International Journal of Neuroscience
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Weak Magnetic Fields in the Treatment of Parkinson's Disease with the “on-off” Phenomenon Reuven Sandyk To cite this article: Reuven Sandyk (1992) Weak Magnetic Fields in the Treatment of Parkinson's Disease with the “on-off” Phenomenon, International Journal of Neuroscience, 66:1-2, 97-106, DOI: 10.3109/00207459208999794 To link to this article: http://dx.doi.org/10.3109/00207459208999794
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0 1992 Gordon and Breach Science Publishers S.A.
Intern J . Neuroscience, 1992, Vol. 66, pp. 97-106 Reprints available directly from the publisher Photocopying permitted by license only
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Clinical Case Report WEAK MAGNETIC FIELDS IN THE TREATMENT OF PARKINSON’S DISEASE WITH THE “ON-OFF” PHENOMENON REUVEN SANDYK NeuroCommunication Research Laboratories, Danbury, CT 06811 , U . S . A .
International Journal of Neuroscience 1992.66:97-106.
(Received March I
I
1992)
Application of external weak magnetic fields recently has been reported to be efficacious in the treatment of a 62-year-old patient with idiopathic Parkinson’s disease (PD) complicated by levodopa-induced fluctuations in motor response (“on-off”). I report an additional case of a 67-year-old man with idiopathic PD and levodopa-related motor fluctuations who likewise experienced marked and sustained improvement in Parkinsonian symptoms and amelioration of “on-off“ symptoms following the application of external weak magnetic fields. Based on these observations it is concluded that artificial weak magnetic fields may be beneficial for the treatment of PD complicated by levodopa-related “on-off” phenomenon. Furthermore, since in experimental animals external magnetic fields alter the secretion of melatonin, which in turn has been shown to regulate stnatal and mesolimbic dopamine-mediated behaviors, it is proposed that the antiParkinsonian effects of weak magnetic fields are mediated via the pineal gland. Keyw,ords: Parkinson’sdisease; weak magnetic field.7; “on-off’;pineal gland; melatonin; dopamine
Application of weak magnetic fields has been reported to be efficacious in the treatment of a 62-year-old man with idiopathic Parkinson’s disease (PD) with severe levodopa-related motor fluctuations (“on-off” phenomenon) (Sandyk et al., 1992). At the time of filing this report the patient had been applying weak magnetic fields at home daily at night (2300 h) for over 5 months and continued to experience benefit. Encouraged by these observations, I proceeded to study the effects of external weak magnetic fields in an additional PD patient who likewise exhibited levodopa related “on-off. ” CASE REPORT This 67-year-old businessman experienced onset of stiffness of his left arm at the age of 55. Several months later he developed resting tremor in his left hand which progressed a few months later to involve the right hand as well. Subsequently, he began to experience insidious deterioration in his condition as evidenced by generalized slowing of movement, progressive difficulties in the initiation of movement, difficulties in writing, and mild postural instability. One year after being diagnosed with PD, the patient was prescribed levodopa (125 mg 3 tabs./day). This resulted in improvement in mobility and reduction in the This work was presented in part at a Neuroscience seminar held at the Institut Fuer Medizin, Forschungszentrum Julich, Germany, December 16, 1991. I am grateful to Prof. P.A. Anninos for providing the device for the treatment with magnetic fields and to Dr. K . Derpapas for referring the patient for treatment. Reprints requests to: Professor Reuven Sandyk, P.O. Box 203, Bedford Hills, NY 10507, U . S . A . 97
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severity of tremor for about 3 years after which he began to experience a decline in response to levodopa (“wearing off”) associated with mild fluctuations of motor performance. These symptoms were controlled initially by increasing in the dosage and frequency of levodopa administration (“dose fractionation”) and subsequently by the addition of small doses of bromocriptine (2.5 mg/d). However, over the following 3 years fluctuations in motor performance gradually worsened and he noted the occurrence of choreic movements in the neck and face at the time of maximal clinical response to levodopa (“peak dose” dyskinesias). Over the following 6 months the patient continued to deteriorate to a point where his symptoms showed clear oscillations between severe Parkinsonism (“off”-period) and complete mobility with choreoathetoid and dystonic dyskinesias of the neck, face, upper limbs, and trunk (“on”-period). According to the patient, “off”-periods tended to occur predominantly in the afternoon and were associated at times with distressingly painful dystonic movements of the feet and toes (“off-period’’ dystonia). Such dystonic movements also occurred occasionally in the early morning hours and were relieved by levodopa. At the time of examination the patient’s medications included levodopa/carbidopa (SinemetR, 250/25 3 tabs/day; 1/2 tab. every 3 hours), bromocriptine (2.5 mg/d), orphenadrine (100 mg/d), and vitamin E (200 I.U./d). The patient’s medical history was unremarkable save for essential hypertension which was managed with diuretics and beta-blockers. There was no history of mental depression, memory disturbances, autonomic, or primary sensory symptoms. Appetite was good and his weight had been stable since the onset of his illness. Sleep was disturbed due to difficulties falling asleep, spontaneous arousals, and inability to turn in bed owing to generalized stiffness. He denied history of exposure to industrial toxins or psychotropic drugs prior to the onset of PD. The patient’s family history was negative for neuropsychiatric disorders. CT scan of the head in 1991 revealed evidence of frontal lobe atrophy with mild dilatation of the lateral ventricles. Laboratory studies including complete blood count, serum electrolytes, serum magnesium, iron, and copper, glucose, thyroid profile, liver function tests, folic acid, and vitamin B,, levels were all in the normal range. The patient was examined during both the “on” and “off” periods. During an “off”-period he was alert and oriented with normal thought processes. His blood pressure was 170/90 mm Hg with a regular pulse of 100/min and no evidence of postural hypotension. His forehead was oily and his facial expression showed a moderate degree of amimia. His speech was slow and hypophonic and there was mild tremor of the tongue and lips. The glabellar tap as well as frontal lobe release signs such as pout, snout, and palmomental reflexes were positive. Extraocular movements were saccadic and upward gaze was slightly limited. Blink rate was 10/min. He had bilateral intermittent resting tremor of 7-8 Hz in the upper extremities which was more accentuated on the left side. His handwriting revealed the classic micrographia of PD and he had difficulties drawing circles (Figure 1). There was prominent cogwheel rigidity of the neck and at the elbows and wrists bilaterally. Wartenberg’s (1958) head-dropping test for rigidity was positive. The patient had difficulties rising from the chair without assistance and on attempts to ambulate he had marked “freezing” with “start hesitation.” Once mobile, he had a prominent festinating gait with stooped posture associated with poor arm swing, gait instability, and a slight tendency to fall backwards. During an “on”-period he was mobile, but disclosed choreoathetoid movements of the neck, upper limbs, and trunk.
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FIGURE 1 .
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A sample of the patient’s drawing obtained prior to treatment with magnetic fields.
APPLICATION OF MAGNETIC FIELDS After obtaining an informed consent from the patient for treatment with magnetic fields. the patient initially underwent a sham (placebo) magnetic treatment. The coils of the magnetic device (vide infra) were placed for 6 minutes (2 minutes over each of the following areas: left and right temporal regions, frontal and occipital regions, and over the vertex) without turning on the device and changes in symptoms were assessed by two independent neurologists during the following 2 hours. Thereafter, magnetic stimulation was applied at 1500h according to the method described elsewhere (Anninos el al., 1991). In brief, magnetic fields were administered via an electronic device, the principles of which have been described previously (Anninos et al., 1991). The coils of the device, which had a diameter of 1 cm, were placed on the patient’s scalp and weak magnetic fields were administered for a total of 6 minutes to the areas corresponding to those applied in the sham magnetic treatment. The frequency of stimulation was 2-7 Hz and the intensity of the magnetic field was 7.5 picotesla (pT). No adverse effects were reported during or after the application of magnetic fields. At the time of magnetic treatment the patient was maintained on his antiparkinsonian medication.
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FIGURE 2.
D
b
A sample of the patient’s drawing obtained 1 hour after treatment with magnetic fields.
RESPONSE TO MAGNETIC STIMULATION While sham magnetic treatment produced no clinical effects application of magnetic fields caused an immediate subjective report of relaxation, sexual arousal, increased hunger, and mood elevation. His blood pressure increased to 190/110 mm Hg and his pulse to 1lO/min. Blood glucose (Glucostix; Miles Laboratories), obtained 5 minutes after completion of the application of magnetic field treatment, was reduced from a pretest value of 103 mg/dl to 68 mg/dl. Objectively, it was observed that the patient’s facies had a normal facial expression and the blink rate was increased from a pretest of lO/min to 18/min. There was a noticeable, significant reduction in cogwheeling rigidity in the neck, elbows, and wrists. Wartenberg’s head-dropping maneuver showed an almost normal response. However, the severity and frequency of tremor was unchanged. He had no difficulty initiating gait which became significantly more stable with good arm swing. Within an hour after treatment with magnetic fields it was noted that his tremor had diminished considerably and he was able, for the first time since onset of his tremor, to hold a cup and drink water without spilling its content. There was an improvement in his handwriting and drawing (Figure 2). Furthermore, the patient reported that he had not experienced any “on” effects in the afternoon of the same day following magnetic treatment. When the patient was interviewed on the following morning, he reported to have had a deep sleep with vivid sexual dreams and he remarked that he did not experience difficulty turning in bed. Upon awakening, he noted that his facial skin was dry and
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FIGURE 3 . A sample of the patient’s drawing obtained the day after treatment with magnetic fields showed sustained improvement of tremor.
not oily. He reported further that his mind was clear and that he was in very good spirits. Examination during an “off”-period revealed only mild generalized bradykinesia and cogwheel rigidity at the wrists and elbows with continued absence of tremor. His facial expression was normal and his forehead skin was dry. Blink rate was 17/min. He was able to hold a cup of water steadily and drink without spillage. His handwriting and drawing remained improved (Figure 3). The patient was able to rise rapidly from a chair without assistance and his gait was almost normal with no evidence of postural instability. On that day he continued to take his antiParkinsonian medication and experienced no “on”-effects. To ascertain whether the responses elicited by the magnetic stimulation were reproducible, the patient was advised to continue with his antiparkinsonian medication and also to apply magnetic field treatment nightly (2300 hours) at home. The patient’s wife was instructed to apply magnetic fields for a total of 6 minutes to the same areas designated in the initial treatment in the laboratory. Application of magnetic fields was performed with a portable electronic device (Ergo, Athens) consisting of a generator which produces alternating weak magnetic fields of power amplitude of the order of 900 f f / H z (cf. Anninos et al., 1991). The electronic device was adjusted to emit magnetic fields of the same intensities and frequencies as those used during the initial treatment in the laboratory. At the time this report was filed the patient had applied magnetic fields nightly for two months, a period during which he continued to benefit from the combined pharmacological and magnetic treatments. Specifically, he reported marked improve-
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ment in mobility and gait and added that he no longer experienced “on”-period dyskinesias or dystonic movements of the feet and toes. As a result of the magnetic treatment he was able to reduce his levodopa dosage by 1/2 tab. daily without experiencing any worsening in motor symptoms. He added that the quality of his sleep had improved considerably since the application of magnetic fields while the early morning foot dystonia did not recur. His appetite increased since the initiation of magnetic treatment and he had put on 2 Kg weight. Finally, he also reported a marked and persistent increase in libido after magnetic treatment. It is noteworthy that on two occasions during the past two months the patient noted gradual deterioration in symptoms and recurrence of the “on-off.’’ In both instances, the cause of the patient’s clinical deterioration was found to be related to malfunctioning of the electronic device.
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DISCUSSION Fluctuations in the severity of symptoms is one of the most characteristic features of PD (Marsden, 1990; Koller & Hubble, 1990). Since the introduction of levodopa therapy, such events have greatly increased in their complexity and frequency (Marsden & Parkes, 1981; Quinn, 1987; Klawans et al., 1990; Koller & Hubble, 1990). Centrally mediated side effects of chronic levodopa therapy such as fluctuations in motor performance and dyskinesias have been noted in 40-90% of PD patients (Klawans & Weiner, 1981) and pose a major challenge in the longterm management of the disease (LeWitt & Chase, 1983; Koller & Hubble, 1990). Levodopa-related motor complications may be divided into two categories; those related to underdosing associated with disease progression (e.g., “freezing”, “endof-dose’’ akinesia, and “off-period’’ dystonia) and those related to overdosing of levodopa (“peak-dose’’ dyskinesia, “peak-dose’’ akinesia, and “diphasic” dyskinesia (Marsden & Parkes, 1981; Marsden, 1990). While unwanted effects due to overdosage may be managed simply by a reduction in dose, side effects related to underdosing have proved more difficult to manage, in part because of the progression of the underlying pathology of the disease (Marsden & Parkes, 1981; Koller & Hubble, 1990). Progressive degeneration of brainstem monoaminergic neurons is probably one of the major causes of decline in the efficacy of levodopa therapy in PD (Marsden & Parkes, 1981). Other important factors determining the potential development of subsequent side effects of levodopa include the age of onset of the disease, alterations in peripheral absorption kinetics and central kinetics of dopa conversion and dopamine storage, pharmacodynamic variables that determine the responsiveness of the dopamine receptors, the development of dopamine receptor hypersensitivity in the striatum, alterations in striatal metabolism of levodopa, and the formation of compounds such as tetrahydroisoquinolines which has been suggested to antagonize the beneficial actions of levodopa (Klawans et al., 1970; Sandler, 1974; Fahn, 1982; Pederzoli et al., 1983; Nutt, 1984; Hardie et al., 1984; Quinn, 1987; Hardie, 1990; Koller & Hubble, 1990). Despite the usual measure to fractionate the dose of levodopa (ie., smaller quantities more frequently), the addition of bromocriptine and/or selegiline hydrochloride (deprenylR) (an MA0,-inhibitor), or the administration of newer long acting preparations of levodopa, a substantial number of Parkinsonian patients develop increasingly severe and rapid oscillations in mobility and dyskinesias (Marsden, 1990). Rescheduling of protein intake or administration of a low protein diet to avoid com-
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petition of neutral amino acids with levodopa absorption and entry into the brain are only partly effective in the control of side effects due to chronic levodopa therapy (Hardie, 1990). Drug holidays, which are aimed at restoring dopamine receptor sensitivity, often lead to exacerbation of Parkinsonian symptoms during the withdrawal period (Marsden, 1990). Intravenous levodopa infusions have been shown to ameliorate the severity of motor fluctuations, but their continuous use is not suitable for long-term therapy. Likewise, continuous subcutaneous infusions of lisuride, a dopamine D2 receptor agonist, has been reported to produce unacceptable psychiatric side effects (Marsden, 1990). Presently, no drug is available to prevent the development of levodopa related fluctuations in motor symptoms (Marsden, 1990), making the prevention of their occurrence in PD the primary challenge of chronic levodopa therapy (Hardie, 1990). Several years after the introduction of levodopa therapy, this patient experienced progressive decline in the efficacy of treatment. Moreover, his Parkinsonism was complicated by disabling fluctuations in response to levodopa therapy. While the symptomatic steps employed to improve his progressive motor disability and the “onoff” were ineffective, application of nightly weak magnetic fields produced a dramatic and sustained improvement in motor disability with an almost complete resolution of the “on-off” phenomenon. The beneficial effects of the magnetic fields were sustained for a period of two months during which the patient experienced no adverse effects or tolerance. Moreover, he was able to decrease the levodopa dosage by 1/2 tab. per day without experiencing deterioration in motor performance or recurrence of the “on-off.’’ Such a dramatic beneficial effect on the Parkinsonian disability and on the “on-off” has been reported in patients who have been given electroconvulsive therapy (ECT), (Balldin et al., 1980; 1981; Andersen et al., 1987), raising the possibility that both magnetic fields and ECT may act centrally via a common mechanism to alter central dopaminergic functions. The mechanisms by which weak magnetic fields improved the patient’s motor disability and led to the resolution of the “on-off” are unknown. The observation that the patient’s spontaneous blink rate, a marker of central dopaminergic activity (Stevens, 1978; Karson et al., 1981 a; b ) , increased shortly after application of magnetic fields indicates that magnetic fields augment central dopamine activity. Such an effect is compatible also with the reduction in the severity of facial seborrhea, which is known to reflect diminished central dopaminergic functions (Burton et al., 1973 a; b). Moreover, the patient’s report of increased libido and sexual arousal following the application of magnetic fields also is in accord with a central augmentation of dopaminergic activity since L-dopa has been reported to increase libido and sexual activity in Parkinsonian patients (Barbeau, 1969; Hyyppa & Rinne, 1970; Duvoisin & Yahr, 1972; Quinn et al., 1983). In addition, augmentation of central dopaminergic activity may account for the patient’s improvement of sleep and the increase in the quantity of dreaming since levodopa has been reported to improve sleep quality, restore REM sleep, and induce vivid dreams in Parkinsonian patients (Kales et al., 1971; Kendel et al., 1972; Nausieda, 1987). Finally, the observation that magnetic fields abolished the “on-off” suggests an effect on striatal dopamine receptor sensitivity since “on-off” has been linked to levodopa-induced dopamine receptor hypersensitivity, either presynaptically , or postsynaptically (Carlson, 1970; Klawans et al., 1970; Obeso et al., 1989). Experimental animal studies indicate that the pineal gland is a “magnetosensor” (Semm et al., 1980; Semm, 1983; Welker et al., 1983; Olcese et al., 1988) and that various intensities of external magnetic fields alter the secretion of pineal melatonin (Welker et al., 1983; Olcese et al., 1985; Rudolph et al., 1988), which in turn, has
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been shown to regulate striatal and mesolimbic dopaminergic functions (Cotzias et al., 1971; Anton-Tay et al., 1971; Bradbury et al., 1985). In addition, melatonin inhibits dopamine release in the hypothalamus, midbrain, and retina (Zisapel & Laudon, 1983; Zisapel et al., 1982; 1983; Dubocovich, 1983; Nowak, 1988) and may be involved in the expression of striatal and mesolimbic dopamine-mediated behaviors and endocrine secretion (Kovacs et al., 1974; Blask et al., 1980; Golus & King, 1981; Sugden, 1983; Gaffori & Van Ree, 1985; Rudolph et al., 1985; Bradbury et al., 1985). In rats, pinealectomy reportedly enhances the emergence of neurolepticinduced purposeless chewing movements, a motor behavior which is related to increased striatal dopaminergic activity and which is considered an animal model for Tardive dyskinesia (Sandyk & Fisher, 1989). Melatonin receptors have been detected in the rat’s substantia nigra and striatum (Cardinali et al., 1979; Niles et al., 1979; Kopp et al., 1980; Laudon et al., 1988; Vitte et al., 1988) and relatively large amounts of immunoreactive melatonin are present in the nucleus accumbens (Seguela et al., 1982). Since magnetic fields acutely suppress melatonin synthesis and secretion in experimental animals and possibly in humans as well (Semm et al., 1980; Welker et al., 1983; Cremer-Bartels et al., 1983; Olcese & Reuss, 1986), it i s conceivable that such an effect may disinhibit striatal and/or mesolimbic dopamine release and alter dopaminergic functions to account for the improvement in the patient’s Parkinsonian symptoms. Moreover, application of artificial magnetic fields has been shown in laboratory animals to alter the activity of neurons in the habenular complex (Semm, 1983), a structure which has been shown to function as a “gate” through which limbic dopaminergic systems interact with and modulate midbrain-stnatal dopaminergic neurons to affect motor behavior (Nauta, 1986; Sandyk, 1991; Sandyk et al., 1991). In summary, although the mechanisms of action of weak magnetic fields in Parkinsonism require further elucidation, this report suggests that weak magnetic fields may alter striatal dopaminergic functions in the disease and adds additional support to suggest that weak magnetic fields are highly beneficial in the treatment of Parkinsonism and associated motor complications of levodopa therapy.
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Nauta, H. J. W. (1986). The relationship of the basal ganglia to the limbic system. In P. J. Vinken, G. W. Bruyn & H. L. Klawans (Eds.), Handbook of clinical neurology: extrapyramidal disorders, vol. 5 , (pp. 19-3 1). North Holland: Elsevier Science Publishers. Niles, L. P., Wong, Y. W., Mishra, R. K. & Brown, G. M. (1979). Melatonin receptors in brain. European Journal of Pharmacology, 5 5 , 2 19-220. Nowak, J. Z. (1988). Melatonin inhibits (’H) dopamine release from rabbit retina evoked by light, potassium, and electrical stimulation. Medical Science Research, 16, 1073-1075, Nutt, J. C., Woodward, W. R., Hammerstad, J . P., Carter, J. H. & Anderson, J. L. (1984). The “onoff” phenomenon in Parkinson’s disease. Relation to levodopa absorption and transport. New England Journal of Medicine, 310, 483-488. Obeso, J. A., Grandas, F. & Vaemonde, J . (1989). Motor complications associated with chronic levodopa therapy in Parkinson’s disease. Neurology, 21 (suppl 2), 11-18. Olcese, J. & Reuss, S. (1986). Magnetic field effects on pineal gland melatonin synthesis: comparative studies on albino and pigmented rodents. Brain Research, 3 6 9 , 365-368. Olcese, J . , Reuss, S . & Vollrath, L. (1985). Evidence for the involvement of the visual system in mediating magnetic field effects on pineal melatonin synthesis in the rat. Brain Research. 333, 382-384. Olcese, J., Reuss, S . & Semm, P. (1988). Geomagnetic field detection in rodents. Life Sciences, 4 2 , 605-61 3. Pederzoli, M., Girotti, F., Scigliano, G., Aiello, G . , Carella, F. & Caraceni, T. (1983). L-dopa long term treatment in Parkinson’s disease: age-related effects. Neurology, 3 3 , 15 18-1522. Quinn, N. P. (1987). Levodopa. In W. C. Koller (Ed.), Handbook of parkinson’s disease (pp. 317337). New York: Marcel Dekker. Quinn, N. P., Toone, B., Lang, A. E., Marsden, C. D. & Parkes, J. D. (1983). Dopa dose-dependent sexual deviation. British Journal of Psychiatry, 142, 296-298. Rudolph, K . , Krauchi, K., Wirz-Justice, A. & Feer, H. (1985). Weak 50-Hz electromagnetic fields activate rat open field behavior. Physiology & Behavior, 3 5 , 505-508. Rudolph, K . , Wirz-Justice, A., Krauchi, K. & Feer, H. (1988). Static magnetic fields decrease nocturnal pineal CAMP in the rat. Brain Research, 446, 159-160. Sandler, M. (1970). Some anomalies in the L-dopa response: recent biochemical studies. Archives of Neurology, 5 , 259-263. Sandyk, R. (1991). Relevance of the habenular complex to neuropsychiatry. A review and hypothesis. International Journal of Neuroscience, 6 1 , 189-219. Sandyk, R., Anninos, P. A., & Tsagas, N. (1991). Magnetic fields and the habenular complex. International Journal of Neuroscience, 5 9 , 263-266. Sandyk, R . , Anninos, P. A., Tsagas, N. & Derpapas, K. (1992). Magnetic fields in the treatment of Parkinson’s disease. International Journal of Neuroscience, 6 3 , 141-150. Sandyk, R. & Fisher, H. (1989). Increased incidence of neuroleptic-induced movement disorders in pinealectomized rats. International Journal of Neuroscience, 4 8 , 303-308. Seguela, P., Geffard, M . , Chauveau, J . , Muyard, J . P., Biziere, K. & Le Moal, M. (1982). Selective increase of melatonin content in pineal gland and nucleus accumbens after peripheral injection of Des-Try’-gamma-endorphin in the rat. Neuroscience Letters, I0, S442. Semm, P. (1983). Neurobiological investigations on the magnetic sensitivity of the pineal gland in rodents and pigeons. Comparative Biochemistry and Physiology, 76A. 683-689. Semm, P., Schneider, T. & Vollrath, L. (1980). Effects of an earth-strength magnetic field on electrical activity of pineal cells. Nature, 288, 607-608. Stevens, J . R. (1978). Eye blink and schizophrenia: psychosis, or ytardive dyskinesia. American Journal of Psychiatry, 135, 223-227. Sugden, J . (1983). Psychopharmacological effects of melatonin in mouse and rat. Journal of Pharmacology and Experimental Therapeutics, 227, 587-591. Vitte, P. A., Harthe, C., Lestage, P., Claustrat, B. & Bobillier, P. (1988). Plasma, CSF and brain distribution of C14-melatonin in rat: a biochemical and autoradiographic study. Journal of Pineal Research, 5 , 437-453. Wartenberg, R. ( 1 958). Neurologische Untersuchungsmethoden in der Sprechstunde. Stuttgart: Thieme Verlag. Welker, H. A., Semm, P., Willig, R . P., Commentz, J . C . , Wiltschko, W. & Vollrath, L. (1983). Effects of an artificial magnetic field on serotonin N-acetyltransferase activity and melatonin content of the rat pineal gland. Experimental Brain Research, 5 0 , 426-432. Zisapel, N . & Laudon, M. (1983). Inhibition by melatonin of dopamine release from rat hypothalamus. Brain Research, 272, 378-381. Zisapel, N., Egozi, Y . & Laudon, M. (1982). Inhibition of dopamine release by melatonin: regional distribution in the rat brain. Brain Research, 246, 161-163. Zisapel, N., Egozi, Y . & Laudon, M. (1983). Inhibition by melatonin of dopamine release from rat hypothalamus in vitro: variations with sex and the estrous cycle. Neuroendocrinology, 3 7 , 41 -47.
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Weak Magnetic Fields in the Treatment of Parkinson's Disease with the “on-off” Phenomenon Reuven Sandyk To cite this article: Reuven Sandyk (1992) Weak Magnetic Fields in the Treatment of Parkinson's Disease with the “on-off” Phenomenon, International Journal of Neuroscience, 66:1-2, 97-106, DOI: 10.3109/00207459208999794 To link to this article: http://dx.doi.org/10.3109/00207459208999794
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Intern J . Neuroscience, 1992, Vol. 66, pp. 97-106 Reprints available directly from the publisher Photocopying permitted by license only
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Clinical Case Report WEAK MAGNETIC FIELDS IN THE TREATMENT OF PARKINSON’S DISEASE WITH THE “ON-OFF” PHENOMENON REUVEN SANDYK NeuroCommunication Research Laboratories, Danbury, CT 06811 , U . S . A .
International Journal of Neuroscience 1992.66:97-106.
(Received March I
I
1992)
Application of external weak magnetic fields recently has been reported to be efficacious in the treatment of a 62-year-old patient with idiopathic Parkinson’s disease (PD) complicated by levodopa-induced fluctuations in motor response (“on-off”). I report an additional case of a 67-year-old man with idiopathic PD and levodopa-related motor fluctuations who likewise experienced marked and sustained improvement in Parkinsonian symptoms and amelioration of “on-off“ symptoms following the application of external weak magnetic fields. Based on these observations it is concluded that artificial weak magnetic fields may be beneficial for the treatment of PD complicated by levodopa-related “on-off” phenomenon. Furthermore, since in experimental animals external magnetic fields alter the secretion of melatonin, which in turn has been shown to regulate stnatal and mesolimbic dopamine-mediated behaviors, it is proposed that the antiParkinsonian effects of weak magnetic fields are mediated via the pineal gland. Keyw,ords: Parkinson’sdisease; weak magnetic field.7; “on-off’;pineal gland; melatonin; dopamine
Application of weak magnetic fields has been reported to be efficacious in the treatment of a 62-year-old man with idiopathic Parkinson’s disease (PD) with severe levodopa-related motor fluctuations (“on-off” phenomenon) (Sandyk et al., 1992). At the time of filing this report the patient had been applying weak magnetic fields at home daily at night (2300 h) for over 5 months and continued to experience benefit. Encouraged by these observations, I proceeded to study the effects of external weak magnetic fields in an additional PD patient who likewise exhibited levodopa related “on-off. ” CASE REPORT This 67-year-old businessman experienced onset of stiffness of his left arm at the age of 55. Several months later he developed resting tremor in his left hand which progressed a few months later to involve the right hand as well. Subsequently, he began to experience insidious deterioration in his condition as evidenced by generalized slowing of movement, progressive difficulties in the initiation of movement, difficulties in writing, and mild postural instability. One year after being diagnosed with PD, the patient was prescribed levodopa (125 mg 3 tabs./day). This resulted in improvement in mobility and reduction in the This work was presented in part at a Neuroscience seminar held at the Institut Fuer Medizin, Forschungszentrum Julich, Germany, December 16, 1991. I am grateful to Prof. P.A. Anninos for providing the device for the treatment with magnetic fields and to Dr. K . Derpapas for referring the patient for treatment. Reprints requests to: Professor Reuven Sandyk, P.O. Box 203, Bedford Hills, NY 10507, U . S . A . 97
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severity of tremor for about 3 years after which he began to experience a decline in response to levodopa (“wearing off”) associated with mild fluctuations of motor performance. These symptoms were controlled initially by increasing in the dosage and frequency of levodopa administration (“dose fractionation”) and subsequently by the addition of small doses of bromocriptine (2.5 mg/d). However, over the following 3 years fluctuations in motor performance gradually worsened and he noted the occurrence of choreic movements in the neck and face at the time of maximal clinical response to levodopa (“peak dose” dyskinesias). Over the following 6 months the patient continued to deteriorate to a point where his symptoms showed clear oscillations between severe Parkinsonism (“off”-period) and complete mobility with choreoathetoid and dystonic dyskinesias of the neck, face, upper limbs, and trunk (“on”-period). According to the patient, “off”-periods tended to occur predominantly in the afternoon and were associated at times with distressingly painful dystonic movements of the feet and toes (“off-period’’ dystonia). Such dystonic movements also occurred occasionally in the early morning hours and were relieved by levodopa. At the time of examination the patient’s medications included levodopa/carbidopa (SinemetR, 250/25 3 tabs/day; 1/2 tab. every 3 hours), bromocriptine (2.5 mg/d), orphenadrine (100 mg/d), and vitamin E (200 I.U./d). The patient’s medical history was unremarkable save for essential hypertension which was managed with diuretics and beta-blockers. There was no history of mental depression, memory disturbances, autonomic, or primary sensory symptoms. Appetite was good and his weight had been stable since the onset of his illness. Sleep was disturbed due to difficulties falling asleep, spontaneous arousals, and inability to turn in bed owing to generalized stiffness. He denied history of exposure to industrial toxins or psychotropic drugs prior to the onset of PD. The patient’s family history was negative for neuropsychiatric disorders. CT scan of the head in 1991 revealed evidence of frontal lobe atrophy with mild dilatation of the lateral ventricles. Laboratory studies including complete blood count, serum electrolytes, serum magnesium, iron, and copper, glucose, thyroid profile, liver function tests, folic acid, and vitamin B,, levels were all in the normal range. The patient was examined during both the “on” and “off” periods. During an “off”-period he was alert and oriented with normal thought processes. His blood pressure was 170/90 mm Hg with a regular pulse of 100/min and no evidence of postural hypotension. His forehead was oily and his facial expression showed a moderate degree of amimia. His speech was slow and hypophonic and there was mild tremor of the tongue and lips. The glabellar tap as well as frontal lobe release signs such as pout, snout, and palmomental reflexes were positive. Extraocular movements were saccadic and upward gaze was slightly limited. Blink rate was 10/min. He had bilateral intermittent resting tremor of 7-8 Hz in the upper extremities which was more accentuated on the left side. His handwriting revealed the classic micrographia of PD and he had difficulties drawing circles (Figure 1). There was prominent cogwheel rigidity of the neck and at the elbows and wrists bilaterally. Wartenberg’s (1958) head-dropping test for rigidity was positive. The patient had difficulties rising from the chair without assistance and on attempts to ambulate he had marked “freezing” with “start hesitation.” Once mobile, he had a prominent festinating gait with stooped posture associated with poor arm swing, gait instability, and a slight tendency to fall backwards. During an “on”-period he was mobile, but disclosed choreoathetoid movements of the neck, upper limbs, and trunk.
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FIGURE 1 .
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A sample of the patient’s drawing obtained prior to treatment with magnetic fields.
APPLICATION OF MAGNETIC FIELDS After obtaining an informed consent from the patient for treatment with magnetic fields. the patient initially underwent a sham (placebo) magnetic treatment. The coils of the magnetic device (vide infra) were placed for 6 minutes (2 minutes over each of the following areas: left and right temporal regions, frontal and occipital regions, and over the vertex) without turning on the device and changes in symptoms were assessed by two independent neurologists during the following 2 hours. Thereafter, magnetic stimulation was applied at 1500h according to the method described elsewhere (Anninos el al., 1991). In brief, magnetic fields were administered via an electronic device, the principles of which have been described previously (Anninos et al., 1991). The coils of the device, which had a diameter of 1 cm, were placed on the patient’s scalp and weak magnetic fields were administered for a total of 6 minutes to the areas corresponding to those applied in the sham magnetic treatment. The frequency of stimulation was 2-7 Hz and the intensity of the magnetic field was 7.5 picotesla (pT). No adverse effects were reported during or after the application of magnetic fields. At the time of magnetic treatment the patient was maintained on his antiparkinsonian medication.
R. SANDYK
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FIGURE 2.
D
b
A sample of the patient’s drawing obtained 1 hour after treatment with magnetic fields.
RESPONSE TO MAGNETIC STIMULATION While sham magnetic treatment produced no clinical effects application of magnetic fields caused an immediate subjective report of relaxation, sexual arousal, increased hunger, and mood elevation. His blood pressure increased to 190/110 mm Hg and his pulse to 1lO/min. Blood glucose (Glucostix; Miles Laboratories), obtained 5 minutes after completion of the application of magnetic field treatment, was reduced from a pretest value of 103 mg/dl to 68 mg/dl. Objectively, it was observed that the patient’s facies had a normal facial expression and the blink rate was increased from a pretest of lO/min to 18/min. There was a noticeable, significant reduction in cogwheeling rigidity in the neck, elbows, and wrists. Wartenberg’s head-dropping maneuver showed an almost normal response. However, the severity and frequency of tremor was unchanged. He had no difficulty initiating gait which became significantly more stable with good arm swing. Within an hour after treatment with magnetic fields it was noted that his tremor had diminished considerably and he was able, for the first time since onset of his tremor, to hold a cup and drink water without spilling its content. There was an improvement in his handwriting and drawing (Figure 2). Furthermore, the patient reported that he had not experienced any “on” effects in the afternoon of the same day following magnetic treatment. When the patient was interviewed on the following morning, he reported to have had a deep sleep with vivid sexual dreams and he remarked that he did not experience difficulty turning in bed. Upon awakening, he noted that his facial skin was dry and
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FIGURE 3 . A sample of the patient’s drawing obtained the day after treatment with magnetic fields showed sustained improvement of tremor.
not oily. He reported further that his mind was clear and that he was in very good spirits. Examination during an “off”-period revealed only mild generalized bradykinesia and cogwheel rigidity at the wrists and elbows with continued absence of tremor. His facial expression was normal and his forehead skin was dry. Blink rate was 17/min. He was able to hold a cup of water steadily and drink without spillage. His handwriting and drawing remained improved (Figure 3). The patient was able to rise rapidly from a chair without assistance and his gait was almost normal with no evidence of postural instability. On that day he continued to take his antiParkinsonian medication and experienced no “on”-effects. To ascertain whether the responses elicited by the magnetic stimulation were reproducible, the patient was advised to continue with his antiparkinsonian medication and also to apply magnetic field treatment nightly (2300 hours) at home. The patient’s wife was instructed to apply magnetic fields for a total of 6 minutes to the same areas designated in the initial treatment in the laboratory. Application of magnetic fields was performed with a portable electronic device (Ergo, Athens) consisting of a generator which produces alternating weak magnetic fields of power amplitude of the order of 900 f f / H z (cf. Anninos et al., 1991). The electronic device was adjusted to emit magnetic fields of the same intensities and frequencies as those used during the initial treatment in the laboratory. At the time this report was filed the patient had applied magnetic fields nightly for two months, a period during which he continued to benefit from the combined pharmacological and magnetic treatments. Specifically, he reported marked improve-
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ment in mobility and gait and added that he no longer experienced “on”-period dyskinesias or dystonic movements of the feet and toes. As a result of the magnetic treatment he was able to reduce his levodopa dosage by 1/2 tab. daily without experiencing any worsening in motor symptoms. He added that the quality of his sleep had improved considerably since the application of magnetic fields while the early morning foot dystonia did not recur. His appetite increased since the initiation of magnetic treatment and he had put on 2 Kg weight. Finally, he also reported a marked and persistent increase in libido after magnetic treatment. It is noteworthy that on two occasions during the past two months the patient noted gradual deterioration in symptoms and recurrence of the “on-off.’’ In both instances, the cause of the patient’s clinical deterioration was found to be related to malfunctioning of the electronic device.
International Journal of Neuroscience 1992.66:97-106.
DISCUSSION Fluctuations in the severity of symptoms is one of the most characteristic features of PD (Marsden, 1990; Koller & Hubble, 1990). Since the introduction of levodopa therapy, such events have greatly increased in their complexity and frequency (Marsden & Parkes, 1981; Quinn, 1987; Klawans et al., 1990; Koller & Hubble, 1990). Centrally mediated side effects of chronic levodopa therapy such as fluctuations in motor performance and dyskinesias have been noted in 40-90% of PD patients (Klawans & Weiner, 1981) and pose a major challenge in the longterm management of the disease (LeWitt & Chase, 1983; Koller & Hubble, 1990). Levodopa-related motor complications may be divided into two categories; those related to underdosing associated with disease progression (e.g., “freezing”, “endof-dose’’ akinesia, and “off-period’’ dystonia) and those related to overdosing of levodopa (“peak-dose’’ dyskinesia, “peak-dose’’ akinesia, and “diphasic” dyskinesia (Marsden & Parkes, 1981; Marsden, 1990). While unwanted effects due to overdosage may be managed simply by a reduction in dose, side effects related to underdosing have proved more difficult to manage, in part because of the progression of the underlying pathology of the disease (Marsden & Parkes, 1981; Koller & Hubble, 1990). Progressive degeneration of brainstem monoaminergic neurons is probably one of the major causes of decline in the efficacy of levodopa therapy in PD (Marsden & Parkes, 1981). Other important factors determining the potential development of subsequent side effects of levodopa include the age of onset of the disease, alterations in peripheral absorption kinetics and central kinetics of dopa conversion and dopamine storage, pharmacodynamic variables that determine the responsiveness of the dopamine receptors, the development of dopamine receptor hypersensitivity in the striatum, alterations in striatal metabolism of levodopa, and the formation of compounds such as tetrahydroisoquinolines which has been suggested to antagonize the beneficial actions of levodopa (Klawans et al., 1970; Sandler, 1974; Fahn, 1982; Pederzoli et al., 1983; Nutt, 1984; Hardie et al., 1984; Quinn, 1987; Hardie, 1990; Koller & Hubble, 1990). Despite the usual measure to fractionate the dose of levodopa (ie., smaller quantities more frequently), the addition of bromocriptine and/or selegiline hydrochloride (deprenylR) (an MA0,-inhibitor), or the administration of newer long acting preparations of levodopa, a substantial number of Parkinsonian patients develop increasingly severe and rapid oscillations in mobility and dyskinesias (Marsden, 1990). Rescheduling of protein intake or administration of a low protein diet to avoid com-
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petition of neutral amino acids with levodopa absorption and entry into the brain are only partly effective in the control of side effects due to chronic levodopa therapy (Hardie, 1990). Drug holidays, which are aimed at restoring dopamine receptor sensitivity, often lead to exacerbation of Parkinsonian symptoms during the withdrawal period (Marsden, 1990). Intravenous levodopa infusions have been shown to ameliorate the severity of motor fluctuations, but their continuous use is not suitable for long-term therapy. Likewise, continuous subcutaneous infusions of lisuride, a dopamine D2 receptor agonist, has been reported to produce unacceptable psychiatric side effects (Marsden, 1990). Presently, no drug is available to prevent the development of levodopa related fluctuations in motor symptoms (Marsden, 1990), making the prevention of their occurrence in PD the primary challenge of chronic levodopa therapy (Hardie, 1990). Several years after the introduction of levodopa therapy, this patient experienced progressive decline in the efficacy of treatment. Moreover, his Parkinsonism was complicated by disabling fluctuations in response to levodopa therapy. While the symptomatic steps employed to improve his progressive motor disability and the “onoff” were ineffective, application of nightly weak magnetic fields produced a dramatic and sustained improvement in motor disability with an almost complete resolution of the “on-off” phenomenon. The beneficial effects of the magnetic fields were sustained for a period of two months during which the patient experienced no adverse effects or tolerance. Moreover, he was able to decrease the levodopa dosage by 1/2 tab. per day without experiencing deterioration in motor performance or recurrence of the “on-off.’’ Such a dramatic beneficial effect on the Parkinsonian disability and on the “on-off” has been reported in patients who have been given electroconvulsive therapy (ECT), (Balldin et al., 1980; 1981; Andersen et al., 1987), raising the possibility that both magnetic fields and ECT may act centrally via a common mechanism to alter central dopaminergic functions. The mechanisms by which weak magnetic fields improved the patient’s motor disability and led to the resolution of the “on-off” are unknown. The observation that the patient’s spontaneous blink rate, a marker of central dopaminergic activity (Stevens, 1978; Karson et al., 1981 a; b ) , increased shortly after application of magnetic fields indicates that magnetic fields augment central dopamine activity. Such an effect is compatible also with the reduction in the severity of facial seborrhea, which is known to reflect diminished central dopaminergic functions (Burton et al., 1973 a; b). Moreover, the patient’s report of increased libido and sexual arousal following the application of magnetic fields also is in accord with a central augmentation of dopaminergic activity since L-dopa has been reported to increase libido and sexual activity in Parkinsonian patients (Barbeau, 1969; Hyyppa & Rinne, 1970; Duvoisin & Yahr, 1972; Quinn et al., 1983). In addition, augmentation of central dopaminergic activity may account for the patient’s improvement of sleep and the increase in the quantity of dreaming since levodopa has been reported to improve sleep quality, restore REM sleep, and induce vivid dreams in Parkinsonian patients (Kales et al., 1971; Kendel et al., 1972; Nausieda, 1987). Finally, the observation that magnetic fields abolished the “on-off” suggests an effect on striatal dopamine receptor sensitivity since “on-off” has been linked to levodopa-induced dopamine receptor hypersensitivity, either presynaptically , or postsynaptically (Carlson, 1970; Klawans et al., 1970; Obeso et al., 1989). Experimental animal studies indicate that the pineal gland is a “magnetosensor” (Semm et al., 1980; Semm, 1983; Welker et al., 1983; Olcese et al., 1988) and that various intensities of external magnetic fields alter the secretion of pineal melatonin (Welker et al., 1983; Olcese et al., 1985; Rudolph et al., 1988), which in turn, has
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been shown to regulate striatal and mesolimbic dopaminergic functions (Cotzias et al., 1971; Anton-Tay et al., 1971; Bradbury et al., 1985). In addition, melatonin inhibits dopamine release in the hypothalamus, midbrain, and retina (Zisapel & Laudon, 1983; Zisapel et al., 1982; 1983; Dubocovich, 1983; Nowak, 1988) and may be involved in the expression of striatal and mesolimbic dopamine-mediated behaviors and endocrine secretion (Kovacs et al., 1974; Blask et al., 1980; Golus & King, 1981; Sugden, 1983; Gaffori & Van Ree, 1985; Rudolph et al., 1985; Bradbury et al., 1985). In rats, pinealectomy reportedly enhances the emergence of neurolepticinduced purposeless chewing movements, a motor behavior which is related to increased striatal dopaminergic activity and which is considered an animal model for Tardive dyskinesia (Sandyk & Fisher, 1989). Melatonin receptors have been detected in the rat’s substantia nigra and striatum (Cardinali et al., 1979; Niles et al., 1979; Kopp et al., 1980; Laudon et al., 1988; Vitte et al., 1988) and relatively large amounts of immunoreactive melatonin are present in the nucleus accumbens (Seguela et al., 1982). Since magnetic fields acutely suppress melatonin synthesis and secretion in experimental animals and possibly in humans as well (Semm et al., 1980; Welker et al., 1983; Cremer-Bartels et al., 1983; Olcese & Reuss, 1986), it i s conceivable that such an effect may disinhibit striatal and/or mesolimbic dopamine release and alter dopaminergic functions to account for the improvement in the patient’s Parkinsonian symptoms. Moreover, application of artificial magnetic fields has been shown in laboratory animals to alter the activity of neurons in the habenular complex (Semm, 1983), a structure which has been shown to function as a “gate” through which limbic dopaminergic systems interact with and modulate midbrain-stnatal dopaminergic neurons to affect motor behavior (Nauta, 1986; Sandyk, 1991; Sandyk et al., 1991). In summary, although the mechanisms of action of weak magnetic fields in Parkinsonism require further elucidation, this report suggests that weak magnetic fields may alter striatal dopaminergic functions in the disease and adds additional support to suggest that weak magnetic fields are highly beneficial in the treatment of Parkinsonism and associated motor complications of levodopa therapy.
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