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Biomedical subjects

C Krarup

Publications and source records attributed to C Krarup.

At least 19 recordsLinked to original sources
PubMed2005

Comparative electrophysiological, functional, and histological studies of nerve lesions in rats.

The aim of this study was to establish a nerve lesion model to compare serial electrophysiological and functional outcome measures with histological findings. The relative significance of the parameters in lesions of diverse severity, the time course of recovery, and the tools for serial longitudinal studies after nerve lesions were studied in rats. We compared weekly electrophysiological and functional studies for 100 or 150 days in rats after crush or section/suture of the sciatic nerve at midthigh level. Finally, tibial nerves were taken for histology. We confirmed that recovery was faster and more complete in nerves regenerating after crush than after section, irrespective of method of evaluation. Furthermore, continuous maturational changes occurred in control nerves, and such continuous growth-related changes should be taken into account when evaluating maturational changes during nerve regeneration. A lack of correlation between evaluation methods supports that functional, morphological, and physiological parameters show different aspects of the recovery process after nerve lesions, and that these outcome measures should be included separately in therapeutic studies.

Action Potentials↗
PubMed2004

Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation.

Complex forms of hereditary spastic paraplegia (HSP) are rare and usually transmitted in an autosomal recessive pattern. A family of four generations with autosomal dominant hereditary spastic paraplegia (AD-HSP) and a complex phenotype with variably expressed co-existing ataxia, dysarthria, unipolar depression, epilepsy, migraine, and cognitive impairment was investigated. Genetic linkage analysis and sequencing of the SPG4 gene was performed and electrophysiologic investigations were carried out in six individuals and positron emission tomography (PET) in one patient. The disease was linked to the SPG4 locus on chromosome 2p as previously reported for pure HSP. Sequence analysis of the SPG4 (spastin) gene identified a novel 1593 C > T (GLN490Stop) mutation leading to premature termination of exon 12 with ensuing truncation of the encoded protein. However, the mutation was only identified in those individuals who were clinically affected by a complex phenotype consisting of HSP and cerebellar ataxia. Other features noted in this kindred including epilepsy, cognitive impairment, depression, and migraine did not segregate with the HSP phenotype or mutation, and therefore the significance of these features to SPG4 is unclear. Electrophysiologic investigation showed increased central conduction time at somatosensory evoked potentials measured from the lower limbs as the only abnormal finding in two affected individuals with the SPG4 mutation. Moreover, PET of one patient showed significantly relatively decreased regional cerebral blood flow in most of the cerebellum. We conclude that this kindred demonstrates a considerable overlap between cerebellar ataxia and spastic paraplegia, emphasizing the marked clinical heterogeneity of HSP associated with spastin mutations.

Adenosine Triphosphatases↗
PubMed2002

Neurophysiological studies in malignant disease with particular reference to involvement of peripheral nerves.

Neurological and neuromuscular disorders are frequent complications in patients with neoplasms and may involve the neuromuscular system, including motor and sensory nerve cell bodies, axons, myelin, neuromuscular transmission and muscle alone or in combination. Electrophysiological studies are of value in delineating the type, degree and extent of involvement, and may be of assistance in pointing towards the underlying cause: paraneoplastic factors, treatment with chemotherapy or radiation or metastatic infiltration. Though some electrophysiological features may be characteristic of certain syndromes, they rarely can stand alone but require clinical, pathological, radiological, and laboratory studies to obtain a diagnosis. Even in cases where such studies are obtained, a final diagnosis may only be ascertained during follow up, since the neuromuscular disorders frequently occur before the neoplasm is detected.

Animals↗
PubMed2001

Axonal elongation through long acellular nerve segments depends on recruitment of phagocytic cells from the near-nerve environment. Electrophysiological and morphological studies in the cat.

The distal nerve stump plays a central role in the regeneration of peripheral nerve but the relative importance of cellular and humoral factors is not clear. We have studied this question by freezing the tibial nerve distal to a crush lesion in cat. The importance of constituents from the near-nerve environment was assessed by modification of the contact between the tibial nerve and the environment. Silicone cuffs, containing electrodes for electrophysiological assessment of nerve regeneration, were placed around the tibial nerve distal to the crush site. The interaction between long acellular frozen nerve segments (ANS) and the near-nerve environment was ascertained by breaching the silicone cuff to allow access of cellular or humoral components. Tibial nerves were crushed and frozen for 40 mm and enclosed in nerve cuffs with 0.45-microm holes or 2.0-mm holes to allow access of humoral factors or tissue ingrowth, respectively. In a second set of experiments, tibial nerves were crushed and either frozen for 20+20 mm, leaving a 10 mm segment with viable cells in the center (stepping-stone segment) or frozen for 50 mm. These nerves were enclosed in cuffs with 2.0 mm holes corresponding to the viable nerve segment. The regeneration was monitored electrophysiologically by implanted electrodes and after 2 months the nerves were investigated by light and electron microscopy. The results indicate that soluble substances in the near-nerve environment, such as nutrients, oxygen or tropic substances did not exert any independent beneficial effect on the outgrowing axons. However, phagocytic cells entering the acellular segment from the near-nerve environment were crucial for axonal outgrowth in long ANS.

Animals↗
PubMed2001

Sensory potentials evoked by tactile stimulation of different indentation velocities at the finger and palm.

Previous studies suggest that the rate of indentation of a tactile probe determines which skin mechanoreceptors are activated. To further investigate this possibility, indentations of 300 microm at velocities of 100 (T100) and 400 microm/ms (T400) were applied to the tip (FT) and the proximal phalanx of digit III (PP) and the thenar eminence (Pm) of ten healthy volunteers, and compared with responses after electrical stimulation at the FT. Compound sensory action potentials (CSAPs) were recorded from the median nerve through needle electrodes at the wrist and elbow. The maximal sensory conduction velocities (SNCVs) between wrist and elbow were similar with electrical and T400 stimulation, but on average were 15% lower with T100 stimulation (P < 0.001). With both indentation velocities, SNCVs were similar regardless of stimulation sites. Amplitudes of tactile CSAPs with FT stimulation were 1--2 microV at T400 and 0.3--0.4 microV at T100. The CSAP areas evoked by T100 stimulation showed a reduction from fingertip to proximal finger to palm (P < 0.05-0.005), whereas those obtained with T400 stimulation showed a reduction only at the palm (P < 0.05). The results support previous studies indicating that fast indentation at 400 microm/ms activated deeply placed Pacinian corpuscles as well as superficially situated Meissner corpuscles, whereas slower indentation at 100 microm/ms activated primarily Meissner corpuscles.

Adult↗
PubMed2000

The effect of baclofen on the transmission in spinal pathways in spastic multiple sclerosis patients.

OBJECTIVES: To measure the effect of baclofen on the transmission in different spinal pathways to soleus motoneurones in spastic multiple sclerosis patients. METHODS: Baclofen was administered orally in 14 and intrathecally in 8 patients. H(max)/M(max), presynaptic inhibition by biceps femoris tendon tap of femoral nerve stimulation, depression of the soleus H-reflex following previous activation of the Ia afferents from the soleus muscle (i.e. postactivation depression), disynaptic reciprocal Ia inhibition of the soleus H-reflex and the number of backpropagating action potentials in primary afferents, which may be a sign of presynaptic inhibition, were examined. RESULTS: Baclofen depressed the soleus H(max)/M(max) ratio significantly following oral and intrathecal baclofen. None of the two tests of presynaptic inhibition, or the postactivation depression or the disynaptic reciprocal Ia inhibition of the soleus H-reflex were affected by baclofen administration. Also the action potentials of the primary afferents were unchanged during baclofen administration. CONCLUSIONS: The antispastic effect of baclofen is not caused by an effect on the transmitter release from Ia afferents or on disynaptic reciprocal Ia inhibition. One possible explanation of the depression of the H-reflex by baclofen is suggested to be a direct depression of motoneuronal excitability.

Administration, Oral↗
PubMed2000

Post reinnervation maturation of myelinated nerve fibers in the cat tibial nerve: chronic electrophysiological and morphometric studies.

The extent to which the long-term recovery of nerve fibers differs according to the cause of Wallerian degeneration is not clear, although outgrowth of axons is better after lesions with continuity of basal lamina of the Schwann cell tubes (nerve crush) compared with lesions with interruption of basal lamina (nerve section). Post-reinnervation maturation of myelinated nerve fibers of the cat tibial nerve was followed in chronic electrophysiologic studies after crushing, sectioning, and section+freeze lesions, and compared with morphometric analysis of the same nerves. The amplitudes of the compound nerve action potentials (CNAPs) recovered to a much lesser extent after sectioning than after crushing the nerve. This difference could be related to a smaller number of large fibers, a greater degree of sprouting after sectioning than after crushing, or less synchronization of conduction in regenerated fibers. In comparison, the compound muscle action potentials (CMAPs) recovered to a greater extent than the CNAP after sectioning and section+freeze, though not to the same degree or as fast as after crushing. The difference between the recovery of the CNAP and the CMAP could be due to better regeneration of motor fibers, to differences in the size of motor units or to a better summation of motor unit action potentials. The maximal conduction velocities (CV) in mixed nerve and in motor fibers increased faster after crushing than after sectioning and section+freeze to 60%-70% of control values. The diameters of the largest myelinated fibers increased in all lesions to about 80% of controls. The relation between fiber diameter and CV was influenced by remodeling of myelin during maturation. Hence, long-term functional recovery is influenced by the nature of the nerve lesion, and a smaller proportion of fibers recovered functionally after nerve section than after crush.

Action Potentials↗
PubMed1999

Factors contributing to preferential motor reinnervation in the primate peripheral nervous system.

Functional recovery after nerve lesions in the peripheral nervous system requires the accurate regeneration of axons to their original target end organs. This paper examines axonal regeneration of the primate median nerve lesioned at the wrist over nerve gap distances of up to 50 mm. Nerve gaps were bridged by either a sural nerve graft or a biodegradable collagen nerve guide tube, and recovery was followed for up to 1100 d. Nondestructive physiological methods were used to serially examine the number of regenerated motor units, and binomial statistics were used to compare the observed number of regenerated motor units with that expected if axonal regeneration of motor neurons were random. We found up to twice the number of motor units expected by random regeneration in direct suture and sural cable graft groups but not in nerve guide repairs of 20 or 50 mm. In all repaired nerves, aberrant motor axon collaterals were detected in digital sensory nerve territory. The results support the contention that the aberrant fibers represent collaterals of an alpha-motor axon, which also innervates muscle. Although the aberrant motor axon collaterals remained in digital sensory nerve territory for long periods, they remained relatively immature compared with their sibling collateral projecting to muscle, or sensory axons within the digital nerve. The number of such aberrant motor axon collaterals decreased over time in some repair groups, suggesting a selective pruning of the inappropriate collateral under certain conditions.

Action Potentials↗
PubMed1999

Pitfalls in electrodiagnosis.

This review describes some of the factors that may lead to erroneous interpretations of electromyographic and nerve conduction studies. Such errors may be due either to technical or to biological factors, and it is imperative that the consequent limitations of the methods be considered in a diagnostic setting. Electrodiagnostic findings should always be interpreted in the clinical context, and since they are rarely specific for a particular disorder or pathology, it is necessary to satisfy several criteria to make a specific diagnosis. The aim of electromyographic examination is to ascertain whether weakness is due to a neurogenic lesion or to myopathy. It is, however, not sufficient to show the presence of denervation activity since this may occur in either condition. Therefore the motor unit potentials from both weak and nonaffected muscles should be examined quantitatively. Nerve conduction studies are carried out to ascertain whether motor or sensory myelinated fibers are lost, and whether the primary pathology is due to demyelination or axonal loss or to both. The nerve conduction velocity is of primary importance in this distinction. However, loss of large myelinated fibers leads to slowing of conduction; in some instances the conduction velocity may be normal if only a few large fibers are spared. In addition collateral sprouting in chronic conditions may lead to apparent sparing of motor fibers. Hence an erroneous diagnosis may be made of a sensory neuropathy if additional electromyography or other tests are not carried out. Conduction studies investigate only large myelinated fibers, and therefore in some instances there is discordance between the morphology and physiology. Acquired demyelinating neuropathies are sometimes associated with focal slowing of conduction or with conduction block. The demonstration of conduction block is important, but several requirements must be fulfilled in terms of technique, clinical context, and temporal development in order to avoid errors.

Diagnostic Errors↗
PubMed1999

Histology and platinum content of sensory ganglia and sural nerves in patients treated with cisplatin and carboplatin: an autopsy study.

Cisplatin is a valuable antineoplastic drug which as a dose-limiting side-effect causes sensory neuropathy, and which therefore is often combined with less neurotoxic carboplatin. It has not been possible to reproduce cisplatin neuropathy in experimental animals, and the neurotoxic mechanism in man is disputed. We investigated post-mortem material from 12 patients and 15 control subjects. Half of the fibres with diameters of > or = 9 microns, or more than 15% of all fibres (P < 0.02), had disappeared in the sural nerves of patients. Signs of axonal regeneration were lacking. The dorsal root ganglia D12 and L2 of some but not of all patients contained necrotic neurons and nodules of Nageotte. The mean volume of the somata was reduced by 18% (P < 0.03). A relation between cumulated doses, treatment free interval and changes in nerve or ganglia was not found. The platinum content was high in all tissues except in the spinal cord when the patient had died shortly after treatment, and it decreased with increasing interval, least so in liver, sensory ganglia and sural nerves. The results support the hypothesis that cisplatin neuropathy is a neuroneopathy rather than a dying-back axonopathy.

Adolescent↗
PubMed1998

[Diagnosis of polyneuropathies].

The accurate diagnosis of peripheral neuropathy is important with respect to the therapeutic possibilities and limitations, which are especially relevant in immune-mediated polyneuropathies. These polyneuropathies may be axonal or demyelinating and have an acute or chronic course, and they may be difficult to distinguish from non-treatable neuropathies on clinical grounds. Efforts have been made to establish clinical, neurophysiological, morphological, biochemical, immunological and molecular biological criteria to attain specific diagnosis. This has shown heterogeneity not only within the treatable neuropathies, which may have implications for the treatment. It has also been shown that hereditary or diabetic polyneuropathy may have features which respond to immunosuppressive treatment. Molecular biology studies have revealed markers for the diagnosis of hereditary neuropathy, and have in some instances also delineated the gene product.

Axons↗
PubMed1998

Axonal elongation through acellular nerve segments of the cat tibial nerve: importance of the near-nerve environment.

Peripheral nerve regeneration is considered to be influenced by structural, cellular and humoral factors in the distal nerve stump. Axonal elongation was, however, not affected by the presence of a 20 mm acellular nerve segment (ANS) distal to a crush lesion in a cat tibial nerve which was shielded from the environment by a silicone cuff [K. Fugleholm, H. Schmalbruch, C. Krarup, Early peripheral nerve regeneration after crushing, sectioning, and freeze studied by implanted electrodes in the cat, J. Neurosci., 14 (1994) 2659-2673]. In the present study axons were challenged to regenerate through crush lesions combined with 30-, 40-, 50-, 60- and 70-mm ANSs. For 30- and 40-mm ANSs, the nerves were shielded by impermeable silicone cuffs containing electrodes for electrophysiological evaluation of axonal elongation. All nerves were examined histologically by light microscopy 9 weeks after the lesion. The elongation through the shielded 30-mm ANS was slower than through a shielded nerve segment with viable cells. In the isolated 40-mm ANS, incomplete Wallerian degeneration and lack of blood vessels were observed, and axonal elongation was severely impaired. Regeneration across 40-70 mm non-shielded ANSs was intact and there was no relation between the number of regenerated fibers and the length of the ANS. There was no reduction in the number of blood vessels in the non-isolated ANSs. The results suggest that regeneration through an isolated acellular nerve segment exceeding 30 mm depends on cellular and humoral support from the near-nerve environment. Thus, the near-nerve environment is crucial for regeneration through long ANSs, and the importance of humoral, cellular and vascular support is discussed.

Action Potentials↗
PubMed1998

Different indentation velocities activate different populations of mechanoreceptors in humans.

We have examined whether different skin machanoreceptors are activated by different indentation velocities of a tactile probe. Indentations of 300 microns at velocities of 100 and 400 microns/ms were applied at the dorsolateral side of the foot and at the tip of digit III. Compound sensory action potentials (CSAPs) were recorded from the sural and median nerves, respectively. The amplitudes of the tactile CSAPs were < 1-2 muV, and less than 15% of the CSAPs evoked by electrical stimulation. The areas of the polyphasic tactile CSAPs were 35-38% smaller at 100 microns/ms than at 400 microns/ms. The maximal sensory nerve conduction velocities (SNCVs) were higher in the median than in the sural nerves. In both nerves, the SNCVs were similar at electrical and 400-micron/ms tactile stimulation but 11-17% lower at 100-micron/ms stimulation. Cocaine hydrochloride was applied iontophoretically at the dorsolateral side of the foot, causing a decrease of 50% of the CSAP evoked by 100 microns/ms but only 14% at 400 microns/ms. These studies suggested that identation at 400 microns/ms activated mainly deeply placed (Pacini corpuscles) and to some extent superficial mechanoreceptors, whereas the 100-micron/ms indentation activated primarily superficially situated receptors (Meissner corpuscles, and some slowly adapting units).

Action Potentials↗
PubMed1998

Gene transfer to Schwann cells after peripheral nerve injury: a delivery system for therapeutic agents.

We transferred a reporter gene to Schwann cells to test whether they might serve as an endoneurial delivery system for therapeutic proteins. A replication-defective adenoviral vector carrying the gene for beta-galactosidase (lacZ) was injected into the distal segment of intact or crushed sciatic nerves of adult rats, and the expression of lacZ was histochemically assessed. Less than 1% of the Schwann cells became reactive in intact nerves, but up to 18% of the proliferating Schwann cells of injured nerves expressed lacZ. Gene expression decayed with time but might persist for up to 2 months. It was enhanced by immunosuppression: daily cyclosporin A injections reduced both proliferation of Schwann cells and lymphocytic infiltration of the nerve, whereas tolerance induced by a single intrathymic injection of the vector 4 days after birth abolished the inflammatory response but not the proliferation of Schwann cells. The vector itself did not impede axonal regeneration. The results indicate that adenoviral gene transfer to Schwann cells in injured nerves is possible and suggest that induced production of neurotrophic factor may represent a therapeutic supplement to surgical nerve repair.

Animals↗
PubMed1996

Sensory pathophysiology in chronic acquired demyelinating neuropathy.

Pathophysiological changes in sensory fibres in chronic acquired demyelinating neuropathy (CADP) are poorly understood, and it is not known to what extent sensory loss may be due to axonal loss or to conduction block. Motor and sensory nerve condition were studied in 18 patients with CADP to delineate abnormalities in the compound sensory action potential (CSAP) recorded proximally along the limb. To distinguish small CSAPs from noise, near-nerve needle electrodes and electronic averaging were used. In all, 58 motor and 78 sensory nerves in the upper and lower limbs were studied, and in 29 nerves, motor and sensory conduction was compared over the same proximal and distal segments of the upper limbs. The proximal/distal amplitude ratio (P/D ratio) of the compound muscle action potential (CMAP) was reduced in 76% of the nerves compared with only 21% of the CSAPs. The amplitudes of CMAPs evoked and of CSAPs recorded distally were reduced to the same extent. The prolongation of the distal motor latency (DML) was linearly related to the reduction in amplitude of the CMAP whereas reduction of the distal sensory conduction velocity (SCVd) mainly occurred if the amplitude of the CSAP was reduced more than 70%. The proximal motor nerve conduction velocity (MCVp) was reduced by 40-50%, twice as much as the reduction in distal MCV (MCVd) (calculated from the reciprocal DML), and related to the reduction in the P/D ratio of the CMAP. The proximal SCV (SCVp) decreased approximately 20%, similar to the reduction in SCVd and out of proportion to the marked reduction of the MCVp. The results suggest different pathophysiological changes in sensory and motor fibres in CADP. Thus, nerve fibre loss could account for most of the abnormal parameters in sensory conduction, whereas demyelination was the dominating cause of motor nerve dysfunction.

Action Potentials↗