Floyd A. Davis

Impulse conduction in multiple sclerosis: a theoretical basis for modification by temperature and pharmacological agents

The simplest model for explaining conduction defects in multiple sclerosis (MS) and other demyelinating diseases assumes that the only abnormality present is loss of myelin. The consequences of such an assumption have been investigated by numerical solution of a well-known set of differential equations describing conduction in a model demyelinated axon. In agreement with clinical findings, we show that this model predicts that the temperature at which conduction block occurs is a steep function of the extent of demyelination, so that small temperature increases may block large numbers of conducting fibres. Decreasing calcium concentration (or increasing pH) is calculated markedly to improve the conduction velocity of conducting demyelinated fibres and will, in addition, restore conduction in blocked fibres. The effects of other pharmacological agents have also been computed. The presence of a demyelinating lesion in a nerve fibre is shown greatly to impair the ability of the fibre to conduct repetitive impulses, conduction failing at much lower frequencies than in normal fibres. These calculations provide some insight into the nature of conduction defects in demyelinated nerve, demonstrate that many clinical features of MS are the expected consequence of loss of myelin and do not require the presence of other defects for their explanation, and provide a useful approach to the search for a symptomatic therapy.

T cell-depleted autologous hematopoietic stem cell transplantation for multiple sclerosis: Report on the first three patients

Multiple sclerosis (MS) is a disease of the central nervous system characterized by immune-mediated destruction of myelin. In patients with progressive deterioration, we have intensified immunosuppression to the point of myeloablation. Subsequently, a new hematopoietic and immune system is generated by infusion of CD34-positive hematopoietic stem cells (HSC). Three patients with clinical MS and a decline of their Kurtzke extended disability status scale (EDSS) by 1.5 points over the 12 months preceding enrollment and a Kurtzke EDSS of 8.0 at the time of enrollment were treated with hematopoietic stem cell (HSC) transplantation using a myeloablative conditioning regimen of cyclophosphamide (120 mg/kg), methylprednisolone (4 g) and total body irradiation (1200 cGy). Reconstitution of hematopoiesis was achieved with CD34-enriched stem cells. The average time of follow-up is 8 months (range 6–10 months). Despite withdrawal of all immunosuppressive medications, functional improvements have occurred in all three patients. We conclude that T cell-depleted hematopoietic stem cell transplantation can be performed safely in patients with severe and debilitating multiple sclerosis. Stem cell transplantation has resulted in modest neurologic improvements for the first time since onset of progressive disease although no significant changes in EDSS or NRS scales are evident at this time.

Altered thermal sensitivity in injured and demyelinated nerve: A possible model of temperature effects in multiple sclerosis

Electrophysiological studies were performed on frog and guinea-pig peripheral nerves to determine the effect of temperature on conduction at the site of pressure and demyelinating lesions. An increased susceptibility to thermally-induced conduction blockade has been demonstrated. In pressure-injured frog and guinea-pig nerves, conduction blocks occur at temperatures approximately 6°C lower than in normal nerves. A similar phenomenon occurs in guinea-pig demyelinated nerve (experimental allergic neuritis) and in some cases at temperatures around 15°C lower than in controls. It is suggested that these effects are the result of a critical lowering by temperature of an already markedly depressed conduction safety factor. In support of this, it has been shown that calcium ion depletion, which would be expected to increase the conduction safety factor by lowering the threshold for excitation, counteracts the increased thermal sensitivity of frog pressure-injured nerve. These findings are discussed in relation to well-known temperature effects in multiple sclerosis. They add support to an earlier proposed hypothesis that the changes in signs and symptoms with a change of body temperature in multiple sclerosis may be caused by an effect of temperature on axonal conduction.

Effect of intravenous sodium bicarbonate, disodium edetate (Na2EDTA), and hyperventilation on visual and oculomotor signs in multiple sclerosis.

The effects of procedures believed to produce a decrease in serum ionized calcium were tested on visual and oculomotor function in nine multiple sclerosis (MS) patients. Transient improvement in scotomas, nystagmus, and oculomotor paresis occurred with intravenous infusions of NaHCO3 or Na2EDTA. Hyperventilation was also tested for its effect on nystagmus and caused marked decreases in frequency. Control experiments with saline infusions did not produce any effect. The probable mechanism and site of action for these effects is discussed. This study demonstrates that certain signs and symptoms in MS can be altered favourably by changes in the internal chemical environment and offers a new approach to the search for a symptomatic therapy in MS.

Impairment of repetitive impulse conduction in experimentally demyelinated and pressure-injured nerves

Repetitive impulse conduction was studied in segmentally demyelinated peripheral nerves in guinea-pigs with experimental allergic neuritis (EAN) and in pressure-injured frog sciatic nerves. Normal guinea-pig sciatic-peroneal nerves maintained at 37°C conducted compound action potentials with only minor amplitude decreases at stimulus frequencies up to 200/sec. In contrast, nerves in EAN guinea-pigs maintained at 37°C demonstrated a rapidly progressive decrease in action potential amplitude when stimulated as slowly as 10-25/sec. The decrease is greater the higher the frequency of stimulation. At 100 stimuli/sec all EAN preparations showed more than a 50% reduction in action potential amplitude. These effects are reversible. In pressure-injured frog sciatic nerves similar effects occurred at stimulus frequencies as low as 50/sec. Normal frog nerves conducted up to 200 impulses/sec with little amplitude decrease. The probable mechanism and clinical significance of these results are discussed.

Acute effects of oral phosphate on visual function in multiple sclerosis

The acute effects of an oral hypocalcemic substance, Na2HPO4/KH2PO4, was tested on visual function in six multiple sclerosis patients with optic nerve dysfunction. Marked improvement in visual function testing occurred in five patients within one hour after phosphate ingestion and generally reversed over one to two hours. Improvement was correlated with elevation of serum phosphate and chemical and clinical evidence of serum calcium lowering. Placebo had no effect on visual function in one multiple sclerosis patient and phosphate had no effect on pupillometry in a normal control subject. Though the results do not represent a practical treatment, they do show the dramatic potential for acute pharmacologic modification of signs and symptoms of multiple sclerosis.

Serial hyperthermia testing in multiple sclerosis: a method for monitoring subclinical fluctuations.

Small elevations of body temperature in multiple sclerosis (MS) patients are known to reversibly worsen existing signs and symptoms as well as provoke the appearance of new findings. In this study serial hyperthermia testing was performed in three MS patients for periods up to seven months in order to detect any significant fluctuations in temperature sensitivity of visual and oculomotor signs. Serial hyperthermia testing revealed marked fluctuations in thermal sensitivity during periods when the patients overt clinical status was essentially stable. In two patients (one with visual, the other with oculomotor signs) recently recovered from clinical exacerbations there was a heightened response to hyperthermia that gradually reversed over days‐weeks. In another patient with bilateral optic nerve involvement in longterm remission and clinically stable, an abrupt, marked, unilateral fluctuation in the thermal sensitivity of vision was observed. These findings suggest that the manifest signs and symptoms in MS as well as characteristic exacerbations‐remissions may, like the peak of an iceberg, reflect only a portion of the extent and activity of the underlying pathology. Serial hyperthermia testing appears to offer a means of uncovering and monitoring these subclinical changes.

EFFECTS OF INDUCED HYPERTHERMIA IN MULTIPLE SCLEROSIS: DIFFERENCES IN VISUAL ACUITY DURING HEATING AND RECOVERY PHASES

Visual acuity in five multiple sclerosis (MS) patients was quantitatively monitored during the induction of hyperthermia and the subsequent spontaneous return of body temperature to base line (“cooling”). During heating acuity decreased monotonically. During “cooling” acuity was restored but, in three of the five patients, along a different temperature‐acuity trajectory; that is, acuity at any temperature during “cooling” tended to be better than acuity at the same temperature reached during heating. In two patients acuity upon return to base‐line temperature was significantly better than it had been before the induction of hyperthermia; in one case the difference was striking and significant at the .001 level. The difference in the second case was smaller but also significant (p < 0.02). The significance of these findings in helping to better understand the physiologic basis of temperature effects in MS is discussed.

The clinico-radiological paradox in multiple sclerosis: novel implications of lesion size.

The clinico-radiological paradox in multiple sclerosis (MS) refers to the weak correlation of magnetic resonance imaging (MRI) lesion load with clinical disability.1 A major factor is believed to be the inability of conventional MRI to detect the heterogeneity of the underlying histopathology. A new factor, MS lesion size, is considered in this letter. In their seminal 1970 study on conduction in demyelinated central nervous system (CNS) axons of cats, McDonald and Sears2 reported an intriguing finding. Conduction was blocked in single axons passing through an experimental, focally demyelinated lesion when the lesion was around 5 mm long while slowed conduction occurred at shorter lengths. Importantly, these axons would appear to have conducted relatively securely as the lowest impulse train frequency failure observed was 290 Hz.2 The authors noted that it was not possible to correlate conduction findings with lesion morphology in the same axon. This was later resolved by the finding that conduction occurred in rat CNS axons that were segmentally demyelinated around 2.5 mm.3 Using a computer model that simulates conduction in segmentally demyelinated axons,4 I have explored whether these effects can be explained solely on the basis of demyelination. The results strikingly replicate the animal findings. Conduction blocks at the junction of myelinated and demyelinated segments when the demyelinated segment is 4 or more mm long. For shorter lengths conduction continues through the demyelinated segment. These results indicate that the animal findings can be explained solely on the basis of the length of demyelination. This is likely related to critical changes in the total capacitance of the demyelinated segment which is directly related to its length (and thereby its membrane surface area). The animal and computer model findings suggest that conduction can occur in axons that are segmentally demyelinated nearly 4–5 mm. Based on the computer model results, all of the axons traversing a hypothetical, totally demyelinated lesion less than 4 mm in nominal diameter (defined as the calculated diameter assuming that lesions have a circular shape)5 would be expected to conduct. Computer model simulations also indicate that the axons with mid-range lengths (approximately 2.5 mm, assuming a 3.9 mm round lesion) can conduct impulse trains at 250 Hz. This lesion would most likely be clinically silent, and if present in sufficient numbers could represent a confounding factor for the correlation of MRI lesion load with clinical disability. These putative confounding lesions could be present in relatively large numbers considering that nearly 20% of brain MRI lesions in MS have nominal diameters less than 3.5 mm and 80% less than 8 mm.5 Furthermore, 4 Tesla MRI frequently detects lesions smaller than 5 mm within confluent periventricular lesions, that are seen only in retrospect with 1.5 Tesla imaging.6 This could also be problematic for the segmentation of large confluent periventricular lesions imaged with conventional MRI. There is the caveat that axonal loss in the postulated confounding lesions might, depending on its magnitude, have an opposing effect. Further study of the clinical significance of these ideas would appear warranted.