Abstract. The purpose of this pilot study was to inves- tigate whether cholinergic stimulation reduces swallow- ing and oral motor disturbances in patients with ...
Dysphagia 14:165–168 (1999)
© Springer-Verlag New York Inc. 1999
Effects of Physostigmine on Swallowing and Oral Motor Functions in Patients with Progressive Supranuclear Palsy: A Pilot Study Carol M. Frattali, PhD,1 Barbara C. Sonies, PhD,1 Gloria Chi-Fishman, PhD,1 and Irene Litvan, MD2 1
Speech-Language Pathology Section, Rehabilitation Medicine Department, W.G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland; and 2Neuropharmacology Unit, Defense & Veteran Head Injury Program, Henry M. Jackson Foundation and the Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA
Abstract. The purpose of this pilot study was to investigate whether cholinergic stimulation reduces swallowing and oral motor disturbances in patients with progressive supranuclear palsy (PSP). A controlled, doubleblind crossover trial of physostigmine, a centrally active cholinesterase inhibitor, and placebo was conducted. Patients were randomized to a 10-day crossover placebocontrolled double-blind trial of physostigmine at their previously determined best dose administered orally every 2 hr, six times per day. Patients were evaluated with ultrasound imaging of the oropharynx and an oral motor examination at baseline and during the third or fourth days of each study phase (placebo and drug). Under the double-blind placebo-controlled conditions, patients showed no statistically significant improvement in oral motor functions or swallow durations. Because patients with PSP have increased sensitivity to cholinergic blockade compared with control subjects, studies with newer, more potent cholinergic stimulating agents need further exploration. Suggestions for future research include the evaluation of newer direct cholinergic agonists in the treatment of the less-impaired PSP patients who may have a greater number of cholinergic neurons preserved and the evaluation of combined therapies. Key words: Dysphagia — Dysarthria — Progressive supranuclear palsy — Cholinergic stimulation — Deglutition — Deglutition disorders.
Disorders of swallowing (dysphagia) and speech (dysarthria) are common in progressive supranuclear palsy
Correspondence to: Irene Litvan, M.D., MNB, NINDS, NIH, Federal Building, Room 714, Bethesda, MD 20892-9130, USA
(PSP), a neurodegenerative disease of the central nervous system [1,2]. Dysarthria and dysphagia have been described among the early features of PSP in as many as 40% of patients [3–7]. Aspiration pneumonia has been reported as a major cause of death [7,8]. Nevertheless, to date, pharmacologic approaches to the clinical management of neurogenic dysphagia and dysarthria have received little attention, with the notable exception of treatments for Parkinson’s disease (PD) [9]. Whereas PD patients benefit from levodopa therapy, PSP patients usually do not benefit or only have a transient levodopa response because in PSP, in addition to the loss of nigrostriatal dopaminergic neurons observed in PD, there is involvement of cholinergic striatal and brainstem neurons [3,10–12]. To investigate whether cholinergic stimulation reduces the disturbances of swallowing and speech in PSP patients, we conducted a controlled, double-blind, crossover trial of physostigmine, a centrally active cholinesterase inhibitor, and placebo.
Materials and Methods Eight patients (four men, four women, aged 64 ± 2.4 years, mean ± SD; symptom duration-32 ± 4 months; years of education-15 ± 1) consented to participate in this study after disclosure of its risks and benefits. The effects of physostigmine on cognition and extrapyramidal function have been previously reported [13]. The diagnosis of PSP was determined by the presence of the following features: progressive onset, at age 50 years or older, of parkinsonism (bradykinesia and axial rigidity), postural or gait disorder, pseudobulbar palsy (dysarthria and dysphagia), supranuclear vertical (with or without horizontal) gaze palsy, and absence of radiologic abnormalities other than subcortical and/or midbrain atrophy. Excluding one subject (patient 6) who continued to receive a constant dose of levodopa-carbidopa (Sinemet, 600 mg/day), none of the patients took other centrally active drugs during the course of this clinical trial. After a baseline evaluation, an open labeled study was
166 performed to determine the best physostigmine dose. Patients were then randomized to a 10-day crossover placebo-controlled double-blind trial of physostigmine at their previously determined best dose (1.25 ± 0.2 mg, range-0.5–2.0 mg) administered orally every 2 hr, six times per day. A 3-day washout period separated the open labeled study and initiation of the crossover trial. During the crossover trial, there was no washout period between phases, but patients were tested only after the third day of initiation of each phase (phyostigmine or placebo) of the trial. Patients’ dysarthria and oral-pharyngeal dysphagia were evaluated with an oral motor examination [13] and ultrasound imaging of the oropharynx [13,14] at baseline and during the third or fourth days of each study phase (placebo and drug). An oral motor examination was conducted in all eight patients; ultrasound imaging was performed in six of the eight patients.
Oral Motor Examination Patients were evaluated with the Oral Motor Scale [13], which rates oral anatomy, physiology, symmetry, and strength. The oral motor examinations were conducted by a certified and licensed speechlanguage pathologist who determined either normal or abnormal physiology and strength of the lips, tongue, and velum.
Ultrasound Imaging of the Oropharynx Scanning was performed by a certified and licensed speech-language pathologist and a biomedical engineer with an Advanced Technologies Laboratories mechanical sectoring real-time ultrasound scanning unit. A 5-MHz transducer was used, with an 90° sector and a frame rate of 30 frames/sec [14,15]. Adjustments in time gain compensation and system gain were made by image inspection. All scans were recorded simultaneously on a 3/4-inch Sony U-matic videotape cassette recorder with a video time code generator (model VTG-33, FOR-A, Natick, MA) recording to hundredths of a second. Alphanumeric characters and time codes were added to the video display to help in locating specific frames of interest. Patients were seated in a dental chair with a headrest to stabilize anterior/posterior head motion. The transducer was positioned submentally until the hyoid shadow appeared at approximately 22° in the left lower quadrant of the scan relative to the midline sector marker displayed permanently on the screen. By using this same criterion to reference hyoid position for all subjects, a resting position was obtained at the start of each swallow. All scanning was performed at the midline sagittal position, with the transducer angled 15–20° anteriorly to image the body of the tongue and the water bolus. A depth setting of 5 was used with the 5-MHz transducer to image a smaller area and obtain a more detailed view of the hyoid bone and posterior tongue. All measurements of the hyoid bone during swallowing were made at this setting. Patients were scanned with the 5-MHz transducer at rest and were instructed to breathe normally without excessive inspiration to inhibit unnecessary excursions of the larynx that could affect hyoid position. Patients were instructed to perform three single dry swallows, followed by three wet swallows using 10 ml of water for each swallow. To prevent head motion that could alter the transducer/hyoid placement, water was injected into the mouth with a syringe. Durational measurements of each swallow (three dry and three wet) were made from a frame-by-frame analysis of the videos using a 10-sec Sony video disk. The duration of both dry and wet swallows was
C.M. Frattali et al.: Effects of Physostigmine Table 1. Physostigmine effects on dry and wet swallow durations Subject Dry swallow 1 2 3 4 5 6 Group Wet swallow 1 2 3 4 5 6 Group
Baseline
Placebo
Physostigmine
15.29 (8.76) 7.16 (4.88) 3.78 (0.11) 10.48 (6.86) 2.12 (0.26) 5.64 (2.32) 7.41 (3.86)
14.57 (15.35) 8.42 (8.65) 3.88 (0.68) 9.18 (5.46) 2.50 (0.81) 13.03 (6.32) 8.60 (6.21)
12.79 (4.58) 7.34 (4.31) 3.14 (1.23) 13.90 (10.35) 2.90 (1.24) 12.99 (6.30) 8.84 (4.67)
4.36 (1.39) 2.13 (0.31) 2.35 (0.24) 4.29 (1.83) 12.77 (10.56) 3.00 (2.38) 4.82 (2.78)
3.09 (3.36) 1.61 (0.60) 3.31 (1.59) 6.33 (2.46) 1.49 (0.42) 5.20 (1.29) 3.50 (1.62)
5.82 (1.79) 1.44 (0.58) 4.56 (2.15) 11.17 (9.53) 1.45 (0.06) 9.78 (14.12) 5.70 (4.70)
Values are the mean (±SD), measured in seconds.
measured from the frame at which the hyoid bone first moved anteriorly and superiorly from rest to the frame, when it returned to the stable resting position [15]. Swallow durations, oral motor function ratings, difference scores (placebo minus baseline versus drug minus baseline scores), and order effects were subjected to multivariate analysis of variance for repeated measures and chi-square analysis at ! ! 0.05.
Results Under the double-blind placebo-controlled conditions, PSP patients showed no statistically significant change in swallow duration or oral motor function. Further, no significant order effect (drug first vs. placebo first) was found. Only one patient (patient 2) demonstrated a decrease in swallow duration in the drug condition for both dry and wet swallows (Table 1). Three other patients (patients 1, 3, and 6) showed an improvement in swallow duration for dry swallows but did not show an improvement for wet swallows during the same test session in the drug condition. In patient 5, notably long mean wet swallow duration in relation to shorter mean dry swallow duration was documented at baseline. This aberrant pattern occurred as a result of multiple swallows of the single wet bolus, thereby lengthening the total time of wet swallow duration. High variability of wet swallow durations during the three repeated trials was shown by the high standard deviation (i.e., 10.56 sec). In patient 6 in both placebo and drug conditions, hyperactivity of the tongue was noted, with extraneous movements and tongue pumping, thereby increasing swallow durations. Even though swallow durations were notably shorter at baseline, this patient’s modified
C.M. Frattali et al.: Effects of Physostigmine
barium swallow (MBS) study1 results at baseline showed lingual pumping, extra movements of velum and pharynx, and decreased bolus transport via gravity. Thus, although not reflected in ultrasound swallow durations, similar deficits were noted at baseline as shown by MBS results. It should also be noted that in wet swallows viewed on ultrasound, particularly during the drug condition, the patient swallowed three times for one bolus and this was reflected in the total swallow duration. Multiple swallows were demonstrated in only one of the three trials, as shown by the high standard deviation. With regard to oral motor functions, a consistent pattern of improvement in the drug condition across oral motor parameters was not noted for any of the PSP patients, with the exception of patient 2. Interestingly, in examination of tongue physiology and tongue strength, all patients either tested within normal range across the three test conditions or demonstrated improvement in placebo and/or drug condition. Although these findings may be suggestive of improvement, they were not statistically significant. Only patient 2 demonstrated improvement from baseline performance, noted in both tongue and velum physiology, as shown by increased tongue elevation/lateralization/protrusion and velar elevation. For this patient, lip physiology and strength were tested to be within normal range at baseline and across test conditions. When compared with normative data [15], overall mean dry and wet swallow durations across the three test conditions were substantially longer than the overall mean durations for normal adults in the same age and gender groups. In all test conditions (baseline, placebo, drug), PSP patients (with the exception of patient 2 for wet swallows) demonstrated longer swallow durations when compared with normative data [15], which were approximately 2–4 sec for dry swallows and 1–3 sec for wet swallows in age-matched normal adults.
Discussion Our study failed to show benefits from physostigmine treatment. Physostigmine treatment did not produce any significant improvement in either oral motor function or swallow duration in patients with PSP. The finding that three patients showed improvement in dry swallow durations but not in wet swallow durations during the same test session in the drug condition suggests the possibility of a fatigue factor causing decreased lingual motility or
1
MBS was not a clinical research procedure for this pilot study and was conducted only at baseline for two of the eight patients followed.
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delayed initiation of swallow reflex during repeated swallows. This is not a surprising finding because fatigue is a common occurrence in PSP [16] as has been observed during repeated trials testing. Our findings of substantially longer swallow durations when compared with those of a normative sample are consistent with the findings of Sonies [1] who reported, on the basis of data from 22 patients with PSP, an overall average duration of 8 sec for dry swallows and an overall average duration of 4 sec for wet swallows. The negative results of our study are similar to those of physostigmine treatment on extrapyramidal function [10] but contrast with the marginal benefits observed in cognition (memory and attention) in these patients [10,17]. In support of the latter findings, there is a vast literature showing that physostigmine marginally improves cognition in Alzheimer’s disease (e.g., [18– 21]). A moderate cholinergic stimulation of the innominatocortical, septohippocampal, and pedunculopontinecortical pathways may be sufficient to improve cognition because cortical cholinergic neurons seem to be preserved in PSP, as shown by a recent positron emmission tomographic study that showed normal cholinergic receptor binding in the cerebral cortex of patients with this disorder [22]. Alternatively, it could be hypothesized that to improve the function of the basal ganglia, in addition to cholinergic stimulation, dopaminergic stimulation may be required. This hypothesis is hardly supported by our present study because the only patient on levodopa therapy did not show any improvement (patient 6). It also is possible that the doses of physostigmine used were insufficient to produce marked inhibition of acetylcholinesterase in the central nervous system despite our attempts to deliver an “optimal dose.” Indeed, physostigmine had very limited central nervous system penetration when cerebrospinal fluid acetylcholinesterase activity was measured [23]. This result is not surprising because physostigmine has a low oral bioavailability. Of interest was the improvement noted in patient 2, whose oral motor and swallowing deficits at baseline were generally of a milder nature when compared with those of the other patients. This finding is supported by Litvan et al. [10] who found in the same group of patients a negative correlation between baseline global motor impairment and selected treatment-associated changes in memory performance. Their findings suggest that only the less-impaired PSP patients, who may have a greater number of spared cholinergic neurons, respond to physostigmine stimulation. This finding can be supported from a pharmacological perspective. Physostigmine is an indirect cholinomimetic whose action requires the presence of intact cholinergic innervation. In PSP, striatal and brainstem cholinergic neurons, among others, degenerate, suggesting that, if the denervation is severe, there
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may not be sufficient neurons that could respond to cholinergic stimulation by physostigmine. Cholinergic stimulation of these denervated structures might still be achieved, however, with direct cholinomimetic agonists (i.e., directly stimulating acetylcholine receptors). Conceivably, then, both nicotinic and muscarinic receptors may require activation for a full therapeutic effect. Further, an animal study [24] that investigated physostigmine effects on fictive swallowing in rats suggests the probable involvement of other neurochemical deficits in PSP as does the finding that global enhancement of central nervous system cholinergic activity (as induced with appropriate doses of physostigmine) may not produce the expected stimulant facilitatory effect on swallowing, thus suggesting the need for research studies using combined pharmacotherapies. Although this pilot study failed to show benefits from physostigmine treatment, we cannot rule out the possibility of a type II error. Because patients with PSP as opposed to control subjects have increased sensitivity to cholinergic blockade (scopolamine challenge) [25], it seems likely that they may also improve when they receive appropriate cholinergic stimulation. Suggestions for future research include studies of the benefits of newer cholinergic agents, particularly agonists in the treatment of the less-impaired PSP patients. Future studies should also evaluate whether combined pharmacologic treatment that includes the use of direct cholinomimetics benefits patients with this devastating neurodegenerative disorder.
References 1.
2.
3.
4.
5.
6. 7.
Sonies BS: Swallowing and speech disturbances. In: Litvan I, Agid Y (eds.): Progressive Supranuclear Palsy: Clinical and Research Approaches. New York: Oxford University Press, 1992, pp 240–253 Litvan R, Sastry BS, Sonies BC: Characterizing swallowing abnormalities in progressive supranuclear palsy. Neurology 48:1654–1662, 1997 Steele JC, Richardson JC, Olszewski J: Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum, with vertical gaze and pseudobulbar palsy, nuclear dystonia and dementia. Arch Neurol 10:333–359, 1964 Agid Y, Javoy-Agid F, Ruberg M, Pillion B, Dubois B, Duyckaerts C, Hauw JC, Scatton B: Progressive supranuclear palsy: anatomoclinical and biochemical considerations. Adv Neurol 45:191–206, 1986 Lebrun Y, Devereux F, Rousseau JJ: Language and speech in a patient with a clinical diagnosis of progressive supranuclear palsy. Brain Lang 27:247–256, 1986 Brin MF, Younger D: Neurologic disorders and aspiration. Otolaryngol Clin North Am 24:691–699, 1988 Golbe LI, Davis PH, Schoenberg BS, Duvoisin RC: Prevalence
8.
9. 10.
11.
12.
13.
14.
15.
16.
17.
18. 19.
20.
21. 22.
23.
24. 25.
and natural history of progressive supranuclear palsy. Neurology 38:1031–1034, 1988 McDowell FH, Cedarbaum JM: The extrapyramidal system and disorders of movement. In: Joynt RJ (ed.): Clinical Neurology, vol. 3. New York: Lippincott, 1990, pp 1–97 Bieger D: Deglutitive pharmacotherapy—a new angle? Dysphagia 13:17–18, 1998 Litvan I, Gomez C, Atack JR, Gillespie M, Kask AM, Mouradian M, Chase TN: Physostigmine treatment of progressive supranuclear palsy. Ann Neurol 26:404–407, 1989 Tagliavini F, Pilleri G, Gemignani F, Lechi A: Neuronal loss in the basal nucleus of Meynert in progressive supranuclear palsy. Acta Neuropathol (Berl) 61:157–160, 1983 Ruberg M, Javoy-Agid F, Hirsch E, Scatton B, LHeureux R, Hauw J, Duyckaerts C, Gray F, Morel-Maroger A, Rascol A, Serdaru M, Agid Y: Dopaminergic and cholinergic lesions in progressive supranuclear palsy. Ann Neurol 18:523–529, 1985 Sonies BC, Weiffenbach J, Atkinson JC, Brahim J, Macynski A, Fox P: Clinical examination of motor and sensory functions of the adult oral cavity. Dysphagia 1:178–186, 1987 Sonies BC, Baum BJ: Evaluation of swallowing pathophysiology. In: Krespi YP, Blitzer A (eds.): Aspiration and Swallowing Disorders. Philadelphia: WB Saunders, 1988, pp 637–648 Sonies BC, Parent L, Morrish K, Baum B: Durational aspects of the oral–pharyngeal phase of swallow in normal adults. Dysphagia 3:1–10, 1988 Duvoisin RC: Clinical diagnosis. In: Litvan I, Agid Y (eds.): Progressive Supranuclear Palsy: Clinical and Research Approaches. New York: Oxford University Press, 1992, pp 240–253 Kertzman C, Robinson DL, Litvan I: Effects of physostigmine on spatial attention in patients with progressive supranuclear palsy. Arch Neurol 47:1346–1350, 1990 Peters BH, Levin J: Effects of physostigmine and lecithin on memory in Alzheimer’s disease. Ann Neurol 6:219–221, 1979 Robbins TW, McAlonan G, Muir JL, Everitt BJ: Cognitive enhancers in theory and practice: studies of the cholinergic hypothesis of cognitive deficits in Alzheimer’s disease. Behav Brain Res 83:15–23, 1997 Thal LJ, Schwartz G, Sano M, Weiner M, Knopman D, Harrell L, Bodenheimer S, Rossor M, Philpot M, Schor J, Goldberg A: A multicenter double-blind study of controlled-release physostigmine for the treatment of symptoms secondary to Alzheimer’s disease. Physostigmine Study Group. Neurology 47:1389–1395, 1996 Stern Y, Sano M, Mayeux R: Effects of oral physostigmine in Alzheimer’s disease. Ann Neurol 22:306–310, 1987 Asahina M, Suhara T, Shinotoh H, Inoue O, Suzuki K, Hattori T: Brain muscarinic receptors in progressive supranuclear palsy and Parkinson’s disease: a positron emission tomography study. J Neurol Neurosurg Physchiatry 65:155–163, 1998 Atack JR, Litvan I, Thal LJ, May C, Rapoport SI, Chase TN: Cerebrospinal fluid acetylcholinesterase in progressive supranuclear palsy: reduced activity relative to normal subjects and lack of inhibition by oral physostigmine. J Neurol Neurosurg Psychiatry 54:832–835, 1991 Bieger D: Neuropharmacologic correlates of deglutition: lessons from fictive swallowing. Dysphagia 6:147–164, 1991 Litvan I, Blesa R, Clark K, Nichelli P, Atack JR, Mouradian MM, Grafman J, Chase TN: Pharmacologic evaluation of the cholinergic system in progressive supranuclear palsy. Ann Neurol 36:55–61, 1994
