Bilateral thalamotomy.

History & signs of postencephalitic disease.

11Aseptic necrosis of femoral head after irradiation for cancer.

Neurologic signs were graded as follows: tremor ++++ prevents use of limb, +++ constant, marked, ++ intermittent, moderate, and + barely perceptible; rigidity ++++ almost inflexible, +++ marked, ++ definite, and barely perceptible; and akinesia ++++ almost totally immobile, +++ extremely slow, ++ slow, and + occasionaly slow. The grading of associated movements, shuffling, festination, salivation and lacrimation is listed in an unabridged preprint of this paper. Motion pictures displayed information more objectively than this grading.

Induction of improvement

RESULTS

Slow, gradually increasing administration of L-dopa to a level of large doses and gradual mobilization of the patients again constituted the difference between failure and success. In several cases, a time lag between reaching a certain dose and achieving maximal benefit seemed to exist. This extended in some cases to several days. Rapid increase of the daily dose was often thwarted by nausea or vomiting, and rapid mobilization by faintness.

The induction of therapeutic effects was variable (Table 2). The patients were divided into inpatients (Cases 1-16) and discharged ones (Cases 17-28). In each subdivision, they were ranked on the basis of the duration of their illness. C

A

B

FIGURE 1. Ergograms from the Right Hand of Case 12, in the Basal State (A), on 4.2 Gm of 1-Dopa per Day (B) and on 5.7 Gm of L-Dopa per Day (C) (Reproduced by Permission of the Asso

In the group as a whole at least partial improvement of some manifestations was induced for at least several weeks in each case. Every symptom responded in this series, but not to the same degree in each patent. Individual improvement in performance ranged from modest to dramatic. In some cases the history of Parkinson's diseases seemed to have been retraced backward while slow titration with L-dopa was in progress. The sequence in which the signs of Parkinsonism responded seemed to be the following: first akinesia, then rigidity and finally tremor (Table 2). Tremor emerged occasionally after the rigidity was improved, responding after the drug was increased further. Improvement of associated movements, shuffling, dysphagia, aphonia, articulation, diaphoresis, lacrimation, salivation, seborrhea, ankle edema, handwriting, posture, festination and facial expression was usually striking, but it could not be fitted into the above sequence. Asignificant dysuria of various degrees was present in 12 patients. Administration of L-dopa abolished dysuria in all but two. In Case 12 a marked dilatation of the bladder and moderate hydronephrosis were almost reversed by L-dopa.* The erographic measurements (Fig. 1), the times required for various tasks and the steps required for 10 meters improved concordantly with other signs. These results will be reported after possible correlations with some biochemical measurements have been evaluated.

Modest improvement in general appearance, performance and state of wellbeing was induced in Cases 4, 12, 22 and 26. Yet in Cases 1 and 26, this appeared to be lifesaving, as discussed below. In Cases 4 and 22 the physical improvement was accompanied by a marked amelioration of outlook, interest and behavior. Moderate improvement was induced in Cases 1, 6, 7 and 23, who became self

*Dr. Morris R. Keen is our urologic consultant.

sufficient for a large part of the day. Marked improvement emerged in Cases 2, 3, 5, 9, 10, 17, 18, 20, 24 and 25, whose performance and appearance nevertheless remained recognizably typical of Parkinsonism for parts of the day. Dramatic amelioration evolved in Cases 8, 11, 13, 14, 15, 16, 19, 21, 27 and 28, whose appearance was virtually normal for most of the day, except for any fixed skeletal deformities.

Maintenance of therapeutic effects

Therapeutic results are considered in terms of diurnal deviation from optional performance and long-term duration.

Several patients reported minor, transitory episodes of suboptimal performance during the day, usually in the early afternoon. Redistribution of the daily dose was useful, but significant emotional or physical stress also induced such episodes, which were characterized by subjective weakness with or without tremor and hypokinesia lasting for a few minutes to about an hour. Significant fluctuations in diurnal performance were noted in Cases 1, 6, 7, 9, 12 and 24 soon after an optimal dose was achieved. In Cases 1 and 12 these took the form of an intermittent decline in performance as the day drew to a close. Sometimes, tremor, rigidity and even hypokinesia re-emerged. By contrast, in Cases 6, 7, 9 and 24 hypokinesia or akinesia lasting for between several minutes and a few hours developed abruptly and intermittently. Disproportionate anxiety was often present. In most patients both the overall performance and the improved state of health have been maintained at a steady state. Thirteen (Cases 9, 16-25, 27 and 28) have achieved outpatient status. Their changing life has often required readjustments of the daily dose or schedule. Cases 16, a carpenter, and 27, a trial lawyer, have returned to successful work, and Case 21, an administrator, is about to do so. Case 22 was transferred elsewhere. In Case 19, after about a year of virtual normalcy, intermittent short periods of tremor or hypokinesia alternating with periods of intermittent involuntary movements developed. Still, she is leading an active life. In Case 10 involuntary movements developed after many months of virtual normalcy, and in Case 6, the dose-dependent choreiform movements appear to be progressing. Four patients with extremely severe disease (Cases 1, 4, 9 and 26) seem to have derived further benefit from the coadministration of anticholinergic agents.

Over the last three years, several refractory periods have developed in Case 1. These initiated themselves with periods of suboptimal performance in the evening. His original tremor and rigidity remained notably absent, and his entire musculature became hypotonic. When he became weak, hyporeflexic and hypotonic during the entire day, loss of potency of L-dopa was erroneously surmised, and standard anti-Parkinsonism medications were given instead. This shift was followed by repaid re-emergence of tremor, extreme rigidity, also total akinesia, severe dysphagia, dysuria and, on one occasion, aspiration pneumonitis of great severity. Readministration of L-dopa, after a lapse of about 10 days, resulted in a striking improvement. Thereafter, he became recurrently self-sufficient and able to visit his family. Combating a refractory period with dopa induced the alarming episodes described below. Reversible but generalized muscular hypotonia was induced in Case 12 by superoptimal does of L-dopa.

Case 26 was admitted to the hospital for tests of rapidly progressing, extremely severe disease. Shortly thereafter aspiration pneumonitis developed. Addition of L-dopa to the previous medication prevented a gastrostomy by alleviating dysphagia. He gradually became able to feed himself, to walk with assistance and occasionally to talk. Dysphagia remained improved, but his other muscular functions slowly declined again over several months. We assumed that L-dopa had lost its potency. Interruption of L-dopa resulted in aspiration pneumonitis that responded to antibiotics and L-dopa therapy. After a year with us he was transferred to another hopsital, where unfortunately, the dopa supplied by us was not given. Aspiration pneumonitis led to death in spite of the late administration of L-dopa. Permission for autopsy was not granted.

Interruption and resumption of L-dopa administration

Several medical and surgical emergencies (listed under "Materials and Methods" as "treatable diseases accompanying Parkinsonism") caused the interruption of L-dopa therapy. Among these, fever due to pyelonephritis was repeatedly mistaken for drug fever. Upon clarification of each emergency, efforts were made to accelerate the readiministration of L-dopa. It seems that if more than three weeks had elapsed between interruption and reinstitution of the regimen one had to follow approximately the original schedule. Among several examples,

after a gastrectomy orthostatic hypotension with fainting developed in Case 24 while he was still receiving ineffective does of L-dopa. He tolerated much larger doses again when the rate of increase was slowed.

The drug was abruptly replaced by placebo for the evaluation of the underlying disease in 26 cases. This led to immediate re-emergence of Parkinsonism only in Case 1. Patients showing a significant diurnal variation reverted into Parkinsonism much more rapidly than those showing a steady state. The former reached a new plateau after a minimum of about four days, whereas a satisfactory state was maintained by the latter for much longer periods. In three patients (Cases 20, 21 and 25) approximately a month elapsed before significant symptoms reappeared, and this new plateau was less severe than the original basal state. The neurologic signs usually re-emerged in reverse sequence from that of their disappearance.

Side effects

These were limited to nausea, vomiting or anorexia, mental effects and involuntary movements.

Nausea and vomiting could usually be prevented by the slow, gradual adminisstration of L-dopa or the coadministration of protein-containing foods or both. Still, "sickness" or nausea, as well as vomiting, was occasionally present, particularly in women like Case 3 (as indicated below under "Alpha-Methyl Dopa Hydrazine"). Moderate, often transitory anorexia was experienced by some of the patients, particularly Case 3.

In Case 16 reversible irritability, anger, hostility and paranoid misinterpretation of innocuous comments developed only while he was receiving 6 to 8 gm of L-dopa per day. Transitory sleeplessness, requiring the use of hypnotics, was both frequent and bothersome. In addition to the improved mental state of Cases 4 and 22, a mental change best described as an "awakening effect" became evident in Cases 3, 8, 19, 20 and 25. In these patients improvement of listlessness, apathy, poor memory and lack of interest appeared to be out of phase both from the withdrawal of previous medications and from the eventual physical improvement induced by L-dopa. In others, an "awakening effect" was recognized during the physical improvement.

Involuntary movements, ranging from fleeting to severe, were seen in 14 patients. Rare, fleeting but definite myoclonus, grimacing or gnawing was exhibited by Cases 8, 13, 16 and 28. Occasional myoclonus associated with panting was noted in Cases 18 and 20. Intermittent gnawing was present almost daily in Cases 1, 2 and 12. Case 10 exhibited intermittent choreiform movements of the legs, more prominent on the more afflicted side. This disappearance on walking and swimming was recorded in moving pictures.

An intermittent wave-like motion of the head with or without gesticulation was seen initially in Cases 5, 6, 7 and 19. Superoptimal doses of L-dopa proved this to be partial hemiballismus: progressive extension into the arm, the forearm and finally the leg could be induced at will, on the side more severely affected by Parkinsonism. In Case 7 the side ipsilateral to the thalamotomy exhibited vigorous hemiballismus while the contralateral side remained at rest. During an attempt to combat a refractory period in Case 1, an alarming episode was induced: although conscious, he exhibited opisthotonos and conjugated deviation of head, eyes and upper trunk toward the side that was more affected. Rhythmic movements of the jaw and the left leg and loud screams all proceeded at a rate of 40 per minute. These lasted for 35 minutes, but re-emerged several hours after L-dopa was discontinued.

The most severe involuntary movements were induced among the patients whose disease had the longest duration-not necessarily among those with the most severe disease. These movements were linked to improved control of Parkinsonism, and their decline to the decrease of this control. They remained dose dependent in each case, but in the group as a whole, the highest doses did not necessarily induce the largest number of involuntary movements. Thus far, the episodes have remained intermittent and reversible. They have been well tolerated even when severe, possibly because it was known that we prefer the consequences of hypermobility to those of immobility.

12

A number of considerations may be pertinent to these movements. Administration of alpha-methyl dopa has resulted in diminution of cerebral dopamine levels. If this agent were to diminish pre-existing involuntary movements, one might surmise their correlation with increased cerebral dopamine levels. Since limiting the variables was a prime consideration, instead of a patient with Parkinsonism one with an advanced form of Huntington's chorea was studied.

A gradual increase in the doses of L-dopa up to 8.0 gm per day failed to affect the neurologic signs. By contrast, when D,L-alpha-methyl dopa administration reached 3.75 gm per day, a striking but intermittent diminution of the choreiform movements revealed itself, and signs of Parkinsonism remained absent during 38 days of treatment.

Toric effects

Statistically significant but moderate and labile hypertension emerged in Cases 1, 24 and 25. Also, hypertension was probably induced in Cases 5 and 10 whereas several others showed isolated spikes of the blood pressure. Low-salt diets have not improved this hypertension, and other regimens were considered unnecessary by our consultant. Orthostatic hypotension was noted in some patients, but was not statistically or clinically significant.

1,4

The granulocytopenia encountered with D,L-dopa was never a serious problem in our patients. After the transition from D,L to L-dopa the total circulating granuloceytes in Case 10 dropped to about 2000 per cubic millimeter. When her granulocytes were counted several times a day leukopenia and granulocytopenia were found during the mornings and not during the afternoons. The drugs was switched to a night schedule, which resulted in hematologic normalcy during the entire day. This persisted after a day schedule was resumed. Granulocytopenia in Case 19 was too short-lived for repetition of this observation. Moderate recurrent cosinophilia was found in some cases regardless of the use of Ldopa.

Elevations of the blood urea nitrogen did not exceed 30 mg per 100 ml and were readily controlled by forcing of fluids. Case 20 had premature ventricular beats that might have increased after administration of L-dopa. Hence, they were controlled with 0.4 gm of quinidine daily. Carotid-sinus syndrome was controlled in Case 24 with propantheline bromine (Pro-Banthine).

High values of protein-bound iodine, possibly attributable to the intake of Ldopa, were encountered in 18 patients. Re-examination of all patients and of their records revealed none of the manifestations of thyroid disease, with the exception of lid lag found among those with hemiballismus. Changes suggestive of thyroid disease were absent on review of the pulse rates, blood pressures, temperatures, serum cholesterol and cholesterol-ester levels. The special thyroid tests done thus far did not suggest induction of thyroid disease.

Cases 1 and 5 had shown diminished blood manganese levels while consuming D.L-dopa.1 There showed a gradual return to pretreatment values after the D,L was changed to the L-compound. Analyses performed by neutron activation, on seven patients showed mean blood manganese concentrations of 8.37±1.5μg per liter before treatment versus 8.39±1.8 μg per liter during treatment lasting up to 12 months.

Urinary excretion of dopa and some metabolites

The urinary concentrations of dopa were not measureable during valuation of the basal state. The average excretion of HVA by five patients was 3.93 mg. per 24 hours, where as that of dopamine was 0.25 mg per 24 hours. Upon administration of L-dopa the concentration of HVA in the urine became elevated. Individual plots of data from five patients showed a direct linear proportionality between the 24-hour excretion of HVA and the corresponding doses of L-dopa. However, the slope of the straight line varied significantly from one patient to the other, as will be detailed elsewhere. Still, a scattergram of 72 analyses representing 19 patients receiving 0.6 to 8.0 gm of L-dopa per day revealed a linear correlation between the 24-hour urinary outputs of HVA and the corresponding intakes of L-dopa. The proportion of L-dopa excreted as HVA was 23.4±0.3 per cent.

Measureable amounts of dopa were detected in the urine after 3.0 gm of L-dopa was administered per day. In 15 patients receiving 3.0 to 7.5 gm of L-dopa per day the output ranged between 2.8 and 41 mg per 24 hours, corresponding to 0.1 to 0.7 per cent of the dopa administered. An almost identical trend was displayed by the urinary concentrations of methoxytyrosine: its urinary excretion varied between 4.5 and 67 mg per 24 hours, or 0.5 to 1.0 per cent of the daily dose of L-dopa. A plot of the respective values against each other showed a linear correlation between the outputs of dopa and of methoxytyrosine.

In contrast to the above substances, it was the percentage of L-dopa excreted into the urine as dopamine that increased linearly with increasing daily doses of L-dopa. This figure reached about 5 per cent of the daily dose at 8.0 gm of L-dope per day, as was clearly evident in individual plots. These curves also