Whitney test and Spearman's correlation coefficient. As a result, the 77C --> G mutation in exon 4 of the CD45 gene was found in 1 of 78 patients versus none of the 303 controls. Thus, no association was detected with this single nucleotide polymorphism in MG patients overall. Surprisingly, however, ratios of CD45RO+ to CD45RA+ T cells were lower among CD8+ T cells from patients with late-onset MG (P = 0.023). Thymoma patients also showed a similar trend among CD4+ and CD8+ T-cells, as expected. These differences were not related to immunosuppressive drug treatment or thymectomy (in the 67 informative patients). Since there is no other evidence for increased thymopoiesis in late-onset MG, we propose an altered subset balance in the circulation.

Retrograde changes in motor and sensory conduction velocity after nerve injury.

Nerve section is followed by a reduction of motor and sensory conduction velocity in the proximal segment of the injured nerve. This reduction of velocity is associated with retrograde changes in fiber size. If reinnervation does not occur within the next 1 1/2--2 years, retrograde degeneration of nerve fibers results, and the amplitude of the evoked nerve potential in the proximal segment of the injured nerve decreases. This retrograde degeneration is probably significant in view of the poor results frequently obtained after nerve transplantation which is carried out too late.

Adult-onset rod disease with abundant intranuclear rods.

The third case of adult-onset rod disease (nemaline myopathy) with abundant myofibrillar as well as intranuclear rods is described. The 61-year-old woman suffered from progressive weakness of proximal extremities and of the neck, mimicking polymyositis. Muscle biopsy revealed a striking myopathic pattern, with intranuclear rods occurring in 31% of the fibres. On light and electron microscopy and by immunohistochemical study, the rods differed from myofibrillar rods. The absence of alpha-actinin in intranuclear rods suggests an enhanced readiness of actin filaments to bind to diverse proteins, instead of overproduction of alpha-actinin as the pathogenetic basis of the rod formation.

Adrenoleukodystrophy in an adult female. A clinical, morphological, and neurochemical study.

A 43-year-old female with adrenoleukodystrophy (ALD) is described, who developed spastic tetraparesis, suffered grand mal seizures, and became stuporous and demented during the last 5 years of her life. Computed tomography revealed symmetrical hypodense lesions in the peritrigonal regions. Adrenal insufficiency was not evident except for skin pigmentation. The ultrastructure of a rectal biopsy specimen showed inclusions with lamellae and interspersed clefts in macrophages of the submucosal layer. At autopsy, the adrenals were found to contain large foam cells filled with similar inclusions. The brain cortex and the spinal cord were histologically normal. However, cerebral white matter exhibited widespread demyelination which spared only the arcuate fibres. In regions of less severe demyelination scattered inflammatory cells were seen. On electron microscopy, aggregates of typical paired leaflets with distinct intermediate lines were demonstrated in perivascular macrophages. Histochemical study showed these cells to contain free as well as esterified cholesterol. Gas chromatographic analysis of very long chain fatty acids (VLFA) from the demyelinated cerebral white matter showed a marked increase of C26:0 fatty acid in cholesterol esters and above-normal values for C24:0 and C24:1 in gangliosides. It is suggested that the condition was a heterozygote form of X-linked ALD. Patients with neurodegenerative symptoms with or without adrenal insufficiency can easily be screened for X-linked ALD by VLFA analysis in blood or cultured fibroblasts.

[Functional healing of compartment syndrome of the tibia. An analysis of follow-up results]. / Funktionelle Ausheilung nach Compartmentsyndrom des Unterschenkels. Eine Analyse der Spätergebnisse.

In a retrospective review 78 compartmental syndromes, treated between 1980 and 1988, were analyzed. The mean follow-up was 42 months. 43 patients (53%) suffered an traffic accident. Direct trauma forces predominated (66 patients). The functional results after crush injuries had been worser than after contusion injuries or direct trauma forces. The functional results depended from the posttraumatic interval of decompression. The later the fasciotomy the worser the functional results had been. A wide fascial decompression is necessary. Two cases of rebound compartmental syndromes after unilateral fasciotomy reveal the skin as an important limiting factor in severe cases of compartmental syndrome.

[Myasthenic syndrome during penicillamine treatment (author's transl)]. / Myasthene Syndrome unter Penicillamin-Therapie.

The clinical and electrophysiological findings in 2 men who had developed a myasthenic syndrome after taking penicillamine for rheumatoid arthritis will be described. The symptoms began with dysfunction of the eye muscles following a generalised muscle weakness. Course of illness after withdrawal of penicillamine was not uniform. In one of the patients a complete remission occurred within a year. The other became steadily worse and required continuous treatment with cholinesterase inhibitors. Electrophysiological examinations showed neuromuscular blockade, posttetanic exhaustion, posttetanic potentiation was found in one patient only. An immunopharmacological block of acetylcholine receptors induced by penicillamine is discussed from a pathogenetical point of view.

[Clinical evaluation system (score) of ocular symptoms in myasthenia gravis]. / Klinisches Bewertungssystem (Score) der oculären Symptomatik bei Myasthenia gravis.

A new rating scheme (score) is presented for ocular symptomatology in myasthenia gravis. The score (0-10) combines separate ratings upper eyelid weakness (ptosis) and paralysis of the outer ocular muscles (double vision). It is relatively insensitive to subjective influences and to the rater's experience. It yields replicable values which are especially important for longitudinal studies, for testing new therapeutic strategies and for their statistical validation.

Accessory nerve stimulation in the assessment of myasthenia gravis.

Repetitive nerve stimulation (5/second) was done at the median nerve at the wrist and at the accessory nerve just behind the sternocleidomastoid muscle before and 20 seconds to 5 minutes after tetanic nerve stimulation (1 minute). Since the degree of the neuromuscular block depends on the body temperature these investigations were done successively at skin temperatures of 32 degrees C and 36 degrees C. A comparison of the results obtained revealed the highest rate of pathologic decrement with posttetanic accessory nerve stimulation (32 degrees C = 77%, 36 degrees C = 87%), whereas with posttetanic median nerve stimulation pathological results were obtained in a significantly lower proportion (32 degrees C = 50%, 36 degrees C = 60%). The advantages of the stimulation of the accessory nerve for the detection of partial neuromuscular block are: 1. The superficially located accessory nerve allows for supramaximal stimulation with rather low stimulus intensities (6-20 mA). 2. Since the accessory nerve is mainly a motor nerve, the stimulation is less painful than the stimulation of a mixed nerve. 3. Stimulation of a proximal nerve is more sensitive for detecting a defect in neuromuscular transmission than stimulation of a distal nerve. 4. There is no risk of a pneumothorax and of a traumatic nerve lesion as there is with stimulation of the brachial plexus by needle electrodes.

[Chronic recurrent meningoencephalitis simulating limbic encephalitis]. / Chronisch rezidivierende Meningoenzephalitis mit dem klinischen Erscheinungsbild einer limbischen Enzephalitis.

We report on a woman patient who since 1976 has suffered eight episodes of a meningoencephalitis with features of limbic encephalitis. The duration of the individual episodes has varied from 3 weeks to 2 months. Each time recovery has always been complete. Despite numerous cultural and serological examinations of blood and cerebral spinal fluid (CSF), no infectious agent has been detected. The etiology and entity of this illness are still unclear. To our knowledge such a clinical course has never been reported.

Normal sensory conduction in the saphenous nerve in man.

Measurements of the sensory conduction velocity and the parameters of nerve action potentials in the saphenous nerve offer many advantages, compared with measurements in other nerves of the leg, regarding accuracy and the time required to complete the investigations. Therefore, the electroneurographical examination of the saphenous nerve is recommended in the early diagnosis of polyneuropathies and is indispensable in the exact diagnosis of proximal neuropathies and lesions of the femoral nerve. In the present study we indicate the proximal and distal segments of the saphenous nerve and illustrate the nerve action potentials from 70 normal subjects.

[Spontaneous oral dyskinesia. Successful treatment with tetrabenazine (author's transl)]. / Spontane orale Dyskinesien. Erfolgreiche Therapie mit Tetrabenazin (Nitoman).

Tetrabenazine (50-150 mg/day) was a moderate to excellent efficacy in each of six patients with severe spontaneous oral dyskinesia. Slight akinesia, rigidity, and transient disorientation were occasional side effects that could easily be controlled and were tolerated by the patient in view of the lasting amelioration of this debilitating symptom. When tetrabenazine was administered for blepharospasm, only two of six cases showed partial improvement with more severe side effects.

[Spongiform leucoencephalopathy after inhaling illicit heroin and due to carbon monoxide-intoxication]. / Spongiforme Leukenzephalopathie nach Inhalation von illegal gehandeltem Heroin und bei Kohlenmonoxid-Intoxikation.

A spongiform leucoencephalopathy sometimes develops as a result of inhaling illicit heroin as well as due to carbon monoxide-intoxication. Clinically psychiatric symptoms precede a neurological deterioration. Some patients die. After a brief description of several epidemiological and historical-cultural aspects regarding the smoking of opiates, the typical neuroradiological signs such as hypodensity of the white matter in CCT and signal alterations in MRT, and neuropathological sequelae such as intramyelinic vacuolisation are listed. Pathophysiologically an edema of the white matter in the beginning is suspected. Second, a dysfunction of the mitochondria is addressed relying on the particular metabolism of the oligodendrocytes. Since smoking of heroin is an increasingly preferred way of application in all continents and therapeutic options are still lacking, the need of further explanation of the underlying processes is stressed.

Gerstmann-Sträussler-Scheinker's disease. Electron-microscopic observations on a brain biopsy.

Light and electron microscopic observations are reported on a brain biopsy of a man of 59 with a rare familial disease of the CNS and a 5-year clinical course. Electron micrographs of the frontal biopsy reveal plaque-like deposits composed of amyloid cores, often multicentric in the cortex and subcortical white matter. They are localized between enlarged astrocytic processes. In the neuropil they are sometimes associated with abnormal neuritic processes, in the white matter with processes of fibrous astroglia and basement membranes. There are no signs of primary neuritic or synaptic involvement in the plaque formation which is more obviously associated with altered astrocytic processes. Moreover, degenerative alterations in the cortical vessels and slight astroglial spongiform changes as well as oligodendroglial proliferation can be found. Plaques are considered to be mainly of the kuru type; the relationship with transmissible spongiform encephalopathies is discussed.

[The ultimate electromyographic patterns in reinnervated muscle (author's transl)]. / Elektromyographische Spätbefunde nach Reinnervation

We investigated 59 patients in later stages after section and suture (n =23) or transplantation (n = 36) of the ulnar or median nerve. The most typical change in electromyographic pattern consists in a markedly increase of mean amplitude, due to an increased number and concentration of muslce fibers in the reconstituted motor-units. The mean duration and the incidence of polyphasic potentials are only slightly increased, indicating a nearly synchronous excitement of the different muscle fibers of the various motor-units. In no case there is a complete recovery; the mean amplitude of evoked potentials in reinnervated muscles varied from 32% in poor-, to 62% in satisfactory reinnervation, compared with the corresponding normal muscle in the opposite hand.

[Correlation of acetylcholine receptor antibodies and clinical severity of myasthenia gravis in combined immunosuppressive therapy]. / Korrelation von Acetylcholin-Receptor-Antikörpern und klinischem Schweregrad der Myasthenia gravis unter kombinierter immunsuppressiver Therapie.

The correlation between the severity of symptoms in myasthenia gravis (score) and the level of acetylcholine receptor-antibodies (ACHR-Ab) was studied in 24 patients treated with immunosuppressive therapy. This correlation was significant in every case regardless of whether or not thymectomy was performed in addition. It was demonstrated by means of a long-term follow up study, that a change in ACHR-Ab preceeds the corresponding change in score by 2-4 months in 80% of our patients. Measurements of ACHR-Ab ease the management of the therapy with immunosuppressants and make it safer. This is particularly true prior to and after termination of the treatment. A change in ACHR-Ab level by more than 20% indicates a change in score.

[Unusual radiological and clinical findings in a calcified chronic extradural haematoma (author's transl)]. / Ungewöhnliche radiologische und klinische Befunde bei verkalkten chronischen epiduralen Hämatomen.

In three of 32 patients with epidural haematomas calcifications and ossifications of the bleeding were found. Quickly developing (3 to 7 weeks) ossifications could be demonstrated by repeated X-rays and CT of the skull in partial drained or untreated haematomas. No ossification could be observed in the remaining 29 cases, in which the haematomas were completely removed. The growth of the ossification from the parietal to the visceral side within the capsules of the haematomas could be monitored in its progress by CT and was histologically verified. The underlying pathological mechanisms are discussed.

[Morbus Gerstmann-Sträussler-Scheinker. The Sch. family-a report of three cases (author's transl)]. / Morbus Gerstmann-Sträussler-Scheinker. Familie Sch. - Ein Bericht über drei Kranke.

The clinical symptoms from three cases and histological findings from two patients suffering from morbus Gerstmann-Sträussler-Scheinker (M-GSS) are reported. This disease belongs to the group of subacute spongiform encephalopathies. It is extremely rare and so far has only been observed in 52 members of four large families, in which the symptoms begin between the age of 33 and 50 and lead to death in 4-5 years. In the family reported here, cerebellar symptoms including myoclonia and later dementia, bulbar, and pyramidal symptoms were typical; two patients also had deterioration of vision and hearing. CSF and other biochemical data were normal. The EEGs showed progressive general slowing without periodic dysrhythmia. Evoked potential gave no evidence of demyelinization. The disease may safely be distinguished from morbus Creutzfeldt-Jakob (M-CJ) and Alzheimer's disease by histology, which reveals kuru plaques in most cases and invariably multicentric plaques as well as cortical spongiform changes of varying degree with loss of nerve cells and glial proliferation; however, only minor degenerative alterations in the cortical vessels are seen. The transmission to monkeys and histological similarities to M-CJ and kuru suggest a slow virus related to that causing scrapie. Alternatively, the genetically determined susceptibility of the patient may decide the type of reaction to the slow virus. The disposition to M-GSS is autosomally dominant.