CSF filtration is an effective treatment of Guillain-Barré syndrome: a randomized clinical trial.

OBJECTIVE: To compare CSF filtration (CSFF) and plasma exchange (PE) in the treatment of patients with Guillain-Barré syndrome (GBS). METHODS: In a prospective controlled clinical trial, 37 patients with acute GBS were randomized to receive either CSFF or PE. Inclusion criteria were fulfillment of National Institute of Neurological and Communicative Disorders and Stroke criteria and disability to walk >5 m unassisted. RESULTS: With similar baseline features in both groups (initial disability grades on the six-point grading scale of the GBS Study Group) the primary outcome variable (improvement within 28 days after randomization) was almost identical (test for equivalence p = 0.0014), the mean grade values being 0.82 in the CSFF group and 0.80 in the PE group. After 56 days, 56% (9 of 16 patients) of the CSFF group and 37% (7 of 19 patients) of the PE group had reached grade 2 (i.e., ability of unassisted walking >5 m). After 6 months, the probability to reach grade 2 was about 80% in both groups. In the CSFF group, transient pleocytosis occurred without apparent clinical complications. Clinically relevant complications were higher in the PE-treated group. CONCLUSIONS: Although the number of patients was small, the authors found that the treatment of GBS with CSFF is at least as effective as with PE. CSFF might work by removing from the CSF inflammatory mediators, autoantibodies, or other factors.

An endogenous pentapeptide acting as a sodium channel blocker in inflammatory autoimmune disorders of the central nervous system.

Reversible blockade of sodium channels by endogenous substances has been claimed to account for the fast exacerbations and relapses commonly seen in demyelinating autoimmune diseases. Evidence has been provided that in the cerebrospinal fluid of patients with multiple sclerosis or Guillain-Barré syndrome, a sodium-channel-blocking factor exists that has properties of local anesthetic agents. This factor could contribute to the nerve conduction block and paresis seen in these disorders. We describe here a previously unknown endogenous substance in human cerebrospinal fluid with distinct channel-blocking properties even at very low (0.00001 M) concentrations. The pentapeptide with the sequence Gln-Tyr-Asn-Ala-Asp exerted its blocking action by shifting the steady-state inactivation curve of the sodium channels to more-negative potentials, as most local anesthetics do. In the cerebrospinal fluid of healthy individuals, its concentration was about 3 microM, whereas in patients with multiple sclerosis and Guillain-Barré syndrome, it increased 300-1,400%. At these concentrations, the peptide's blocking efficacy was higher than that of 50 microM lidocaine. At a concentration of 10 microM, lidocaine is able to 'unmask' subclinical lesions in multiple sclerosis; thus, the endogenous pentapeptide may well contribute to the fast changes of symptoms. Furthermore, it may become valuable as a marker of disease activity.

A small sodium channel blocking factor in the cerebrospinal fluid is preferentially found in Guillain-Barré syndrome: a combined cell physiological and HPLC study.

The cerebrospinal fluid (CSF) of patients with Guillain-Barré syndrome (GBS) contains a low molecular weight factor with sodium channel blocking activity. This study investigated whether such activity also exists in the CSF of patients with other neurological diseases. Further, using high-performance liquid chromatography (HPLC) we tested whether the electrophysiological effect of the CSF is correlated with the size of the corresponding peak in the chromatograms. The existence of sodium channel blocking activity was tested in 27 native CSF samples of three groups of patients (group 1: GBS, n = 13; group 2: other inflammatory diseases, n = 8; group 3: controls, n = 6). NH15-CA2 neuroblastoma x glioma cells in the whole-cell recording configuration was used as a system for assaying the sodium channel blocking activity of CSF specimens. CSF shifted the steady-state inactivation curve of the sodium channels reversibly by -10.2 +/- 4.4 mV in group 1, -6.7 +/- 3.9 mV in group 2, and - 3.5 +/- 2.8 mV in group 3 (P < 0.01). The shift was greater in demyelinating (9.3 +/- 4.7 mV) than in nondemyelinating (5.6 +/- 3.9 mV) diseases (P < 0.04). HPLC analysis of CSFs showed a well separated peak containing the substance responsible for the electrophysiological effect at about 41 min elution time. The peak covered the molecular weight range of 600-800 Da. Sodium channel blocking activity of CSFs and areas of the corresponding peak in the chromatograms were well correlated. We conclude that sodium current inhibition by a low molecular weight factor is generally present but increased in GBS.

Localisation of epileptic foci with electric, magnetic and combined electromagnetic models.

We compare the localisation of epileptic foci by means of (1) EEG, (2) magnetoencephalography (MEG) and (3) combined EEG/MEG data in a group of patients suffering from pharmaco-resistant focal epilepsy. Individual epileptic events were localised by means of a moving dipole model in a 4-shell spherical head approximation. A patient's epileptic activity was summarised by calculating the spatial density distribution (DD) of all localised events, and the centre of gravity of DD was considered the most likely locus of seizure generation. To verify these loci a subgroup of 6 patients was selected, in which seizures could be related to a clearly identifiable lesion in MRI. On average, the combined EEG/MEG approach resulted in the smallest error (1.8 cm distance between calculated locus and the nearest lesion border); using only MEG yielded the largest error (2.4 cm), while EEG resulted in an intermediate value (2.2 cm). In the individual patients, EEG/MEG would also rank intermediate, but never worst. In summary, combining EEG/MEG appears to be a more robust approach to localisation than using only EEG or only MEG. Finally, we also report on the use of the barbiturate methohexital as a safe method of increasing the number of spike events during an EEG/MEG recording session.

Autotransfusion--bacterial contamination during hip arthroplasty and efficacy of cefuroxime prophylaxis. A randomized controlled study of 40 patients.

40 patients undergoing primary hip arthroplasty, given autologous processed blood transfusion, were randomized a receive no antibiotic prophylaxis (group A, n 20) or cefuroxime (1.5 g single injection; group B, n 20). Bacterial contamination at various steps in the autotransfusion procedure was assessed in liquid and solid culture media. The operation field and the wound drainage blood were never contaminated either of the groups but some of the suction tips were. Parts of the Vacufix blood collection bags of group A contained bacteria, but none in group B. Processed red blood cell concentrates in both groups showed bacterial growth. Greater blood loss did not increase the contamination rate in general. Isolated bacteria included the species Staphylococcus epidermidis, coagulase-negative staphylococci and Propionibacteria in both groups, but with different cell counts. In addition, Corynebacterium bovis et minutissimum and Moraxelle were identified in group A. In conclusion, autologous blood transfusion was a safe procedure. If contamination occurred, the bacterial count was low, and the bacteria of low pathogenicity. Antibiotic prophylaxis with cefuroxime reduced this contamination of suction tips and collection bags and limited the transfer of autologous blood products.

The human endogenous local anesthetic-like factor (ELLF) is functionally neutralized by serum albumin.

The cerebrospinal fluid (CSF) of patients with multiple sclerosis or Guillain-Barré syndrome contains a factor that inhibits excitation of nerve and muscle cells like local anesthetics. CSF samples containing the endogenous local anesthetic-like factor (ELLF) were analyzed by gel filtration chromatography and ultraviolet (UV) absorption at 210 nm. The active component was in a single peak corresponding to a molecular weight of 600-800 Da. This peak was decreased and the Na+ channel blocking activity was neutralized by the addition of 40 g/l human serum albumin to the CSF. When the albumin was separated from the CSF/albumin mixture by acetonitrile treatment, the Na+ channel blocking activity reappeared. The ELLF and its neutralization may be of relevance for the clinical fluctuations known with these diseases.

[Preoperative risk assessment of children with Duchenne muscular dystrophy and relevance for anesthesia and intra- and postoperative course]. / Präoperative Risikoerfassung bei Kindern mit Muskeldystrophie Typ Duchenne und ihre Relevanz für die Anästhesie sowie den intra- und postoperativen Verlauf.

BACKGROUND: Patients suffering from muscle disorders have an elevated anesthetic risk, i.e. to develop malignant hyperthermia or rhabdomyolysis. In addition serious cardial and pulmonal complications are imminent during anesthesia for surgery. PATIENTS AND METHODS: We investigated retrospectively the preoperative risk factors of 81 Duchenne patients undergoing 101 anesthesia (79 for muscle releasement operations and 23 for spine surgery) and the relation to possible complications due to the anesthesia and the intra- and postoperative course. RESULTS AND DISCUSSION: 83% of the patients showed pathologic ECG, 26% cardiac insufficiency in echocardiography, 31% pathologic X-rays of the thorax and 73% serious pulmonary restriction. Consequently avoiding of anesthetic agents with a high trigger potential for developing malignant hyperthermia (i.e. halothane or muscle relaxants type succinylcholine) prevented severest complications as malignant hyperthermia, rhabdomyolysis or cardiac arrest. Nevertheless other complications (i.e. arrhythmia, cardiac insufficiency) occurred due to the cardiac and pulmonary limitations more pronounced in the older patients of the spine surgery group.

On the nature of endogenous antiexcitatory factors in the cerebrospinal fluid of patients with demyelinating neurological disease.

The cerebrospinal fluid (CSF) of patients with demyelinating neurological disease, such as Guillain-Barré syndrome or multiple sclerosis, contains factors that inhibit the excitatory Na+ current. Such antiexcitatory factors are occasionally also detectable in CSF from patients with other neurological diseases but were absent from an artificial CSF containing all major CSF constituents (electrolytes, amino acids, vitamins, metabolites, albumin). In an attempt to characterize these factors, unphysiological pCa or pH values were excluded by the application of the Ca2+ chelator EGTA and the use of buffers. Heating the CSF for 10 min to 95 degrees C or digesting it with proteases did not destroy the antiexcitatory potency. Fractionation of the CSF contents according to molecular weight showed that the factors have a molecular weight < 3 kD. This excludes proteins, such as antibodies or cytokines, as candidates. Small peptides are known to be resistant to some proteases and heating.

Influence of hemodilution on cefuroxime levels and bacterial contamination of intra- and postoperative processed wound blood during hip replacement.

MATERIALS AND METHODS: In a prospective randomized study we investigated the effect of hemodilution on cefuroxime levels and bacterial contamination of processed shed blood during hip arthroplasty. 10 patients received cefuroxime 1,5 g as single shot prophylaxis before (group A), 10 after hemodilution (15 ml/KG) (group B). Cefuroxime levels in serum 1 h after administration, at the end of operation, after 12 h and in drainage-blood after 12 h were assessed by HPLC. Bacteriological study was performed from collecting bags (Vacufix), wound drainage blood and processed red blood cell concentrates, using pour plate technique and broth culture enrichment. RESULTS AND DISCUSSION: Mean concentrations of cefuroxime were higher in group B than group A, but differed not significantly. No bacterial contamination was found in collecting bags and wound drainages in both groups. Processed red cell concentrates in group B showed no growth. In group A, however, 3/10 were contaminated with < or = CFU/ml of coagulase-negative Staphylococcus, Staphylococcus epidermidis and Propionibacterium acnes. The differences between groups did not reach the level of statistical significance and could not be related to lower cefuroxime levels. No wound infection occurred in either group.

Cerebrospinal fluid and serum from patients with inflammatory polyradiculoneuropathy have opposite effects on sodium channels.

The effects of cerebrospinal fluid (CSF) and serum from patients having Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) on voltage-dependent Na+ channels were compared. Bathing human myoballs in CSF substantially reduced their Na+ currents (by > 40% with 8 of 10 patients) elicited at 1 Hz under whole-cell recording conditions. This was because, at the resting potential, more Na+ channels were inactivated (left-shift of the h infinity curve). CSF from patients with other neurological diseases (OND) produces a similar, but smaller, effect. In contrast, serum samples from the same GBS and OND patients caused an increase of the Na+ currents by reducing the number of Na+ channels inactivated at the resting potential. This right-shift of the h infinity curve is in part explained by the effect of serum albumin. We confirm that the CSF of most GBS and CIDP patients contains factors inhibiting voltage-dependent Na+ currents. There is no indication that such factors are effective in the serum of these patients.

[Effectiveness of home ventilation of young children and infants]. / Effektivität der Heimbeatmung bei Kleinkindern und Säuglingen.

BACKGROUND: The home care ventilation of patients with chronic respiratory insufficiency is a well-established method. In treating infants and newborns a lot of problems arise that deal with indication, prognosis and management. PATIENTS AND METHODS: We investigated 7 newborns and infants with chronic respiratory insufficiency after cervical spine trauma causing "pentaplegia" or due to inherited neuromuscular disorders (spinal muscular atrophy, myopathy) during homecare ventilation. RESULTS AND DISCUSSION: In contrast to experience with adults the management of the children with "pentaplegia" was relatively harmless. All were tracheostomized primarily, but 1 tracheostomy could be closed, because the patient finally achieved to be ventilated only during night-time in the iron lung. The 3 children with neuromuscular diseases were ventilated noninvasively by specially fitted nasal masks. Despite coming to the frontiers of feasibility, and taking into account the psychological stress for patients, relatives, doctors and nurses, satisfactory results were obtained.

Filtration of cerebrospinal fluid in acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome).

INTRODUCTION: Acute Guillain-Barré syndrome (GBS) is a disease where cell-mediated and humoural immune reactions play a key role. Breakdown of the blood-nerve barrier, inflammation of the nerve roots and conduction block are leading symptoms. As it is likely that pathological humoural or cellular factors are concentrated in the subarachnoid space and since factors in the cerebrospinal fluid (CSF) of GBS patients were shown to block sodium channels, a direct therapeutic intervention in the intrathecal compartment seemed worthwhile. METHODS: For this purpose, we developed a technique to purify CSF from pathological factors. Filtration was achieved by withdrawal of CSF (through a lumbally inserted 18 G catheter) and reinfusion via specially developed filters. RESULTS: Twenty severely affected GBS patients were treated with 4 to 38 CSF filtrations. This eliminated cells (> 99%) and reduced the protein content. Clinical improvement was achieved probably by improvement of nerve conduction following a reduction of sodium channel blocking factors. The median time to one grade improvement was 19 days, to reach grade 2 (independent walking) was 42 days. Ventilated patients were weaned from the ventilator after 16 days (median). Patients for which CSF filtration was the first kind of treatment improved faster than patients that had not responded to other treatments, such as plasma exchange or intravenous immunoglobulins. DISCUSSION AND CONCLUSION: Severe side effects were not observed, except sometimes transient headache during the withdrawal phase. This therapy seams to shorten treatment time (in comparison to times reported in studies with and without GBS-specific treatment by plasma exchange or immunoglobulins) and to reduce the degree of remaining neurological deficits. An open randomized controlled study is currently being conducted to compare CSF filtration with plasma exchange.

Factors in the cerebrospinal fluid of multiple sclerosis patients interfering with voltage-dependent sodium channels.

The effect of cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS) on voltage-dependent Na+ channels in human myoballs was studied. The transient Na+ currents, elicited by whole-cell depolarization from -85 to -20 mV, were decreased to 75-25% the control value in the presence of CSF from all 7 MS patients investigated. The effect was complete in about 5 s and was fully reversible on admission of standard external fluid. Such decrease was not or only to a minor extent observed with 10 out of 11 control CSFs from patients without inflammatory neurological disease. The origin of the factors interfering with the Na+ channels is unknown. It is suggested that, in addition to demyelination, impaired Na+ channel function might cause the symptoms in MS.

The acute paralysis in Guillain-Barré syndrome is related to a Na+ channel blocking factor in the cerebrospinal fluid.

The effect of cerebrospinal fluid (CSF) from patients with severe polyradiculoneuritis (Guillain-Barré syndrome, GBS) on voltage-dependent Na+ channels of myoballs was studied. The transient Na+ currents, elicited by repetitive stimulation at 1 Hz, were inhibited by the CSF from most of the GBS patients to 10%-40% the control value. The inhibition was complete in about 5 s and was fully reversible. Such inhibition was never seen with control CSF. The blocking property of the CSF from GBS patients was lost after the number of cells and the protein content had been lowered by means of a clinical filtration technique for cerebrospinal fluid. The results demonstrate that in Guillain-Barré syndrome blocking factors of Na+ channels are present in the CSF, impairing neuron impulse conduction, and thereby causing muscular weakness and sensory disturbances in the affected patient.

Cerebrospinal fluid pheresis in Guillain Barré syndrome.

While plasmapheresis is established in the treatment of acute polyneuroradiculitis, disabling pareses may last long, persisting neurological deficits remain frequent, and costs and side-effects are considerable. Repeated filtration of cerebrospinal fluid may remove pathogenetically relevant cells and polypeptides. Observations in 12 severe Guillain-Barré patients treated with CSF pheresis indicate that it is a safe and effective procedure. We hypothesize mechanisms of action of and potential indications for CSF pheresis as a more general concept. In inflammatory demyelinating polyneuropathy, CSF filtration could be combined with 'dynamic' cerebrospinal fluid pheresis, intravenous immunoglobulin therapy, cryoprecipitation, and/or immuno-adsorption to increase its effectiveness.

Dermal, serological and CSF changes in amyotrophic lateral sclerosis with and without intrathecal interferon beta treatment.

In 12 patients with amyotrophic lateral sclerosis (ALS) participating in a therapeutic trial with intrathecally applied human fibroblast interferon-beta (IFN-beta) and in 9 untreated ALS patients, we found significantly elevated circulating serum IgG immune complexes (CIC), quantitative immunoglobulin changes, and creatine kinase (CK) elevation; CK reached significantly more often pathological levels in non-bulbar disease. Dermal ultrastructural changes were equally present in all treated as well as untreated ALS patients. Some time ago IL-6 was quantitatively cleaned out of the Fiblaferon-preparation. Erythrocyte sedimentation rate (ESR) rose during intrathecal IFN therapy in 9/10 ALS patients. In 4/4 adequately monitored motoneuron patients, this elevation coincided with a decrease of serum CK, while ESR and CK did not correlate in 60 non-ALS non-IFN neurological controls. Collagen ultrastructure, CSF total protein or barrier function, immune complexes, immunoglobulin quantitation and serum CK may contribute to differentiated diagnosis and should be included in future study protocols.