Signs of critical illness polyneuropathy and myopathy can be seen early in the ICU course.

BACKGROUND: Critical illness polyneuropathy and myopathy (CIPNM) is recognized as a common condition that develops in the intensive care unit (ICU). It may lead to a prolonged hospital stay with subsequent increased ICU and hospital costs. Knowledge of predisposing factors is insufficient and the temporal pattern of CIPNM has not been well described earlier. This study investigated patients with critical illness in need of prolonged mechanical ventilation, describing comprehensively the time course of changes in muscle and nerve neurophysiology, histology and mitochondrial oxidative function. METHODS: Ten intensive care patients were investigated 4, 14 and 28 days after the start of mechanical ventilation. Laboratory tests, neurophysiological examination, muscle biopsies and clinical examinations were performed. Neurophysiological criteria for CIPNM were noted and measurements for mitochondrial content, mitochondrial respiratory enzymes and markers of oxidative stress were performed. RESULTS: While all patients showed pathologic changes in neurophysiologic measurements, only patients with sepsis and steroid treatment (5/5) fulfilled the CIPNM criteria. The presence of CIPNM did not affect the outcome, and the temporal pattern of CIPNM was not uniform. All CIP changes occurred early in ICU care, while myopathy changes appeared somewhat later. Citrate synthase was decreased between days 4 and 14, and mitochondrial superoxide dismutase was increased. CONCLUSION: With comprehensive examination over time, signs of CIPNM can be seen early in ICU course, and appear more likely to occur in patients with sepsis and corticosteroid treatment.

Myelinated nerve fibres in the CNS.

(1) Lamellated glial sheaths surrounding axons, and electrogenetically active axolemmal foci have evolved independently in widely different phyla. In addition to endowing the axons to conduct trains of impulses at a high speed, myelination and node formation results in a remarkable saving of space and energy. This is particularly important in the CNS, where space is restricted. Unlike the PNS, most CNS axons are myelinated, and several axons may be myelinated by a single cell. This adds further economy of space and energy. On the other hand the high level of complexity of the CNS white matter makes it vulnerable. There are several different kinds of disease affecting myelinated fibre tracts, particularly with respect to CNS white matter. (2) The CNS node of Ranvier presents a more complex structure the larger the fibre. The constricted nodal axon is encircled by perinodal astrocytic processes which contain large gliosomes and emit delicate processes towards the nodal axolemma. One astrocyte may project to several nodes. The node gap contains a polyanionic extracellular material. (3) Lamellated myelinoid bodies are frequent along paranodes of large myelinated CNS fibres. These bodies probably form through budding off from the paranodal myelin sheath. Similar bodies are seen inside astrocytes and microglia. The observation that these bodies are Marchi-positive and argyrophilic, and the presence of acid phosphatase activity around myelinoid bodies inside microglia suggests that they might represent degenerating myelin quanta, involved in the turnover of large myelin sheaths. This putative quantal release and breakdown of myelin material must be compensated for by a production of new myelin at other sites. Therefore, myelination may be viewed as a process that continues throughout life. (4) Biochemical analysis of a sub-cellular fraction enriched in myelinoid bodies shows that these bodies have a composition basically similar to that of myelin. However, breakdown products of myelin constituents, as well as exotic high molecular substances, not present in conventional myelin, can also be found. In addition, the myelinoid body fraction contains proteolytic activity. Studies using isotope labelling of myelin proteins show a source-product relation between myelin and myelinoid bodies. Altogether these data strongly support the hypothesis that myelinoid bodies reflect the catabolic side of myelin turnover. (5) Axons in the nerve fibre layer of the adult rat retina are all unmyelinated, although their diameters range up to over 2 microns. These axons exhibit focally differentiated axolemmal areas. At these sites the axolemma presents a dense undercoating with externally associated Müller cell processes or astrocytic processes.(ABSTRACT TRUNCATED AT 400 WORDS)

Nimodipine and microsurgery induced recovery of the vocal cord after recurrent laryngeal nerve resection.

Transection of the recurrent laryngeal nerve leads to permanent palsy of the vocal cord. Experimental studies have confirmed that nimodipine increases the pace of axonal regeneration. We present a case of a 19-year-old male, suffering a thyroid cancer disease, who was subjected to unilateral resection of the recurrent laryngeal nerve during surgery. The nerve was repaired with a nerve graft and the patient further treated with nimodipine for 3 months. Evaluation of the patient showed normalization of voice, movement of the vocal cord on the injured side, and electromyography evidence of reinnervation of the larynx muscles at 15 months after surgery.

Long-term outcome of facial palsy in neuroborreliosis.

OBJECTIVES: The objectives of this study were to examine children with previous manifest neuroborreliosis and concommitant facial palsy to see whether there were any persisting symptoms and/or signs of persistent residual facial palsy. STUDY DESIGN: Open, controlled prospective study. SETTING: Tertiary referral center (University Hospital). PATIENTS: The study was conducted on twenty-four patients with clinically manifest neuroborreliosis and facial palsy 3 to 5 years prior to the investigation. MAIN OUTCOME MEASURES: Results of the clinical examination using the House-Brackmann scale were compared to results from two neuro-physiological examinations (qEMG and ENoG). RESULTS: Approximately one-half of the patients with reported subjective symptoms of residual facial palsy had signs of slight dysfunction in the clinical examination using the House-Brackmann scale. There was no correlation between the subjective feeling of facial dysfunction and presence of clinical signs. Likewise, about one-half of the subjective facial dysfunction group, as well as the control group, were found to demonstrate pathological values in their neurophysiological examinations using qEMG and ENoG. CONCLUSIONS: This study shows that the assumption is not true that all children who had neuroborreliosis with facial palsy will heal 100%. A small proportion of the children claim that several years after the infection, they have subjective symptoms of slight facial weakness on the affected side. Our study shows that some of these children, as well as some children without subjective symptoms of facial palsy, demonstrate a slight facial weakness when examined clinically. Likewise, signs of slight-to-moderate facial motor dysfunction were revealed in about half of the children with the two neurophysiological methods utilized in this study. It is interesting to note that there was no clear correlation between the presence of subjective symptoms, objective signs, and neurophysiological results.

Peptide-immunoreactive neurons and nerve fibres in lumbosacral sympathetic ganglia: selective elimination of a pathway-specific expression of immunoreactivities following sciatic nerve resection in kittens.

The distributions of peptide-immunoreactive nerve fibres and cell bodies in lumbosacral paravertebral sympathetic ganglia of young cats were analysed with antibodies to calcitonin gene-related peptide, enkephalin, neurotensin, somatostatin, substance P, galanin, neuropeptide Y and vasoactive intestinal polypeptide. Fairly dense networks of nerve fibres showing enkephalin-, neurotensin-, somatostatin- or substance P-like immunoreactivity were observed in the ganglia. Double-staining experiments revealed that enkephalin- and somatostatin-immunoreactive nerve fibres preferentially surrounded calcitonin gene-related peptide- and/or vasoactive intestinal polypeptide-immunoreactive cell bodies. Neurotensin- and substance P-immunoreactive nerve fibres were mainly associated with neurons showing neuropeptide Y and/or galanin-like immunoreactivity. Occasional nerves containing calcitonin gene-related peptide-, galanin-, neuropeptide Y- or vasoactive intestinal polypeptide-like immunoreactivity were observed. These fibres did not seem to have any direct regional distribution within the ganglia. In kittens surviving for three months after early postnatal sciatic nerve resection, no calcitonin gene-related peptide-immunoreactive cell bodies could be detected in ganglia ipsilateral to the operation. In contrast, vasoactive intestinal polypeptide-like immunoreactivity, which partly co-exists with calcitonin gene-related peptide, was observed to the same extent as in control ganglia. Furthermore, almost all of the somatostatin-immunoreactive varicose nerve fibres had disappeared, whereas a fairly dense network of calcitonin gene-related peptide-immunoreactive nerve fibres could be observed. This change was paralleled by an increased content of nerve fibres that were immunoreactive to antibodies against the growth-associated protein GAP-43 (also known as B-50). The present findings suggest that experimental perturbations where postganglionic neurons are separated from their target areas by axotomy, not only induce differential changes in neurotransmitter expression in the principal ganglion cells, but also in preganglionic sympathetic neurons projecting to the ganglia. One possible explanation for the occurrence of an axotomy-induced network of calcitonin gene-related peptide-immunoreactive nerve fibres, is that extrinsic sensory nerve fibres grow into the ganglia after the sciatic nerve lesion. Thus, these findings seem to suggest one additional possibility with regard to the question of a possible interaction between sympathetic and sensory neurons after peripheral nerve injury.

Myelinated non-axonal neuronal elements in the feline olfactory bulb lack sites with a nodal structural differentiation.

Myelinated dendrites in the external plexiform layer (EPL) of the feline olfactory bulb and myelinated axons in the lateral olfactory tract (LOT), were examined by transmission electron microscopy. The results show that the non-axonal myelin sheaths are extremely thin and short and that the number of myelin lamellae does not increase with increasing dendritic diameter. In myelinated LOT axons the sheaths tend to be thicker and the myelin lamellar number increases with axon diameter. Domains with node-like structural characteristics are not encountered along myelinated dendrites, neither between successive myelin sheaths nor where single sheaths terminate. The partly myelinated neuronal perikarya, which occur in the EPL, also lack node-like domains. In contrast, typical nodes are easily found in myelinated LOT axons. In the periglomerular region dendrites and neuronal perikarya are surrounded by non-compacted glial sheets. It is concluded that myelination and node formation are relatively independent events and that morphogenetic glial-neuronal interactions may give different results in different parts of the same neuron.

Dimensions and branching patterns of triceps surae alpha-motor axons and their recurrent axon collaterals in the spinal cord during the postnatal development of the cat.

Triceps surae alpha motoneurons in the cat were stained intracellularly with horseradish peroxidase (HRP) at different postnatal ages from birth to the adult stage. The motor axons and axon collaterals were studied with regard to length, diameter and branching pattern. The postnatal increase of internodal length, measured as the distance between two subsequent axon collateral origins, was about 100% which paralleled the total length increase of the main axon in the grey matter. The axon collaterals were unmyelinated at birth and branched exclusively dichotomously until after 3 weeks of age when a substantial fraction of the branching points gave off 3-5 daughter branches. This was interpreted as signs of a fusion between neighboring branching points during the period of myelination of the axon collaterals. The length analysis of the collaterals indicated that the postnatal elimination of collateral branches described previously is preferentially located in the distal parts of the collateral tree.

Extravasation of staphylococcal alpha-toxin in normal and injured CNS regions lacking blood-brain barrier function: observations after ventral root replantation.

Staphylococcus aureus plays an important role as a bacterial pathogen after traumatic injury. The majority of isolated strains produces alpha-toxin, a 33-kDa protein, with membrane-damaging and lethal effects. The central nervous system (CNS) has been considered as the possible target for the lethal action of this toxin. A transfer of alpha-toxin across an intact blood-brain barrier (BBB) is however unlikely. The aim of the present study was to determine if alpha-toxin is accumulated in CNS regions which lack the BBB function. The distribution of alpha-toxin after intravascular injections, in normal mice and rats as well as in rats subjected to ventral root replantation, was assessed using immunogold technique. The results show that, although alpha-toxin does not cross the BBB, alpha-toxin-like immunoreactivity could be detected in the area postrema and at the optic nerve-retinal junction. Extravasation of alpha-toxin was also shown to occur in the spinal cord even 22 months after ventral root replantation. This finding suggests that axon regeneration after ventral root replantation takes place in a macromolecular environment which is totally different from the normal CNS. The implications of vascular spread of alpha-toxin to regions devoid of BBB function are discussed in relation to the bacterial infections which might complicate severe spinal injuries.

Changing relation between onset of myelination and axon diameter range in developing feline white matter.

The size spectra of unmyelinated, ensheathed and initially myelinating CNS axons were examined by electron microscopy in the spinal cord ventral funiculus and the corpus callosum of the cat during development. The first myelin sheaths appeared 4 weeks before and 3 weeks after birth in the spinal and callosal areas, respectively. De novo myelination had largely ceased by 4 months in the ventral funiculus and by 7 months in the corpus callosum. The result show that the diameter ranges, within which spinal and callosal axons undergo primary ensheathment and initial myelination, are markedly different if similar levels of myelination are compared. In both areas, these diameter ranges shift towards smaller sizes with development. However, spinal and callosal axons, which undergo primary ensheathment and initial myelination simultaneously, present comparable diameter ranges. The findings support the view that other factors than the absolute physical size of the axon trigger initiation of CNS myelination. In this respect the developmental stage of the animal appears to play an important role.

Age-related changes in occurrence of Marchi-positive granules and Marchi-positive myelinoid bodies in postnatally developing feline white matter.

The occurrence of clusters of Marchi-positive granules and of Marchi-positive myelinoid bodies at different postnatal developmental stages was examined lightmicroscopically in Vibratome sections from the cervical lateral funiculus of the cat, after perfusion-fixation with glutaraldehyde. The findings show that clusters of Marchi-positive granules are most common at birth and rapidly decrease in number with development, being largely absent in animals older than 1 month. The pattern of change resembles the postnatal changes in content of esterified cholesterol in the cervical lateral funiculus and is compatible with the view that the clusters of Marchi-positive granules may result from spontaneous myelin sheath disintegration occurring early postnatally. The incidence of Marchi-positive myelinoid bodies increases 7 times during the first 4 months after birth to a peak and declines about 40% during late maturation. The size spectrum of the Marchi-positve bodies shifts markedly towards larger sizes with development and presents a close to mature picture from 120 days on. Comparisons between the Marchi-positive myelinoid bodies and the myelin sheaths in the same region, with respect to postnatal change in occurrence and size spectrum, suggest that the Marchi-positive bodies are related to myelin sheaths of large fibres or fibres destined to become large.

Relations between axons and oligodendroglial cells during initial myelination. II. The individual axon.

Axo-glial relations in the ventral funiculus of the spinal cord (SC) and in the corpus callosum (CC) of the cat were examined by electron microscopy during initial myelination. In addition to random transverse and longitudinal sections from several stages, two series of sections were studied. As a first step in myelination the axons become ensheathed by one to three uncompacted glial lamellae (E-sheaths). E-sheaths present a length range from less than 5 microns to 149 microns (SC) or to 93 microns (CC). E-sheaths are more frequent along SC-axons than CC-axons, and the mean E-sheath is 3.3-fold longer in the former compared to the latter. In both areas naked axon portions occur between successive E-sheaths, but these gaps are insufficient to allow elongation of all short E-sheaths into long ones. Sheaths composed of mixed compacted (M-sheaths) and uncompacted segments have a length range of 66-212 microns in the SC and 66-171 microns in the CC. In relation to the undifferentiated terminations of E-sheaths or mixed E/M-sheaths, undercoated axolemmal domains are always lacking. Fully compacted sheaths were not found in the series from the SC. In the CC, 141-212 microns long compact sheaths were found, with tight axoglial junctions at their terminations. Axolemmal domains with a 'nodal' undercoating occur in relation to some of these terminations. In both areas, individual developing axons present a chaotic mixture of naked, ensheathed and myelinated portions; bulges with clusters of vesiculotubular profiles are frequent along naked and ensheathed axonal portions, particularly in the SC. The axon diameter is clearly larger in myelinated than in naked portions of the same axon. On the basis of these results, we propose that the early glial sheaths of developing CNS axons actively elongate and undergo extensive remodelling before compaction. The maximal length of uncompacted E-sheaths, and the sheath length at which axoglial junctions and nodes of Ranvier form, are markedly different in the two areas.

Relation between axons and oligodendroglial cells during initial myelination. I. The glial unit.

The morphology of oligodendroglial-axon units was examined by electron microscopy during ensheathment and initial myelination in developing feline spinal cord and corpus callosum white matter. In addition to a qualitative examination of single sections from many stages of development, a morphological analysis of spinal cord and corpus callosum units was made on the basis of serial sections from a few stages. The results show that myelination commences around embryonic/fetal day 40 and the 20th postnatal day in the spinal cord and corpus callosum areas, respectively. In both areas immature glial cells, lacking the cytological features of typical oligodendrocytes, initially associate with several axons and provide them with cytoplasmic sheaths. Serial section analysis of units, which have begun formation of compact myelin, indicates that individual cells are associated with single myelin sheaths in the spinal cord area, in a way principally similar to the Schwann cell-myelin units in developing peripheral nerves. This suggests the possibility that early spinal cord oligodendrocytes might shift from a polyaxonal to a monoaxonal association after initial ensheathment and before formation of compact myelin. In the corpus callosum area the examined serially-sectioned cells were found to be connected to several myelin sheaths through long thin processes. The myelin sheaths related to one cell are relatively uniform in terms of number of myelin lamellae and axon diameter, but the clockwise/counter-clockwise course of the myelin spiral varies randomly. Units containing both homogeneously uncompacted (cytoplasmic) and fully compacted (myelin) sheaths have not been found. In both areas the ensheathing cells achieve an oligodendrocyte-like cytology during formation of the first layers of compact myelin. These observations support the view that oligodendrocytes are structurally heterogeneous: those myelinating prospective large axons seems to differ from those myelinating axons destined to remain small. The possible functional and pathophysiological implications of this heterogeneity remain to be elucidated.

Effects of sciatic nerve resection on L7 spinal roots and dorsal root ganglia in adult cats.

The size, distribution, and number of nerve fibers and neuronal perikarya in the L7 spinal roots and ganglia of adult cats were examined 35, 90, and 190 days after ipsilateral sciatic nerve resection. With increasing survival time the size spectra of myelinated ventral root nerve fibers showed a progressive flattening of the alpha peak. In the dorsal roots the myelinated fiber size distribution exhibited a marked shift toward smaller sizes. The reduction in the proportion of large myelinated axons was particularly evident in the dorsal roots. Less clearcut changes were found in the size distribution of spinal ganglion neuronal perikarya. No significant loss of axons could be detected in ventral or dorsal roots. There was, however, a marked reduction in the number of dorsal root ganglion neurons. This discrepancy suggested the possibility that an initial loss of dorsal root axons was concealed by recurrent sprouting of axons from the proximal nerve stump. However, neuroma excision 90 days after nerve resection did not lead to any reduction in dorsal root axon numbers. Thus, any ingrowth of new axons to the dorsal root should occur from levels proximal to the neuroma. In comparison with previous findings in kittens, peripheral nerve resection in adult cats had significantly smaller effects on sizes and numbers of spinal root nerve fibers as well as of dorsal root ganglion neurons. Therefore, the potential for restitution of the peripheral innervation by axon regeneration appeared to be basically greater in mature than in immature animals.

Axo-glial relations in the retina-optic nerve junction of the adult rat: electron-microscopic observations.

The retina-optic nerve junction (ROJ) was examined by electron microscopy in adult rats, with particular emphasis on the unmyelinated-myelinated nerve fibre transition. Both single sections and serial sections were used. The non-retinal part of the ROJ is covered by an extensively folded glia limitans, facing the choroidea, sclera and pia mater. The blood vessels within the ROJ follow a transverse course and are surrounded by unusually wide perivascular spaces with a glia limitans-like outer delimitation. The endothelial cells exhibit numerous pinocytotic vesicles on their abluminal aspect. In the unmyelinated part of the ROJ the axons are embedded in an extensive meshwork of fibrous astrocytic processes. Some unmyelinated axons exhibit patches of axolemmal undercoating with externally associated astrocytic processes. Typical oligodendrocytes are not found, but a few small dark glial cells of unknown identity can be observed. Atypical ensheathment and myelination of axons at this level by ectopic Schwann cells occurred in one case. In the transition segment of the ROJ a pattern similar to that along dysmyelinated axons is observed, including aberrant axo-glial contacts, unusually thin and short myelin sheaths, intercalated unmyelinated segments, distorted myelin termination regions, bizarre paranodes and myelin termination regions without associated nodally differentiated axolemma. Neither sheath length nor number of myelin lamellae is related to axon diameter in the transition region. Axon diameter tends to be somewhat larger at myelinated than unmyelinated levels of the same axon. We suggest that the unusual axo-glial relations in this region are due to a deficient proliferation and differentiation of oligodendroglial cells, and that the pattern of glial ensheathment in the ROJ might be a consequence of the locally deficient blood-brain barrier.

C-peptide improves autonomic nerve function in IDDM patients.

In order to determine the possible influence of C-peptide on nerve function, 12 insulin-dependent diabetic (IDDM) patients with symptoms of diabetic polyneuropathy were studied twice under euglycaemic conditions. Tests of autonomic nerve function (respiratory heart rate variability, acceleration and brake index during tilting), quantitative sensory threshold determinations, nerve conduction studies and clinical neurological examination were carried out before and during a 3-h i.v. infusion of either C-peptide (6 pmol.kg-1.min-1) or physiological saline solution in a double-blind study. Plasma C-peptide concentrations increased from 0.11 +/- 0.02 to 1.73 +/- 0.04 nmol/l during C-peptide infusion. Clinical neurological examination quantitative sensory threshold evaluations and nerve conduction measurements failed to detect significant changes between C-peptide and saline study periods. Respiratory heart rate variability increased significantly from 13 +/- 1 to 20 +/- 2% during C-peptide infusion (p < 0.001), reaching normal values in five of the subjects; control studies with saline infusion did not alter the heart rate variability (basal, 14 +/- 2; saline, 15 +/- 2%). A reduced brake index value was found in seven patients and increased significantly during the C-peptide infusion period (4.6 +/- 1.0 to 10.3 +/- 2.2%, p < 0.05) but not during saline infusion (5.9 +/- 2 to 4.1 +/- 1.1%, NS). It is concluded that short-term (3-h) infusion of C-peptide in physiological amounts may improve autonomic nerve function in patients with IDDM.