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1-Center for Neurologic Study San Diego, California;
2-Houghten Pharmaceuticals, Inc. San Diego, California, USA.
Although breakthroughs in scientific research deservedly capture our imagination, the principal advances made in Amyotrophic Lateral Sclerosis involve the day-to-day management of patients. Over the course of some 25 years Ted Norris wrote extensively, usually with collaborators, about this subject as have others, including Don Mulder, David Goldblatt, and more recently Alan Hillel.6,7,10,12,22 Each in his own way was aware that there was something special, something intimate about sharing the experience of ALS. To the degree that this has been communicated to the general medical community, there has been an amelioration in the level of care provided to the ALS patient. While a state of the art review has often been part of the meeting agenda of ALS conferences, a somewhat different emphasis is undertaken here, in part, because extensive, current reviews have been published recently.5,9 The question we wish to raise here is what are the limits of palliative care? A number of patients have elected to live with ALS using life support equipment and other advanced technologies to enhance their communication and mobility.
Over the course of Ted's career the care of ALS has changed dramatically. This has occurred for several reasons. Firstly, there has been a general technical advance. Components have been miniaturized, and a myriad of aids have been put at the disposal of the handicapped. Secondly, there has been a change in public attitudes towards the disabled. In short, not only has technology advanced but the will to use it on behalf of the chronically ill has gained public support.21
Most of the advances that have been made in the care of ALS have involved a 'systems approach'. In lieu of being able to arrest the underlying disease, physicians have intervened in support of specific 'systems' which have failed. This has led to the notion of 'life support' which has achieved the goal of maintaining vital functions. The key elements are the use of a percutaneous gastrostomy and a positive pressure ventilator which respectively circumvent failure of the alimentary and respiratory systems. The patient with a will to live can survive for months or years without any semblance of voluntary motor control. At this juncture one must question whether there is much else that could be done for patients, short of finding a cure for ALS.
Our own recent interests have focused on two problems which have heretofore not been well palliated in the past. The first relates to the problem of emotionailty in patients, with ALS. Ted Norris along with Brian Gould and Jeffrey Houpt found this to be an interesting aspect for study.8 They picked up on an earlier report which suggested that ALS patients were distinguished from other chronically ill patients by excessive use of denial.2 The inference was that ALS patients exhibited a pre-morbid personality somewhat akin to the Type IA personality associated with coronary artery disease. After careful study it was determined that ALS patients, in fact, were no different from peers with similar, serious illnesses.
Another aspect of emotionality which has received little attention is that of pseudobulbar emotionality. It is characterized by inappropriate laughter or tearfulness. Both occur explosively, often with very minimal provocation. Although reactive depression occurs commonly in patients who are neurologically afflicted, emotional lability appears to be an independent phenomenon which does not correlate with the mood of the patient. This behavior was commented upon by Ted in several publications. He described it as 'one of the most demoralizing problems affecting patient, family, friends and medical attendants. Everyone is demoralized by sustained weeping, laughter, or laughter making a transition to frustrated weeping'.13
Although there have been several anecdotal references to successful treatment of this symptom, including mention made by Ted of the utility of treating patients with lithium carbonate, there have been no controlled studies focusing specifically on ALS. Assuming that this behavioral disorder is similar, irrespective of the many causes including stroke, MS, tumor, trials with a mixed group of patients may be informative. In 1979 Wolf reported that levodopa was effective in patients with pathologic laughter.26 Following up this report, Ukeda et. al. treated 25 patients with 0.6-1.6 grams of levodopa per day.25 Ten of these patients showed a 'remarkable effect'. Further, it was reported that the concentration of homovanilic acid (HVA) in the spinal fluid of patients with athologic laughter and tearfulness was depressed, compared to a control group. More recently, tricyclic antidepressants have been found to be effective.17
Recently, one of the authors (R. Smith) discovered that dextromethorphan, a N-methyl-d-aspartate (NMDA) antagonist, exerts a profound effect on pseudobulbar emotionality. This observation was made in the context of an experimental treatment trial which was based on the notion that an NMDA antagonist might modify or arrest the course of ALS which is thought to be an example of a disease in which the excitotoxic mechanisms play an etiologic role. Although there have been treatment trials with dextromethorphan, to our knowledge the effect on behavior has not been previously commented upon.1 It is likely that this is due to the fact that dextromethorphan is rapidly metabolized by most persons (Fig. 1).23 This is mediated by one of the cytochrome oxidases (P-452-D6). Since most persons are 'fast metabolizers' of dextromethorphan, it is unlikely that an observable eftect of DM on behavior would have been noticed by persons given dextromethorphan alone. Studying a group of 13 patients, it was found that administration of dextromethorphan along with quinidine resulted in a conversion of all persons from fast to 'slow' metabolizers of DM (Fig. 2).28 Further, administering 150 mg of quinidine daily to ALS patients it was demonstrated that serum levels could be markedly boosted with the co-administration of quinidine (Fig. 3).
Although we are not able to comment upon the effect of this combination of drugs on the course of ALS, the following cases dramatically illustrate its effect on emotionality.
Case 1: J-C. B. The patient, a 46 year old French male, was referred by Dr. I. Bakst in August of 1992. Earlier in the year he had begun to note slurring of speech along with inappropriate laughter and tearfulness. Combination treatment with DM and quinidine was initiated, starting with a night time dose which was gradually increased. On this regimen the patient's emotionality resolved completely. At the end of the year he ran out of medication and within a few days he noted a marked return of emotionality particularly laughing which was uncontrollable. In the office he exhibited paroxysmal laughter which interfered with his respiration and ability to communicate. After two days of retreatment the patient's behavior was normal.
Case 2: M. B. The patient, a 70-year-old female minister, was referred by the ALS Association because of the occurrence of uncontrollable tearfulness. The patient was quadriparetic, dysarthric, wheelchair bound and complained of difficulty swallowing. Her arms were almost useless. Thinking and recall were completely normal, but at times the patient lost 'total control over her emotions'. This happened daily at which time she experienced severe choking and inability to communicate. According to her report she noted benefit after taking her first night time dose of 30 mg of DNV75 mg of quinidine. Although it had been assumed that the dose would gradually be increased, it was not felt necessary to do so.
Case 3: W.M. The patient, a 57-year-old male, was referred by Dr. M. Graves for possible inclusion in the DM treatment trial of ALS. Starting in March of 1991 the patient noted a change in 'emotional control'. With rather slight provocation the patient would become tearful. This became particularly troublesome in the context of his work for an aerospace company which held frequent planning meetings. After treatment with DM and quinidine the patient's emotionality was completely controlled. It is noteworthy that the patient had been taking Robitussin on a regular basis prior to his consultation for the purpose of controlling a persistent cough. Robitussin, which contains dextromethorphan (10 mg/5 ml), was taken daily up to 30 cc/day.
A total of 15 ALS patients have responded similarly. When treatment has been stopped, emotionality has returned within a day or so. With the resumption of treatment, svmptoms have resolved rapidly.
Surprisingly, a standardized tool to assess emotionality was not developed until this year when Robinson and his colleagues published a measurement scale.15 This was based on a study of 54 stroke patients. Over the last year we have been in the process of developing a similar scale which we hope to validate in a large ALS population (more than 300 patients). This will allow us to get a better idea as to the incidence of emotional lability in the ALS population and will provide for general use a tool for clinical trials.
Our scale currently contains 65 items which are included for the purpose of assessing the presence of cognitive, affective, behavioral and situational factors associated with affective lability.
Although the anatomic substrate for emotional lability is not known, a variety of pathologic correlations have been made. Lesions in the frontal and temporal lobes, third ventricle, hypothalamus, putamen, caudate and brain stem have all been associated with the occurrence of pathological laughter or tearfulness.14 Reduced to conceptual form, pseudobulbar emotionality can be seen as an example ot a disconnection syndrome. The simplest explanation to explain the treatment effect reported for a variety of agents including L-dopa, lithium, amantadine, nortriptyline and dextromethorphan is that all these agents act on the dopamine pathway. In short, lessons gleaned from treating ALS may have broad implications for understanding and treating neurologic and psychiatric disorders.
Weakness more than any other symptom is central to the problem of ALS. If one wanted to find the limits of palliative care, this singular symptom would seem to loom as an insurmountable barrier. One aspect of this problem is the failure of neuro-muscular transmission that occurs peripherally. This phenomenon, first described by Drs. Mulder and Lambert, was later investigated by Eric Denys and Ted Norris, who demonstrated a decremental response in proximately 65% of ALS patients (Fig. 4).11,4 Although there might be short term situations where treatment with an anticholinesterase may be clinically useful, long term use of such medication has been ineffective and could, on theoretical grounds, be disadvantageous.
Another approach is to provide hormonal stimulation which could influence nerve terminal sprouting in the periphery or directly affect muscle. An example is growth hormone which augments the synthesis of IgF-1 mRNA in muscle.3 Following denervation or paralysis of muscle IgF-1 mRNA increases. This would suggest that growth hormone may exert a direct trophic effect on muscle. Further, direct injection of IGF-I into adult muscle induces intramuscular nerve sprouting, implying that growth hormone might facilitate the peripheral repair process that is ongoing in the instance of ALS. Although we have not demonstrated a direct effect of growth hormone on sprouting or muscle, we could find no evidence that exogenous administration of growth hormone altered the course of ALS, as determined by periodic assessment using the Tuft's quantitative neuromuscular exam (TQNE) (Fig. 5).20 Further experimental efforts to promote regeneration of the motor unit by hormonal or growth factors involve the use of ciliaryneurotrophic factor and brain derived neurotrophic factor which, in animal models, prevent the retrograde degeration which accompanies axotomy and retard the progression of weakness in the Wobbler mouse.18,27 (R.M. Lindsay, Regeneron Pharmaceuticals, Inc., unpublished)
Along with the effects of denervation, ALS might be expected to exert an effect on muscles as a result of disuse atrophy due to inactivity. Ted Norris often referred to this possibility. Several of the hallmarks of physical deconditioning are seen in patients with ALS. Blood lactate is elevated as is the pulse rate, and the oxygen cost of exercise is significantly increased.16 Although it has been generally assummed that these changes are due primarily to denervation, it may be reasonable to test the hypothesis that deconditioning is an added factor.
Deconditioning has been studied in animals using a number of paradigms. Comparing sedentary dogs to those which were exercised, physiologic and biochemical differences were established within four weeks.9 Over the course of a longer period, evidence of deconditioning can be demonstrated in rats whose limbs are suspended. In both of these animal models dobutamine, a beta-I selective adrenergic agonist, has been shown to prevent the physiologic and biochemical concomitants of deconditioning. Along with significant effects on heart rate and blood lactate, dobutamine appears to have a significant effect on mitochondria, as determined by the measurement of citrate synthetase (Fig. 6). These results have been confirmed in human studies. During a period of bed rest intravenous infusion of dobutamine maintained most of the physiologic parameters associated with physical conditioning.24
While the use of a beta-I adrenergic agonist to prevent disuse atrophy in ALS may seem fanciful, in lieu of the overwhelming denervation, there may be at least one circumstance where such treatment could be immediately valuable. It is a common experience, possibly universal, to find that ALS patients are unable to be weaned from ventilators. There are some medical settings in which ventilatory support might be undertaken on a short term basis, most notably in the instance of complicating pulmonary infection when respiratory muscles are likely to be susceptible to fatigue. It might be anticipated that patients could ventilate on their own once their complicating pulmonary infection has been successfully treated. Unfortunately this often proves to be impossible to achieve. In such circumstances it is usually assumed that the diaphragm and the intercostal muscles were more involved than previously recognized or that the disease process has moved on, leaving the patient-respirator dependent. Considering that ventilator dependence apparent rather rapidly, over one or two days, it seems more likely that something else is going on. The most probable scenario is that the respiratory muscles are rapidly deconditioned as a result of ventilator use. If this is the case one might expect that ALS patients needing short-term ventilatory support may benefit from treatment with dobutamine or a similar beta-I adrenergic agonist. This remains to be tested.
This notion was rooted in an unabiding faith in the power of observation. There were times when Forbes Norris' observations seemed to rankle the sensibilities of colleagues, but intuition and experience remain the wellsprings of the discovery process. This tribute to the career of Forbes Norris is ample evidence of his insight into the biology of ALS and its human dimensions.
Acknowledgements - The following persons and organizations have generously contributed either time or support to the reserach efforts described in the manuscript: Chin Pan Engineering Co. Ltd.; Tanya Dafashy; The Muscular Dystrophy Association; Curtis Robert, Sr.; The SDG&E Employee's Contribution Fund; Lisa Silverman; and The Thagard Foundation.
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