Micrographia in Parkinson's Disease PDF

141 Journal of the neurological Sciences Elsevier Publishing Company, Amsterdam - Printed in The Netherlands Micrographia in Parkinson's Disease. J. E. McLENNAN, K. NAKANO, H. R. TYLER AND R. S. SCHWAB Department of Neurology, Massachusetts General Hospital, Section of Neurology of the Peter Bent Br...

141 Journal of the neurological Sciences Elsevier Publishing Company, Amsterdam - Printed in The Netherlands Micrographia in Parkinson's Disease. J. E. McLENNAN, K. NAKANO, H. R. TYLER AND R. S. SCHWAB Department of Neurology, Massachusetts General Hospital, Section of Neurology of the Peter Bent Brigham Hospital, and Department of Neurology, Harvard Medical School, Boston, Mass. (U.S.A.) (Received 27 May, 1971) INTRODUCTION Micrographia, or abnormally small handwriting, is widely accepted as part of the clinical picture of Parkinson's disease. The incidence, severity and modifying features of this phenomenon are not known and have not been discussed in most reviews of the disease. Micrographia was first noted by Pick (1903) in certain patients with localized cerebral disorders. LSwry (1905) described micrographia in arteriosclerotic patients associated with rigidity and hemiplegia. He correlated it with lesions of the corpus striatum and thought it was related to the regulation of muscle tone. Fischer (1906) reported its presence in patients with defects in visual accommodation. In the next two decades, there were many reports of postencephalitic extrapyramidal syndromes associated with micrographia. Handwriting changes specific to postencephalitic Parkinsonism are described by Froment ( 1921). Bing (1923) noted micrographia in company with akathisia and kinesia paradoxa. Bing (1923), Bernhard (1924) and Foerster (1921) all discuss the etiology of micrographia as a striatal syndrome. Kinnier Wilson (1925) discussed micrographia in his Croonian Lectures on disorders of motility and muscle tone. He noted that micrographia "is certainly neither confined to striatal cases or in any sense pathognomonic of them". He demonstrated cases of cerebral syphilis and cerebral arteriosclerosis without striatal involvement with pathologically small handwriting. Kinnier Wilson considered three possible neurological substrates in discussing the etiology of this phenomenon. These included infracortical disorders, such as rigidity of antagonists; central dysfunction, such as disturbance of pyramidal innervation for fine acquired movement; and "highest level, transcortical" impairment, such as absence or diminution of the "will to act". His conclusion was that the higher cortical functions are just as important in the etiology of micrographia as those of lower centers. We have attempted to define the incidence and to describe the phenomenon of micrographia in a large series of Parkinsonian patients. Other handwriting difficulties seen in these patients will also be noted. * The levodopa clinical trial was supported by U.S.P.H. grant No. 5-M01-RR-31-11 to the General Clinical Research Center, Peter Bent Brigham Hospital, Boston, Mass. J. neurol. Sci., 1972, 15:141-152 142 J. E. MCLENNAN, K. NAKANO, H. R. TYLER. R. S. SCHWAB METHODS Records containing sequential examination and performance data on about 800 Parkinsonian patients at 6-month to l-year intervals were reviewed for signs of micrographia. Ninety-five cases were selected which demonstrated the phenomenon to a sufficient degree to be of further interest. We estimated the incidence of severe micrographia in this population of patients to be 10-i 5 % at various stages during the progression of disease. Of 95 patients contacted and asked to complete a detailed questionnaire, 63 were able to respond; these patients, in general, represented the less severely handicapped of the group. Patients were asked to submit samples of their writing prior to the onset of their disease and serial specimens during the period that their symptoms were progressing. Serial signatures, often from cancelled checks, were found to be the most standardized source of handwriting and the most easily obtainable. There was considerable difficulty in getting Parkinsonian patients to complete a long questionnaire requiring handwriting exercises and moderate concentration. The nature of the data did not lend itself readily to quantification, and each case was analyzed individually. To test the effect of therapy on micrographia in Parkinson's disease, serial signatures were obtained from 30 other patients participating in a double-blind study (Nakano and Tyler 197t) which compared the therapeutic efficiency oflevodopa to procyclidine hydrochloride (Kemadrin) and a placebo. One of the authors, not involved in the collection of data from the levodopa trial, evaluated in double-blind fashion the entire spectrum of handwriting samples from each patient for specific improvement in size. These patients, contrary to those selected for the first part of the study, did not all have micrographia at the inception of the study. The handwriting of several of these patients reflected severe tremor and rigidity. All of the patients had wellestablished Parkinson's disease, although the degree of involvement varied considerably on a I-V scale from unilateral involvement to confinement to bed or wheelchair. Data from the patients in this portion of the study is evaluated separately from that of the 63 patients involved in the first portion. RESULTS The patient with micrographia is unable to sustain normal-sized writing for more than a few letters, if at all (Fig. 1). There is a tendency for the handwriting to have a left to right slant with what seems to be a compression of words into insufficient space as the end of the message is reached. Most patients with fully-developed micrographia are unable to write larger; a few can increase the size of their writing temporarily and seem to be helped by guidelines which force them to make larger letters (Fig. 2). A few patients show remarkable improvement in handwriting after specific writing therapy, usually similar to improvement obtained with physiotherapy for rigidity and tremor. Patients generally reported that they performed poorly under stress and were often unable to write at all when anxious or upset. These patients were not under the pressure of time which is a major factor in the quality of handwriting in the Parkinsonian patient. Many patients took several sessions, often with the aid of acomJ. neurol. Sci., 1972, 15:141-152 143 MICROGRAPHIA IN PARKINSON'S DISEASE 'A.............. Fig. 1. Attempt by a patient with micrographia to copy a sentence, writing as large as possible. On three successive trials, normal size is maintained for only a few letters. This demonstrates the tendency to write progressively smaller as the end of a line approaches; renewed effort on each succeeding trial produces temporarily larger writing, but each repetition is somewhat smaller than the previous one. Now repeat; ~ sine mnt4me bel~ l d. t ~ a ~ t~" l i n e s t,o luidle l ~ t. Fig. 2. Demonstrates the ability of an occasional patient with severe micrograpbia to maintain large handwriting through the use of guidelines. A second trial without guidelines produces immediate deterioration of size. TABLE 1 DOCUMENTED COURSE OF THE DEVELOPMENT OF MICROGRAPHIA IN 17 PATIENTS WITH AN ONSET OF CHANGES IN HANDWRITING COINCIDENT WITH OR PRE-DATING THE ONSET OF THE OTHER CLINICAL SYMPTOMS OF PARKINSONISM Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Handedness Side of onset of Parkinsonism r r r r r r r r r r r r r r r r r r r r r r 1 r r r r r r 1 r 1 r r Years beJbreonset 6 5 4 3 2 4 4 4 4 4 4 3 4 4 3 3 4 3 4 4 4 1 4 3 443 4 4 4 Onset 4 3+ 3 4 3 2 4 4 4 3 3 3 3 4 4 3 3 3 3 3 1 3 3 3 3 4 3 3 3 2 3 3 3 2+ 3 3 3 1 3 3 3 3 3 3 Years aJter symptoms begin 1 2 3 3 2 2 3 3 3 2 3 3 3 2 2 3+ 2 3 2 2 1 2 1 2 1 3 2 2 3 3 1 2 3 2 3 2 1 1 2 2 3 2+ 3 3 456 1 2 3 1 3 22 3 1 2 1 1 3 3 1 0 3 1+ 3 1 3 2 3 3 Key : 4, Normal handwriting for that patient; 3, early change noted; 2, moderate micrographia; 1, severe micrographia; 0, unable to write at all. J. neurol. Sci., 1972, 15:141-152 144 J. E. MCLENNAN, K. NAKANO, H. R. TYLER, R. S. SCHWAB panion, to complete a questionnaire because of fatigue and poor powers of concentration. Generally the quality of the handwriting did not deteriorate with reduction in size unless advancing tremor and rigidity involved the writing arm. Micrographic signatures look like smaller photographic reductions of the patient's earlier signature. Samples of severe and progressive micrographia leading to agraphia are seen ill Fig. 3. In 17 of the 63 cases, serial signature documentation was made of definite onset of smallness in handwriting pre-dating or coincident with the appearance of other symptoms of Parkinson's disease. The progression in these cases is seen in Table 1, and a typical example appears in Fig. 4. The longest prodrome of progressive micrographia was 4 years. Micrographia appears to be a very early definable symptom in a minimum Fig. 3A. ,L neurol. Sci., 1972, 15:141-152 MICROGRAPHIA IN PARKINSON'S DISEASE ~ ";,._....~.-.---~ 145 ,..~,.,~---- Fig. 3B. Fig. 3. Examples of progressive micrographia leading to agraphia during the progression of clinical Parkinson's disease. A : serial signatures at yearly intervals ; B: samples of handwriting from the log book of a sea captain who entered the same phrase daily for several years while developing progressive symptoms of clinical Parkinson's disease. The last 5 specimens are at yearly intervals; the first ten years earlier when he was asymptomatic. of 5 ~ of all Parkinsonian patients and in about 30 ~o of l h.,c patients who will later develop severe micrographia. All 17 patients with early onset of handwriting changes were right-handed; in 3 of these cases, clinical symptoms of tremor and stiffness began on the left side. There was 1 patient who was left-handed in all activities, including handwriting, and whose clinical disease began on the right side and has progressed only on the right to date. Micrographia in the left hand began at the same time and has remained in the absence of other Parkinsonian symptoms (Fig. 5). This indicates that there need not be much correlation between micrographia and the side of the body upon which other symptoms are evident. Thirty-five patients (57 ~o) had either unilateral or bilateral operative procedures for control of tremor and rigidity. Three of these patients were left-handed and had right-sided operations. Twenty of the patients who were right-handed underwent leftsided operations. Of the 23 patients who had had unilateral thalamotomy done for symptoms related to their dominant hemisphere, 12 noted deterioration in writing after the operation. There was no example of improvement ofmicrographia that could be attributed to an operative procedure. Fifty-three of the 63 patients reported that they had difficulty with reduced volume of speech; 29 patients believed they could draw a definite temporal relationship between the development and progression of difficulty in speech and handwriting. Fifteen of 23 patients undergoing dominant-sided operations noted definite and often considerable post-operative worsening of speech, often correlating closely with deterioration in handwriting. J. neurol. Sci., 1972, 15:141-152 146 J. E. MCLENNAN, K. NAKANO, H. R. TYLER, R. S. S('HWAB J = !~ '"t ' C 4 onset ,2 Fig. 4. Yearly serial signatures from a patient before onset of clinical symptoms of Parkinson's disease (first five) and after appearance of clinical disease (last four). Incipient micrographia is demonstrated two years before clinical symptoms began. While the effect of tremor and rigidity is readily apparent in the handwriting of many Parkinsonian patients, the correlation with the development of micrographia is very poor. The connection with hypokine$ia is somewhat better, but the two phenomena are still largely independent. The relationship of mood and motivation to handwriting performance is certainly the most difficult area in which to make meaningful comment. Anxiety was universally J. neurol. Sci., 1972, 15:141-152 147 MICROGRAPHIA IN PARKINSON'S DISEASE lij' ', Fig. 5. This left-handed patient dewloped micrographia in the left hand while clinical Parkinson's disease began on the right side and progressed only on this side. The first three signatures are 11, 5 and 4 years before onset and the last one is 1 year after disease began on the other side. noted to make all tasks, including handwriting, more difficult. Although many of the patients were taking mood-elevating drugs for periodic depression, we were not able to determine any effect of mood variation on the micrographic process. In most cases the micrographia was not changed by any eventuality, the handwriting remaining consistently small once it had deteriorated. Many patients reported a slowing of the process of acquiring information; they read more slowly, thought in single words or small phrases, and had to concentrate on each word as they wrote. They often had trouble in appreciating the meaning of spoken phrases the first time. A lag was commonly reported at the beginning of a period of writing which might possibly have been related to the characteristic akinetic freezing noted by many patients. Double-blind trial of levodopa Sixteen of 30 patients showed a significant increase in size of handwriting (specifically in serial signatures) during therapy with levodopa; 11 patients showed no improvement; 1 patient deteriorated; and 2 were unable to write at any time during the trials. Samples of signatures before and after levodopa treatment are given in Fig. 6. Neither the placebo nor procyclidine hydrochloride had any significant effect on handwriting in more than a very transient situation. The 11 patients who showed no increase in J. neurol. Sci., 1972, 15:141-152 148 J. E. MCLENNAN, K. NAKANO, H. R. TYLER, R. S. SCItWAII rI _ _ 13aC/ lda/Ju Fig. 6. Improvement in micrographia with levodopa treatment during a double-blind trial. The first column shows patient signatures while on previous medication or on no medication prior to starting the clinical trial on levodopa. The second column shows repeat signatures from these patients after a period on levodopa. Signatures were obtained every two days, along with many other monitors of clinical status. Definite increase in handwriting size began as early as three weeks after start of levodopa in certain patients and often progressively improved for several months. Other patients showed quite dramatic improvement in clinical symptoms without any real change in micrographia. handwriting size during the study did not have micrographia at the outset. Several of this group, however, manifested much less tremor and rigidity in their writing after levodopa. DISCUSSION There is no uniformity in the nature of the micrographic process except that the patient writes smaller than was previously characteristic. The abnormality lies in the fact that this is not a voluntarily-controlled smallness. Some persons naturally have a very small handwriting without any sign of neuromuscular disease. Kinnier Wilson separates the expression of progressive smallness with increasing muscular fatigue from that of true micrographia or constant smallness. All of our patients wrote consistently small; only a few were able voluntarily to increase the size of their writing, J. neurol. Sci.,1972,15:141 152 MICROGRAPHIA IN PARKINSON'S DISEASE 149 and then for just a short time. There was often a progressive diminution in muscular effort reflected in the handwriting pattern as a trailing-off of lines in a slant. This was accompanied by a progressive smallness as the end of the message or the edge of the paper approached. Many patients were not able to complete a simple sentence because of progressive akinesia. Encouragement may produce renewed effort with increase in speed of writing or increased size (as measured by increased amplitude or ergograph testing), demonstrating the central nature of this defect (England 1966). The use of guide-lines may preserve larger writing temporarily in some cases. We observed that in general the patient's former individual characteristics of handwriting were preserved. The micrographic signature is a reduction in size but not a change of morphology or style. This has been noted by England (1966). Lonsdale (1966), on the other hand, states that the micrographic process also involves progressive rigidity and reduction in the number of curves and roundings in the letters. That the two processes often overlap is not disputed; we have, however, many examples of micrographic signatures that, if magnified, would superimpose well on earlier signatures of the patient. Although the number of patients in which the symptom of micrographia will be an important feature of their disease is small, it often forms a relatively specific prodrome that may alert the neurologist to the basic process evolving. The handwriting of some patients in our series had become progressively smaller for up to 4 years before any measurable tremor or rigidity was noted. That micrographia is not a secondary result of some other symptom is supported by a lack of correlation with the side of akinesia, rigidity and tremor in several of our cases with unilateral involvement. Further evidence here might be the lack of improvement of micrographia after an operation which alleviates peripheral symptoms. Meier, Story, French and Chou (1966) note, in a study of the motions of handwriting before and after thalamotomy, that with operation on the left side, even with good postoperative reduction in tremor, the functional component motions in handwriting were not dramatically affected. Following right thalamotomy, however, marked improvements in various measurements of writing control in the right hand were noted. These authors analyze the precise electrical measurement (Meier and Ayers 1961) of basic components of handwriting and not the more complex phenomenon of micrographia. They explain this effect of improvement of manipulation of the dominant hand after right thalamotomy as suggesting a reduction of interfering effects of transmitted tremor and rigidity from the opposite side. In our series, 17 patients underwent only a right thalamic operation; 16 noted no change in their micrographia and 1 thought his handwriting became worse. Tremor and rigidity seem to have no correlation with micrographia; this is seen by development of severe micrographia in several limbs without measurable clinical involvement. Although there is a more benign form of Parkinson's disease with essentially unilateral involvement, most patients with unilateral disease will develop bilateral signs and symptoms within 10 years of the onset (Scott, Brody, Schwab and Cooper 1970). In our 4 patients with micrographia as an isolated phenomenon on the side opposite to the obvious clinical abnormalities, this could, of course, be a manifestation of the prodromal state in the dominant arm. While we could often show a J. neurol. Sci., 1972, 15:141-152 150 J. E. MCLENNAN, K. NAKANO, H. R. TYLER, R. S. SCHWAB moderate correlation between akinesia and micrographia, the two are frequently separable in kind and quantity. Kinnier Wilson (1925) gave examples of handwriting of normal size by a post-encephalitic Parkinsonian patient who was one of the most immobile and rigid that he had ever observed ; conversely he noted that the most severe micrographia in his clinical material was that of a lady who otherwise had minimal symptoms. Discussions of akinesia and rigidity in relation to the clinical situation of Parkinsonian patients are numerous; it is the interaction of mood or "will" and the symptomatology of this syndrome that is more difficult to study and which may be of importance in understanding micrographia. There is an extensive literature on various psychiatric aspects of performance in Parkinson's disease which cannot be ignored. With specific regard to handwriting, there are reports, e.9. that of Knopp (1967), of handwriting-size change during treatment with psychotropic drugs or other therapy of psychiatric disease (Knopp, Paulson, Allen, Smeltzer, Brown and Kose 1970). Nonetheless, elevation or depression of mood in our patients did not seem to have much effect on micrographia, which remained constant once it had deteriorated maximally. Although 11 patients regularly used medication to combat depression, micrographia was not improved in any case; furthermore, the use of phenothiazine derivatives did not cause handwriting to become smaller in any case. It is difficult, of course, to deal with the fact that depressed people don't write, or if they do, it is under a situation of increased anxiety. Schwab and Zieper (1965) and Prichard and Schwab (1951) discuss the relationship of mood and stress to performance in Parkinson's disease. Some patients noted difficulty in beginning to write, much like the well-known akinetic freezing during initiation of gross movements, such as rising from a chair. This was noted even in an uninvolved limb with unilateral disease on the opposite side. Possibly the appearance of micrographia contralaterally to the side of the body showing marked tremor and rigidity is related to the difficulty Parkinsonian patients have with bi-manual performance, which seems to stem from a deficiency of the central programming function (Talland and Schwab 1964). Levodopa is the first anti-Parkinsonian drug to have a significant effect on micrographia. We have a few cases of very temporary improvement during vigorous physical therapy; following stereotaxic surgery or treatment with other drugs, handwriting, in our experience, remained the same or became progressively smaller. There are a few instances reported of an increase in size of writing during placebo treatment, e.g. Coleman (1970), but these are of doubtful significance, and certainly short-lived. Reports are appearing on multiple aspects of the Parkinsonian patient during levodopa therapy. Knopp et al. (1970), with heavy emphasis on the psychiatric implications of handwriting, feel they can show an increase in the area of a paragraph of writing during clinical improvement on levodopa. This study was not double-blind and the authors admit to possible erroneous conclusions when measuring a parameter so sensitive to patient expectation. They make no effort to select patients with severe micrographia, but merely require that they have Parkinson's disease. We feel that handwriting area is probably a useless variable. There is no absolute smallness ; each case must be handled separately and must be followed over a reasonably long period J. neuroI. Sci.,1972~15:141-152 MICROGRA PHIA IN PARKINSON'S DISEASE 151 of time to assess properly the multiple transient sources of variation. One of us (Schwab 1968) mentioned editorially that levodopa had little effect on micrographia in Parkinsonian patients, but has subsequently published some evidence to the contrary (Timberlake, Zieper and Schwab 1969). Obviously information on the total effect of this drug is still accumulating. Two recent papers (Stellar, Mandel, Waltz and Cooper 1970; Wycis, Cuningham, Kellett and Spiegel 1970) combine the use of stereotaxic surgery and levodopa and state that both handwriting and speech are improved by this therapy, although this does not refer to micrographia but rather to the reduction of tremor and rigidity. We feel certain that in selected cases of severe micrographia a definite sustained increase in the size of handwriting can be attributed to levodopa treatment. With the data of this analysis at hand, it seems that micrographia deserves recognition as a neurologic phenomenon that probably depends on several complex and interrelated mechanisms. It cannot be explained adequately by any simple clinical observation such as a progressive fixation of the writing limb. It bears only a cursory relationship to the akinesia of Parkinsonism, and probably none to rigidity and tremor. The unique response of some cases of severe micrographia to levodopa therapy suggests a central neurophysiologic etiology and thus strengthens its possible involvement with the "will to act" and the thalamic and extrapyramidal regulation of motor expression. Perhaps the next step in analysis of the mechanism of micrographia should be investigation of the peripheral effector deficit, possibly by extension of the complex electromyogram analysis of handwriting (Ruesch, Finesinger and Schwab 1940), using specific muscle electrodes. Recordings done in this fashion from agonist and antagonist muscles of the forearm of Parkinsonian patients attempting to execute rapid alternating movements demonstrate the fatigue effect both behaviorly and electrically. As the movements become progressively slower, there is a reduction in amplitude from the antagonist muscle as well as prolongation of its action (Cohen, personal communication). We cannot use the simple explanation of increasing antagonist action as an explanation for the etiology of micrographia. SUMMARY Micrographia has been of interest to many neurologists; the phenomenon, however, remained unexplained. We have defined the incidence and characteristics of severe micrographia in a large population of Parkinsonian patients. It is totally separable from tremor and rigidity in these patients and has only an indefinite relationship to akinesia. In about 5 ~o of all Parkinsonian patients, micrographia is present as a prodromal symptom before any other manifestation of the disease is noted; this is true in 30 ~ of those patients who will later develop severe micrographia during the course of their disease. It remains essentially uninfluenced by various forms of treatment of Parkinsonism including stereotaxic thalamotomy ; however, during treatment with levodopa some cases of micrographia improve. We feel that micrographia is of central origin, and evidence is offered in support of this hypothesis. A more complete understanding of J. neurol. Sci.,1972,15:141-152 152 J. E. M( 1J!NNAN, K. NAKANO, H. R. TYLER, R. S. S('llWAB the mechanism of micrographia would add much to our understanding of sonw subtleties of extrapyramidal motor dysfunction. REFERENCES BERNHARD, H. (1924) Zur Frage der M ikrographie, Mschr. Psychiat. Neurol., 56: 301-316. BING, R. (1923) Ueber einige bemerkenswerte Begleiterscheinungen der "extrapyramidalen Rigidit~it" (Akathisie-Mikrographie-Kinesia paradoxa), Schweiz. reed. Wschr., 4 : 167--171. COHEN, L., Personal communication. COLEMAN,M. (1970) Preliminary remarks on the L-dopa therapy of dystonia, Neurology (Minneap.), 20: No. 11, Part 2, pp. 114-121. ENGLAND, JR., A. C. (1966) Testing for akinesia, J. Neurosurg., 24: 279-280. FISCHER, O. (1906) ~ b e r Makropsie und deren Beziehungen zur Mikrographie, sowie fiber eine eigentfimliche St6rung der Lichtempfindung, Mschr. Psychiat. Neurol., 19: 290-305. FOERSTER, O. (1921 ) Zur Analyse und Pathophysiologie der stri~iren Bewegungsst6rungen, Z. ges. Neuro/. Psychiat., 73: 1-169. FROMENT, M. F. (1921) De la micrographie darts les 6tats Parkinsoniens postenc6phalitiques et des conditions qui sont susceptibles de la modifier, Rev. neurol., 37: 637-638. KINNIER WILSON, S. A. (1925) The Croonian Lectures on some disorders of motility and of muscle tone, with special reference to the corpus striatum, Lancet, ii: 1-10. KNOPP, W. (1967) In discussion to G. CHALLAS,J. L. CHAPEL AND R. L. JENKINS,Tourette's disease: control of symptoms and its clinical course, Int. J. Neuropsychiat., 3, Suppl. No. 1 : S105-S108. KNOPP, W., G. PAULSON, J. N. ALLEN, D. SMELTZER, F. D. BROWN and W. KOSE (1970) Parkinson's disease: L-dopa treatment and handwriting area, Current ther. Res., 12:115 125. LONSDALE, H. G. (1966) In discussion of B. BOSHES,Voice changes in Parkinsonism, J. Neurosurg., 24: 289. LOwv, M. (1905) Mikrographie durch hemiplegischen Anfall, wahrscheinlich in Folge auf die Schreibkoordination beschr~inkter Rigidit/it, Mschr. Psychiat. Neurol., 18: 372-399. MEIER, M. J. AND F. W. AVERS (1961) Quantitative effects of basal ganglia surgery on handwriting and gait, J. Lancet, 81 : 70-73. MEIER, M. J., J. STORY,L. A. FRENCH AND S. N. CHOW (1966) Quantitative assessment of behavioral changes following subthalamotomy in the treatment of Parkinson's disease, Confin. neurol. (Basel), 27: 154-161. NAKANO, K. AND H. R. TYLER (1971) Neurology (Minneap.), In press. PICK, A. (1903) Ueber eine eigentfimliche Schreibst6rung, Mikrographie, in Folge cerebraler Erkrankung, Prag. reed. Wschr., 28: 1--4. PRICHARD, J. S., R. S. SCHWABAND W. A. TILLMANN(1951) Effects of stress and results of medication in different personalities with Parkinson's disease, Psychosom. Med., 13 : 106-111. RUESCH, J., J. E. FINESINGERAND R. S. SCHWAB(1940)The electromyogram of handwriting, Psyehosom. Med., 2: 411~137. SCHWAB, R. S. (1968) Limitations in treatment of Parkinson's disease, New Engl. J. Med., 279: 943-944. SCHWAB, R. S. AND ZIEPER, I. (1965) Effects of mood, motivation, stress and alertness on the performance in Parkinson's disease, Psychiat. et Neurol. (Basel), 150: 345-357. SCOTT, R. M., J. A. BRODY, R. S. SCHWABAND I. S. COOPER (1970) Progression of unilateral tremor and rigidity in Parkinson's disease, Neurology (Minneap.), 20: 710-714. STELLAR, S., S. MANDEL, J. M. WALTZ AND I. S. COOPER (1970) L-dopa in the treatment of Parkinsonism. A preliminary appraisal, J. Neurosurg., 32: 275-280. TALLAND, G. A. AND R. S. SCHWAB(1964) Performance with multiple sets in Parkinson's disease, Neuropsychologia, 2: 45-53. TIMBERLAKE, W. H., I. ZIEPER AND R. S. SCHWAB (1969) Double-blind study of L-dopa treatment of Parkinsonism. In: M. YAHR (Ed.), Neurology and Neurosurgery (Abstracts of papers presented at the 9th World Congress o£ Neurology and the 4th International Congress of Neurological Surgery, New York, September, 1969) (International Congress Series, No. 193), Excerpta Medica, Amsterdam, 1969, p. 170. WYcIS, H. Z., W. CUNNINGHAM, G. KELLETTAND E. A. SPIEGEL (1970) L-dopa in the treatment of postsurgical Parkinson patients, J. Neurosurg., 32: 281-285. J. neurol. ScL, 1972, 15:14l--152