Neurophysiology of inflammatory demyelinating disease

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Kenneth J Smith

Diseases such as multiple sclerosis (MS) and Guillain-Barre syndrome (GBS) result in inflammatory demyelinating lesions within the central and peripheral nervous systems (CNS, PNS) respectively. The lesions cause a range of conduction abnormalities and these lead directly to the symptoms expressed. The nature of the particular symptoms expressed depends upon the pathway affected by the lesion.

RELAPSE—AXONAL CONDUCTION BLOCK Demyelination

Perhaps the most prominent conduction deficit in inflammatory demyelinating disease is conduction block, and this is responsible for the most disabling, 'negative' symptoms such as blindness, paralysis and numbness. The most studied cause of conduction block is demyelination (Fig. 51.1), which will block conduction (initially at least; see below) even if only a single whole internode of myelin is lost. The block occurs specifically at the site of demyelination, irrespective of the direction of conduction: the morphologically unaffected portions of the axon appear to conduct normally.1 In the author's experience, conduction block is the dominant electrophys-iological feature of experimentally demyelinated axons at body temperature, in both the CNS and PNS, and it appears to be obligatory for at least the first few days following the loss of whole internodes (i.e. segmental myelin loss).2-4 The initial failure of conduction is believed to arise primarily from an inadequate density of sodium channels in the newly exposed axolemma.5

Even partial loss of an internode can be sufficient to cause conduction block, especially if the loss is focused at the paranodes to cause nodal widening. Block due to nodal widening results primarily from a reduction in the safety factor for conduction, due both to the dispersion of action currents from the excitable nodal membrane, and to the decreased internodal resistance and increased membrane capacitance of the demyelinated axolemma. (The safety factor for saltatory conduction is calculated by

Figure 51.1 Records showing the changing pattern of conduction over an approximately 5-month period prior to, and during, the evolution of a central demyelinating and remyelinating lesion. Excluding the lesion (left), the records were quite stable, but through the lesion (right) conduction was blocked during the period of demyelination, and restored to the same axons during the period of remyelination. Modified from Smith et al,2 and reproduced with permission. Cal, calibration.

Figure 51.1 Records showing the changing pattern of conduction over an approximately 5-month period prior to, and during, the evolution of a central demyelinating and remyelinating lesion. Excluding the lesion (left), the records were quite stable, but through the lesion (right) conduction was blocked during the period of demyelination, and restored to the same axons during the period of remyelination. Modified from Smith et al,2 and reproduced with permission. Cal, calibration.

dividing the current available to depolarize a node to its firing threshold, by the current necessary to do so.6 Across normal internodes the safety factor is approximately 3-5, i.e. the local action current flowing from an active node to the next node is 3-5 times greater than is actually necessary to excite it.7 In demyelinated axons the safety factor is much reduced,8 and if it is reduced to less than unity, conduction fails.) These biophysical mechanisms are considered in more detail elsewhere.9-15

Inflammation

Although demyelination causes conduction deficits and will contribute directly to the symptoms of demyelinating disease, it is becoming clear that inflammation may also play an important role in symptom production. For example, there is evidence that inflammation contributes to visual loss in optic neuritis,16 and that acute exacerbations in MS patients can be precipitated by a surge in circulating pro-inflammatory cytokines:17-18 interferon gamma (IFN-7) has been especially implicated. Cytokines are known to have both direct19-21 and indirect effects on neural function,22 and there is particular evidence that IFN-7 may act via the increased production of nitric oxide (NO). IFN-7, particularly in combination with tumour necrosis factor alpha (TNF-a), is potent in stimulating the formation of the inducible form of the enzyme nitric oxide synthase (iNOS),23-25 and this enzyme is prominent within MS lesions.26-30 iNOS produces NO in sustained, high (i.e. low micromolar) concentrations, and the expression of the enzyme implies that NO production is raised in MS

Disease Hysteria

Figure 51.2 Plots showing compound action potentials obtained every 2 min from three spinal roots using the recording arrangement shown (inset): the earliest records are shown at the front. During the recording period, the roots were exposed for 2 h, either to a control solution in which NO was scavenged by the inclusion of haemoglobin (Hb) (left), or to a solution containing nitric oxide (NO) (centre and right). At 1 Hz stimulation (centre), the NO reversibly blocked conduction in all the axons, but if the axons were continuously stimulated at 100 Hz (right), the conduction block was rendered persistent. Reproduced with permission.82

Figure 51.2 Plots showing compound action potentials obtained every 2 min from three spinal roots using the recording arrangement shown (inset): the earliest records are shown at the front. During the recording period, the roots were exposed for 2 h, either to a control solution in which NO was scavenged by the inclusion of haemoglobin (Hb) (left), or to a solution containing nitric oxide (NO) (centre and right). At 1 Hz stimulation (centre), the NO reversibly blocked conduction in all the axons, but if the axons were continuously stimulated at 100 Hz (right), the conduction block was rendered persistent. Reproduced with permission.82

lesions.31 This production may be important, since there is experimental evidence that low micromolar concentrations of NO can block axonal conduction within minutes of NO exposure (Fig. 51.2),32-33 especially in demyelinated axons.32 NO might act via a direct effect on ion channels,34-39 or perhaps by inhibition of mitochondrial energy production.40-43 The role of reactive nitrogen and oxygen species in demyelinating disease has recently been reviewed.44

Blood-brain barrier/neuroelectric blocking factors

Apart from effects mediated by NO, it is also possible that inflammation may impair conduction by opening the blood-brain barrier,45 thereby exposing axons to potentially deleterious factors in the vascu-lature. These might include putative 'neuroelectric blocking factors', although the identity of such factors, and their relevance to MS remains uncertain (reviews: Smith8, Smith and McDonald46). Some evidence suggests that the factors may be anti-bodies,47-50 and the possibility that antibodies may directly interact with ion channels has been reviewed.51 Whether anti-ganglioside antibodies are involved remains unclear,52-57 and some experiments suggest that serum blocking activity is not specific for demyelinating disease.58 Apart from antibodies, there is evidence for the presence of unidentified, small molecular weight factors in the cerebrospinal fluid (CSF) of MS patients which may directly impair sodium channel function.59-61

Other factors

Inflammation might also affect conduction by modifying the properties of glial cells, particularly astrocytes and microglia.62-65 Indeed, a functional coupling between neurons and astrocytes has recently been reported, perhaps involving gap junctions.66 Also, since inflammation in MS occurs within the grey as well as the white matter, and since synaptic function can be disturbed by some inflammatory mediators,67-71 especially NO,72-76 it is possible that some neurological deficit may result from a disturbance in synaptic transmission. If so, the promptly beneficial effects of 4-aminopyridine (4-AP) in MS (review: Bever77) are easily explained, since this potassium channel blocking agent is a potent potentiator of synaptic transmission at therapeutic concentrations.78,79 Recent reports indicate that inflammation may also result in an amplification of neurological deficit via the activation of glutamate receptors, especially AMPA/kainate (a-amino-3-

hydroxy-5-methyl-4-isoxazolepropionic acid/kainate) receptors.80-81 These studies found that AMPA antagonists, such as NBQX, ameliorate the neurological deficit in experimental autoimmune encephalomyelitis (EAE).

REMISSION—RESTORATION OF CONDUCTION, ADAPTIVE MECHANISMS

Remissions arise primarily from the restoration of conduction to blocked axons, although adaptive 'plastic' changes also presumably play a role, as they do following other central damage such as that resulting from trauma. These adaptive changes are beyond the scope of this chapter, but they may help to compensate for both axonal loss and persistent conduction block.

There are at least three mechanisms underlying the restoration of conduction: the resolution of inflammation, the restoration of conduction to demyelinated axons, and repair by remyelination. These mechanisms can probably occur concurrently, perhaps even affecting different axons within the same lesion. It seems likely that the relative importance of each mechanism will vary between patients, and in individual patients at different times. It is widely accepted that the restoration of conduction will tend to reverse the neurological deficit caused by conduction block.

Inflammation

With regard to inflammation, it is reasonable to believe that the resolution of inflammation will relieve the conduction block arising from it, and certainly, in experimental lesions at least, conduction block mediated by NO is reversed within minutes of the removal of the NO, even when the conduction block has been imposed for some hours.32,82 In agreement with this belief, clinical recovery in patients with MS tends to coincide with the resolution of inflammation (as judged by gadolinium diethylene-triaminepentaacetic acid (DTPA)-enhanced MRI), suggesting that this event permits the restoration of conduction.16 Furthermore, the acute exacerbation of neurological deficit associated with a transient cytokine surge83 tends to subside with the reduction in cytokine concentration, and it is prevented entirely by anti-inflammatory pretreatment with steroids.

Demyelination

The first conclusive evidence that conduction could be restored to segmentally demyelinated axons was provided by a sophisticated examination of conduction in spinal root axons demyelinated by the intrathecal injection of diphtheria toxin (Fig. 51.3a).84 Conduction is restored by a process which includes the appearance of sodium channels along the demyelinated axolemma,84,85 and these channels permit the transition from a saltatory to a more continuous mode of conduction across the demyeli-nated region. The mechanisms involved in the appearance of excitability along the demyelinated axolemma remain incompletely understood, but on physiological criteria both a seemingly continuous distribution of sodium channels (Fig. 51.3a),84 and, in contrast, the aggregation of sodium channels into nodes' (Fig. 51.3b) have been described.85 ^-Nodes appear to be the precursors of the new nodes of Ranvier formed during remyelination, and it may be significant that the initial observation of a continuous distribution of sodium channels was made in a lesion (diphtheria toxin) in which repair by remyeli-

nation is only slowly achieved. A debate persists regarding the mechanism(s) involved in the aggregation of sodium channels at the new nodes of Ranvier formed during remyelination. Seemingly convincing evidence favours a view that the axon forms the channel aggregations and that the myeli-nating cells myelinate the gaps between them,85-89 but also a view that the myelinating cells are primarily responsible for organizing the sodium channels.90-94

The likelihood that sodium channels appear along axons demyelinated by MS has been strengthened by the observation that the density of saxitoxin binding is increased within MS lesions.95 However, these data are inconclusive, since although saxitoxin binds to sodium channels, the resolution of the study was insufficient to distinguish axonal from glial binding. A higher resolution was achieved in a more recent ultrastructural study of central axons experimentally demyelinated by ethidium bromide.87

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