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Clinical features of malignant syndrome in Parkinson's disease and related neurological disorders
Parkinsonism and Related Disorders 9 (2003) S15–S23 www.elsevier.com/locate/parkreldis
Clinical features of malignant syndrome in Parkinson’s disease and related neurological disorders Toshihide Haradaa,*, Kyoko Mitsuokaa, Rumi Kumagaia, Yoshio Murataa, Yumiko Kasedaa, Hidekazu Kameia, Fumiko Ishizakib, Shigenobu Nakamuraa a
Department of Clinical Neuroscience and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551 Japan b Hiroshima Prefectural College of Health Sciences, 1-1, Gakuen-machi, Mihara 723-0053 Japan
Abstract Introduction. We elucidated the cause and clinical characteristics of malignant syndrome (MS) in patients with Parkinson’s disease (PD), early-onset parkinsonism (EOP), and other neurological disorders. Materials and methods. Subjects were 260 patients with PD or EOP, and three patients with other neurological disorders associated with MS. We studied clinical symptoms before and after the onset of MS, and evaluated autonomic function particularly before the onset of MS. Results. The overall incidence of MS accompanying PD and EOP in our department was eight of 260 patients (3.1%). The incidence of MS in EOP was significantly higher than that in PD. All patients with MS showed comparatively longer duration of illness and advanced stage of PD and EOP. Factors triggering MS included reduced dosage or discontinuation of anti-parkinsonian drugs, reduction of oral intake, dehydration, infectious disease, postoperative state, and treatment with major tranquilizers. Although patients demonstrated marked autonomic symptoms at the onset of MS, in many cases autonomic dysfunction developed before the onset of MS. Even EOP patients, who usually demonstrated milder autonomic dysfunction, showed abnormalities in the correlation between circadian rhythm of blood pressure and pulse rate, and/or abnormal gastric emptying test, suggesting that autonomic dysfunction plays an important role in the cause of MS. Cooling the body, fluid replacement, resumption or increasing the dosage of anti-parkinsonian drugs and administration of dantrolene sodium overcame MS in all cases. Conclusion. Autonomic dysfunction is related to the cause and clinical features of MS in PD, EOP and some other neurological disorders. q 2003 Elsevier Science Ltd. All rights reserved. Keywords: Malignant syndrome; Parkinson’s disease; Early-onset parkinsonism; Autonomic dysfunction; Cause of onset
1. Introduction Malignant syndrome (MS) is not uncommon [1 – 4] following the withdrawal of anti-parkinsonian drugs from patients with Parkinson’s disease (PD) or as the result of administering dopamine depleting drugs to patients with PD and other neurological disorders. Autonomic symptoms associated with MS are sometimes life threatening especially in elderly patients. During the course of drug treatment for PD, patients or their caregivers sometimes reduce or discontinue levodopa abruptly; the reasons for this may be intercurrent infections, nausea and vomiting for any reason, or the development of delusions and hallucinations. In the past ‘drug holidays’ were used as a treatment for drug-induced intractable motor fluctuations in PD and this * Corresponding author. Tel.: þ 81-82-257-5201; fax: þ81-82-505-0490. E-mail address: [email protected] (T. Harada).
was another cause of MS. Thus patients with PD taking levodopa are at risk for developing MS. We undertook to study the causes and clinical features of MS that complicate PD, early-onset parkinsonism (EOP) [5] and other neurological diseases, focussing on autonomic dysfunction.
2. Subjects and methods We enrolled PD and EOP patients who attended our department between July 1991 and 1997, and who developed MS according to the diagnostic criteria proposed by Levenson [6]. PD patients were defined as adult onset patients with PD (age of onset above 40) and EOP patients were early onset patients with PD (age of onset before 40) [5,12]. We studied clinical symptoms before and after the onset of MS, the cause of MS, treatment, and clinical outcomes.
1353-8020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1353-8020(02)00124-4
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T. Harada et al. / Parkinsonism and Related Disorders 9 (2003) S15–S23
Fig. 1. The incidence of malignant syndrome (MS) as a complication of Parkinson’s disease (PD) and early-onset parkinsonism (EOP).
Although the patients demonstrated marked autonomic symptoms at the onset of MS, we were particularly interested in investigating the presence of autonomic symptoms before the onset. We also examined other neurological diseases associated with MS in a similar way as in patients with PD and EOP.
3. Results 3.1. Incidence The overall incidence of MS as a complication of PD and EOP in our department was 3.1%, 8 of 260 patients (Fig. 1, Table 1). The age at the time of examination was 62.4 ^ 11.7 (mean ^ SD) years in the PD and EOP patients without MS ðn ¼ 252Þ; and 56.3 ^ 12.7 years in the patients with MS ðn ¼ 8Þ: The duration of illness was 5.8 ^ 5.0 years in the group with PD and EOP without MS, and 13.2 ^ 11.2 years in the group with MS. The Hoehn and Yahr (HY) stage was 2.6 ^ 0.8 in the group without MS, and 3.5 ^ 0.5 in the group with MS. In the patients with MS, the duration of illness was significantly longer, and the HY stage higher than that in the patients without MS. The incidence of complications of MS was 2.1% (5 of 239 in PD patients) and 14.3% (three of 21 in EOP patients), showing a significantly higher value in the EOP group than that in the PD group (Fig. 1, Table 1). The age at the time of the examination was 61.2 ^ 11.0 years in the PD patients with MS, and 64.1 ^ 11.3 years in the PD patients without MS. The duration of illness was 7.9 ^ 3.9 years in the PD group with MS and 5.0 ^ 3.3 years in the group without MS. The HY stage was 3.4 ^ 0.5 in the PD group with MS and 2.7 ^ 0.8 in the group without MS. In the PD patients with MS, the duration of illness was significantly longer, and the HY stage was significantly higher than that in the PD
patients without MS. The age at the time of examination was 48.0 ^ 12.5 years in the EOP patients with MS, and 42.1 ^ 11.0 years in the patients without MS. The duration of illness was 22.2 ^ 14.8 years in the EOP group with MS and 12.6 ^ 7.3 years in the group without MS. The HY stage was 3.7 ^ 0.6 in the EOP group with MS and 2.6 ^ 1.0 in the group without MS. In the EOP patients with MS, the duration of illness was not significantly longer and the HY stage was not significantly higher than that in the EOP patients without MS, but the EOP patients with MS showed comparatively longer duration and a more advanced stage of illness (Fig. 1, Table 1). 3.2. Clinical characteristics of parkinsonism Table 2 shows the clinical features before the onset of MS in PD and EOP. All PD and EOP patients with MS had Table 1 Demographic data on the patients studied
Total No (PD þ EOP) Age Duration of illness Hoehn & Yahr No with PD Age Duration of illness Hoehn & Yahr No with EOP Age Duration of illness Hoehn & Yahr
Without MS
With MS
252 62.4 ^ 11.7 5.8 ^ 5.0 2.6 ^ 0.8 234 64.1 ^ 11.3 5.0 ^ 3.3 2.7 ^ 0.8 18 42.1 ^ 11.0 12.6 ^ 7.3 2.6 ^ 1.0
8 56.3 ^ 12.7 13.2 ^ 11.2** 3.5 ^ 0.5** 5 61.2 ^ 11.0 7.9 ^ 3.9* 3.4 ^ 0.5* 3 48.0 ^ 12.5 22.2 ^ 14.8 3.7 ^ 0.6
MS: malignant syndrome, PD: adult onset patients with Parkinson’s disease (age of onset above 40), EOP: early onset patients with Parkinson’s disease (age of onset before 40), *P , 0:05; **P , 0:01:
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‘wearing-off,’ and showed comparatively longer duration of illness and advanced stages of PD and EOP compared to those patients without MS. Psychiatric disorders such as hallucinations and delusions were noted in four patients, and dementia was found in two. PD patients exhibited various autonomic dysfunctions, such as constipation, urinary disturbance, oily face, orthostatic hypotension, impairment of peripheral circulation, dyshydrosis, and edema, while EOP patients demonstrated only mild autonomic symptoms, consisting of mild constipation and urinary disturbance.
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in two patients (Table 2). L -dopa, trihexyphenidyl hydrochloride (THP HCl), amantadine HCl, bromocriptine, droxidopa (L -DOPS), and tolcapone (a catechol-o-methyl transferase inhibitor: COMT inhibitor) were reduced or discontinued simultaneously in some patients. A reduced dosage or discontinuation of L -dopa was one of the most frequent causes of MS. It occurred within three or four days following a reduction in dosage or discontinuation of the drugs, and in six patients, MS developed during hot weather, i.e. from June through September in Japan. 3.4. Clinical features at the onset of MS
3.3. Cause of onset The causes of onset of MS included reduced dosage or discontinuation of anti-parkinsonian drugs in six patients, dehydration in three, and a reduction of oral intake in two. In addition, an infection and treatment with a major tranquilizer was noted in one patient each. These causes overlapped
Clinical features at the onset of MS are shown in Table 3. Most patients demonstrated hyperthermia, muscle rigidity and high levels of serum creatine kinase (CK), whereas some demonstrated an incomplete type such as patient 7, who had a normal body temperature without any notable autonomic symptoms. Patients manifested pronounced
Table 2 Clinical features before onset of malignant syndrome in Parkinson’s disease and early-onset parkinsonism Case Age*sex Diagnosis Duration Duration Hoehn and Wearing-off Phychiatric Dementia Autonomic of disease of therapy Yahr stage symptoms dysfunction (years) (years) 1
35*F
EOP
11.0
0.8
IV
þ
þ
2
urinary dusturbance, constipation
2
49*F
EOP
16.5
3.6
III
þ
2
2
constipation
3
51*F
PD
4.2
2.0
IV
þ
2
2
4
52*F
PD
11.1
10.5
III
þ
þ
þ
constipation urinary disturbance, orthostatic hypotension, disturbance of peripheral circulation constipation, decrease of skin temperature, orthostatic hypotension, CVR-R #
5
57*F
PD
3.1
3.0
III
þ
2
2
6
60*M
EOP
39.0
10.0
IV
þ
2
2
7
72*F
PD
10.2
9.3
III
þ
þ
2
8
74*M
PD
10.8
10.6
IV
þ
þ
þ
Cause of onset
intramuscular injection of haloperidol reduced dosage of antiparkinsonian drug dehydration
infection, reduction of oral intake, dehydration, reduced dosage or discontinuation of antiparkinsonia drug pollakisuria, hypersalivation, discontinuation of oily face antiparkinsonian drug constipation reduced dosage of antiparkinsonian drug constipation, oily face, discontinuation of hypohydrosis, tolcapone disturbance of peripheral circulation, pretibial edama constipation, oily face, reduction of oral orthostatic hypotension, intake, dehydration, pretibial edema discontinuation of antiparkinsonian drug
EOP: early-onset parkinsonism, PD: Parkinson’s disease, *CVR-R # : coefficient of variation of R-R interval.
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Table 3 Clinical features at onset of malignant syndrome in Parkinson’s desease and early-onset parkinsonism Case Diagnosis Body Muscle Serum Disturbance of Variation of Tachycardia Hyperhidrosis Change of Outcome temperature rigidity CK level consciousness blood pressure Hoehn and Yahr stage (8C) (IU/l) 1 2 3 4 5 6 7 8
EOP EOP PD PD PD EOP PD PD
37.8 37.2 39.2 38.2 37.4 38.2 36.3 39.0
þþ þþ þþ þþ þþ þþ þ þþ
222 11,013 2517 216 121 555 625 324
2 2 2 þþ 2 2 2 þ
2 2 þ þ 2 2 2 2
þ þ 2 2 þ þ 2 þ
þ þ 2 þ þ þ 2 þ
IV ! V III ! IV IV ! V III ! V III ! IV IV ! V III ! IV IV ! V
recovery recovery recovery recovery recovery recovery recovery deterioration
EOP: early onset parkinsonism, PD: parkinson’s disease, *normal range of serum CK: 30 t 120.
autonomic signs such as hyperthermia, hyperhidrosis, tachycardia, fluctuation in blood pressure, abnormal respiration and urinary disturbance. Some autonomic symptoms were observed even in EOP patients, who usually showed milder autonomic symptoms. Increased muscle rigidity was observed, and the HY stage progressed by 1 or 2 stages in all patients. An altered level of consciousness was noted in two patients and generalized convulsions in one patient,. The serum CK level, (normal range 30– 120 international unit/l (IU/l)), ranged widely between 121 and 11,013 IU/l. Rhabdomyolysis developed in two patients who showed serum CK levels of 2000 IU/l or more, but acute renal failure or disseminated intravascular coagulation (DIC) did not follow. Treatment consisted of adding or resuming anti-parkinsonian drugs, cooling the body, and fluid replacement. Only patient 2, who showed a serum CK level higher than 10,000 IU/l, received dantrolene (100 mg/day) in addition. An intramuscular injection of haloperidol to prevent hallucinations and delusions was discontinued in patient 1. MS resolved in all patients, and their parkinsonism recovered to the former state in all but one patient. 3.5. Case presentation Patient 7 was a 72-year-old woman with PD. Her parkinsonism began with a movement disorder in the fingers at 59 years of age, and gradually progressed. The following year, treatment with THP HCl was initiated, and then L dopa was added and gradually increased. Eight years later, she was in a debilitated state; drug-induced hallucination appeared, and her parkinsonism became uncontrollable. In 1995, 13 years after the onset, 300 mg/day of tolcapone, a COMT inhibitor, was administered orally. Because the patient felt so well, the drug was suspended for 3 days. Subsequently, her muscle rigidity, freezing gait, and hypokinesia worsened. After the tolcapone was discontinued, there were no marked autonomic symptoms such as hyperthermia, hyperhidrosis or tachycardia, although there was an aggravation of her parkinsonism. However,
the serum CK level increased to 625 IU/l. The attending physician believed that she had incomplete MS and told the patient to resume tolcapone. The patient recovered without further difficulty. In patient 7 (PD patient), autonomic dysfunctions such as constipation, oily face, hypohidrosis, and orthostatic hypotension were noted before the onset of MS. Cutaneous blood flow was decreased in the peripheral part of the limbs. Fig. 2 shows the results of gastric emptying assessed by an acetaminophen (AAP) test [7,8]. Since AAP is not absorbed by the stomach but rapidly absorbed by the duodenum or more distal parts of the intestine, the time course of the blood level after oral administration of AAP reflects the gastric emptying time. In patient 7, the AAP level remained low until 60 min after ingestion, suggesting a gastric emptying disorder. Fig. 3 shows the circadian rhythm of blood pressure and pulse rate (PR) in patient 7. A non-dipper type circadian rhythm was observed, and the correlation between systolic blood pressure (SBP) and PR disappeared (Fig. 3). In parkinsonian patients and patient 7, the correlation coefficient between SBP and PR was significantly lower than that in healthy controls [9,10] (Fig. 3). Fig. 4 shows the clinical course of patient 6 (EOP patient). This patient was diagnosed as ‘autosomal recessive EOP [11] with diurnal fluctuation (AR-EPDF)’ reported by Yamamura et al. [12]. In January 1996, about 40 years after the onset, the oral dose of L -dopa was decreased from 600 to 400 mg on the patient’s own initiative in order to suppress dyskinesia. This reduction of L -dopa led to the development of MS several days later. Increasing the L -dopa dose, cooling the body, and fluid replacement resulted in a rapid recovery. An AAP test before the onset of MS was performed. The plasma AAP levels between 15 and 45 min were low, indicating a gastric emptying disorder with an autonomic dysfunction. Circadian rhythms of the blood pressure and PR before the onset of MS were studied. The circadian blood pressure rhythm was characterized as the dipper type. However, there was a negative correlation between the blood pressure and PR, showing a minus number as the correlation coefficient. Changes in plasma
T. Harada et al. / Parkinsonism and Related Disorders 9 (2003) S15–S23
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Fig. 2. Time course of plasma acetaminophen concentration after oral administration in healthy controls, parkinsonian patients and patient 7. In patient 7 and parkinsonian patients, the plasma acetaminophen level remained low until 60 min after ingestion compared with that in healthy controls, suggesting a gastric emptying disorder.
dopamine and L -dopa levels were examined during the recovery period from MS (Fig. 5). Despite being treated with frequent and divided doses of anti-parkinsonian drugs, pronounced circadian variations of plasma dopamine and L dopa levels were noted. Thereafter, incomplete MS comprised of increased muscle rigidity, hyperhidrosis, mild fever, and high level of serum CK, developed twice without any reduction in the dose of anti-parkinsonian drugs. These symptoms were also treated by cooling the body and with fluid replacement. The clinical features of other neurological diseases before and at the onset of MS are summarized in Tables 4
and 5. At the onset of MS all three patients demonstrated hyperthermia, high levels of serum CK, extrapyramidal tract signs, and various autonomic symptoms (Table 5). Patient 9 was treated for schizophrenia at another hospital and had taken several major tranquilizers including haloperidol (21 mg/day) by mouth over the previous 5 years. A cerebral infarction occurred in an extensive region of the left middle cerebral artery territory (left putamen, internal capsule, temporal lobe, parietal lobe, and hypothalamic feeding arteries), which was then complicated by aspiration pneumonia. During the recovery period (5 days after the cerebral infarction), a nasal administration of
Fig. 3. Circadian rhythm of blood pressure and pulse rate in patient 7. A non-dipper type circadian rhythm was observed (a), and the correlation between Systolic blood pressure (SBP) and pulse rate (PR) disappeared (b). In parkinsonian patients and patient 7, correlation coefficient between SBP and PR was significantly lower than that in healthy controls (c).
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Fig. 4. Clinical course in patient 6 (EOP patient). The reduction of L -dopa led to the development of malignant syndrome (MS). Thereafter, incomplete MS developed twice without reducing the anti-parkinsonian drug dosage. These episodes of MS were treated by cooling the body and with fluid replacement.
haloperidol (2.25 mg/day) was resumed at a low dose. MS developed the next day. Patient 10 was a 55-year-old man with Shy-Drager syndrome. MS was triggered by a reduction of his L -dopa dose and a urinary tract infection. Shy-Drager syndrome had developed at 49 years of age, with autonomic symptoms such
as orthostatic hypotension, impotence, edema, urinary disturbance, paridrosis, and Horner’s syndrome. Cerebellar ataxia and extrapyramidal tract signs were also noted. The patient had taken L -dopa orally for extrapyramidal tract symptoms since 54 years of age. A head-up tilt test resulted in severe orthostatic hypotension before the onset of MS.
Fig. 5. Circadian variation of plasma dopamine and L -dopa level in patient 6. Despite being treated with frequent and divided doses of anti-parkinsonian drugs, pronounced circadian variations were noted.
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Table 4 Clinical features before onset of malignant syndrome in other neruological disorders Case
Age*sex
Diagnosis
Duration of disease (years)
Duration of therapy (years)
Neurological findings
Autonomic dysfunction
Cause of onset
9
52*M
Sch
30
5.3
hallucination and delusion
unknown
10
55*M
SDS
6
0.7
cerebeller ataxia extrapyramidal tract sign
11
67*F
Dep
9
9.0
2
orthostatic hypotension, impotence, pretibial edema, pollakisuria, urinary incontinence, residual urine, dyshidrosis Horner’s syndrome unknown
cerebral infarction, aspiration pneumonia, haloperidol p.o. reduction of L-dopa dose urinary tract infection
operation of colon cancer intramuscular injection of haloperidol
Sch: Schizophrenia, SDS: Shy-Drager syndrome, Dep: depression.
Although pronounced orthostatic hypotension developed, the heart rate was not increased. The autonomic dysfunction was prominent. A glucose tolerance test revealed alimentary hypotension. A 123I-methaiodobenzylguanidine (MIBG) scintigraphic image in this patient showed a defect in the myocardial part. The uptake in the overall cardiac muscles was markedly decreased, indicating an extensive impairment of cardiac sympathetic nerve endings. With respect to circadian rhythm in blood pressure and heart rate, the day and night blood pressures were reversed, and the correlation between blood pressure and PR had disappeared. In addition, autonomic function tests such as a cold pressor test, Valsalva maneuver, measurements of the coefficient of variation in the R-R interval of ECG (CVR-R), noradrenaline test, drug instillation test, sympathetic skin response (SSR), and cystometry were performed. As a result, an extensive and pronounced autonomic dysfunction was revealed from the center to the periphery in both the sympathetic and parasympathetic nerves. The first MS appeared with a gradually decreasing dosage of L -dopa. Cooling the body, fluid replacement and increasing the L -dopa dosage facilitated recovery (Fig. 6). Thereafter, a second episode of incomplete MS, comprised of increased muscle rigidity, hyperhidrosis, mild fever, and high levels of serum CK developed without any reduction in the antiparkinsonian
drug dosage. These symptoms were also treated successfully by cooling the body and with fluid replacement (Fig. 6). In patient 11, MS developed 3 days after undergoing surgery for colon cancer, following two intramuscular injections of haloperidol (5 mg) given for insomnia. Extrapyramidal tract signs including marked dystonia in the neck, shoulder, and upper limbs as well as muscle rigidity and hypokinesia with mild fever were observed. Cooling the body and fluid replacement, discontinuation of haloperidol, and administration of dantrolene sodium (40 mg/day, intravenous injection, 3 days), and biperidine were effective in this patient.
4. Discussion The incidence of MS was five of 239 PD patients (2.1%) and three of 21 EOP patients (14.3%), showing a higher rate in the EOP group. All PD and EOP patients with MS showed HY stage of III or more, prolonged duration of illness, as well as a debilitated state. The episodes were triggered by a reduced dosage or discontinuation of antiparkinsonian drugs, reduction in oral intake, dehydration, infectious disease, cerebral infarction, and the postoperative
Table 5 Clinical features at onset of malignant syndrome in other neruological disorders Case
Diagnosis
Body temperature (8C)
Muscle rigidity
Serum CK (IU/l)
Unconsciousness
Variation of blood pressure
Tachycardia
Hyperhidrosis
Clinical course
Prognosis
9 10 11
Sch SDS Dep
38.2 38.8 37.8
þþ þþ þþ (with dystonia)
273(N:18 t 86) 567(N:30 t 120) 434(N:40 t 240)
þþ þ 2
2 þ þ
þ þ þ
þ þ þ
deterioration deterioration deterioration
recovery recovery recovery
Sch: schizophrenia, SDS: Shy-Drager syndrome syndrome, Dep: depression, N: normal range.
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Fig. 6. Clinical course of patient 10. The first episode of malignant syndrome (MS) appeared with a gradually decreasing dosage of L -dopa. Cooling the body, fluid replacement and increasing the L -dopa dosage facilitated recovery. Thereafter, a second episode of incomplete MS developed without a reduction in the anti-parkinsonian drug dosage. The MS was also treated by cooling the body and with fluid replacement.
state and treatment with a major tranquilizer, with some overlap of causes in some patients. The autonomic dysfunction had developed before the onset of MS in many cases. The time course of the blood level after oral administration of AAP reflects the gastric emptying time because AAP is not absorbed by the stomach but rapidly absorbed by the duodenum or more distal parts. The AAP level was significantly decreased 15 –60 min after oral administration in the PD group compared to that in the control group, indicating a prolonged gastric emptying time due to a reduced gastric emptying ability in the PD patients (Fig. 2). Each AAP level between 15 and 60 min correlated well with the CVR-R, and is generally considered a good index of parasympathetic function [7,8]. We investigated the circadian rhythms of the blood pressure and PR in healthy humans. Both blood pressure and PR showed a constant day-night rhythm in which the values were higher during the day and lower during the night (dipper-type rhythm). Thus, there was a significant correlation between the blood pressure and PR. The correlation coefficient was significantly lower in PD patients than that in healthy humans [9,10] (Fig. 3). Patient 7 also demonstrated an extremely low correlation coefficient. These abnormalities in circadian rhythms of the blood pressure and PR in PD patients are believed to impair the central autonomic nervous system [9,10]. Such
abnormalities in the biological rhythm are thought to be associated with the impairment of the supraoptic nucleus in the hypothalamus [13]. We therefore, suspect that there may be a relationship between MS and abnormalities in the circadian rhythms of the blood pressure and PR. We speculate that measurements of circadian rhythm of blood pressure and PR would be able to provide some clues in investigating the conditions in which MS occurs. There have been some reports demonstrating that imbalance among neurotransmitters and their receptors in the center for autonomic control, mainly the hypothalamus, is implicated in the development of MS. Namely, the dopamine-noradrenaline imbalance hypothesis [14] and dopamine-serotonin imbalance hypothesis [15] in the thermoregulatory center of the hypothalamus have been reported to be responsible. Even EOP patients, who are usually considered to demonstrate milder autonomic symptoms, showed abnormalities in the correlation between the circa the autonomic dysfunction does exist in EOP. Patient 6, an EOP patient, was treated with frequent and divided doses of antiparkinsonian drugs. This patient had pronounced circadian variations of blood L -dopa and dopamine levels while recovering from MS. Intracerebral dopamine kinetics are believed to demonstrate a marked circadian variation. Thus, it is speculated that there are conditions in which MS is more likely to develop, such as when changes in the receptor
T. Harada et al. / Parkinsonism and Related Disorders 9 (2003) S15–S23
sensitivity occur. Changes in the kinetics and neurotransmitter receptors such as dopamine, serotonin, and noradrenaline may also lead to conditions similar to those caused by altering the drug dosage. In addition, patients with conditions such as Shy-Drager syndrome (SDS) who show extensive and pronounced autonomic dysfunction, may be predisposed to MS. Changes in the kinetics and receptors of neurotransmitters such as dopamine, serotonin, and noradrenaline may also lead to conditions similar to those caused by altering drug amounts in patients with SDS. It is for these reasons therefore, that it is postulated that incomplete MS developed without a reduction in the antiparkinsonian drug dosage in patient 6, an EOP patient, and patient 10, an SDS patient. In conclusion, the factors in clinical background associated with the development of MS in PD, EOP and other neurological diseases associated with parkinsonism include high HY stage, long duration of disease, diurnal fluctuations such as ‘wearing off’, early-onset (EOP), the acute phase following organic or functional brain damage such as the acute stage of cerebrovascular disease or after general anesthesia, and overt or latent autonomic dysfunction. In patients with these background factors it is particularly important that levedopa should not be reduced or discontinued abruptly for any reason. Testing autonomic nervous system function may be useful for determining a patient’s susceptibility to MS. Cooling the body, fluid replacement, resuming or increasing the dosage of antiparkinsonian drugs and administering dantrolene helped all patients in overcoming MS. Thus, even when MS develops, the prognosis is good if it is detected and treated early by the appropriate methods. Because some patients demonstrated an incomplete pattern of MS, the possibility of MS should be considered when reducing the anti-parkinsonian drug dosage or administering major tranquilizers.
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Clinical features of malignant syndrome in Parkinson’s disease and related neurological disorders Toshihide Haradaa,*, Kyoko Mitsuokaa, Rumi Kumagaia, Yoshio Murataa, Yumiko Kasedaa, Hidekazu Kameia, Fumiko Ishizakib, Shigenobu Nakamuraa a
Department of Clinical Neuroscience and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551 Japan b Hiroshima Prefectural College of Health Sciences, 1-1, Gakuen-machi, Mihara 723-0053 Japan
Abstract Introduction. We elucidated the cause and clinical characteristics of malignant syndrome (MS) in patients with Parkinson’s disease (PD), early-onset parkinsonism (EOP), and other neurological disorders. Materials and methods. Subjects were 260 patients with PD or EOP, and three patients with other neurological disorders associated with MS. We studied clinical symptoms before and after the onset of MS, and evaluated autonomic function particularly before the onset of MS. Results. The overall incidence of MS accompanying PD and EOP in our department was eight of 260 patients (3.1%). The incidence of MS in EOP was significantly higher than that in PD. All patients with MS showed comparatively longer duration of illness and advanced stage of PD and EOP. Factors triggering MS included reduced dosage or discontinuation of anti-parkinsonian drugs, reduction of oral intake, dehydration, infectious disease, postoperative state, and treatment with major tranquilizers. Although patients demonstrated marked autonomic symptoms at the onset of MS, in many cases autonomic dysfunction developed before the onset of MS. Even EOP patients, who usually demonstrated milder autonomic dysfunction, showed abnormalities in the correlation between circadian rhythm of blood pressure and pulse rate, and/or abnormal gastric emptying test, suggesting that autonomic dysfunction plays an important role in the cause of MS. Cooling the body, fluid replacement, resumption or increasing the dosage of anti-parkinsonian drugs and administration of dantrolene sodium overcame MS in all cases. Conclusion. Autonomic dysfunction is related to the cause and clinical features of MS in PD, EOP and some other neurological disorders. q 2003 Elsevier Science Ltd. All rights reserved. Keywords: Malignant syndrome; Parkinson’s disease; Early-onset parkinsonism; Autonomic dysfunction; Cause of onset
1. Introduction Malignant syndrome (MS) is not uncommon [1 – 4] following the withdrawal of anti-parkinsonian drugs from patients with Parkinson’s disease (PD) or as the result of administering dopamine depleting drugs to patients with PD and other neurological disorders. Autonomic symptoms associated with MS are sometimes life threatening especially in elderly patients. During the course of drug treatment for PD, patients or their caregivers sometimes reduce or discontinue levodopa abruptly; the reasons for this may be intercurrent infections, nausea and vomiting for any reason, or the development of delusions and hallucinations. In the past ‘drug holidays’ were used as a treatment for drug-induced intractable motor fluctuations in PD and this * Corresponding author. Tel.: þ 81-82-257-5201; fax: þ81-82-505-0490. E-mail address: [email protected] (T. Harada).
was another cause of MS. Thus patients with PD taking levodopa are at risk for developing MS. We undertook to study the causes and clinical features of MS that complicate PD, early-onset parkinsonism (EOP) [5] and other neurological diseases, focussing on autonomic dysfunction.
2. Subjects and methods We enrolled PD and EOP patients who attended our department between July 1991 and 1997, and who developed MS according to the diagnostic criteria proposed by Levenson [6]. PD patients were defined as adult onset patients with PD (age of onset above 40) and EOP patients were early onset patients with PD (age of onset before 40) [5,12]. We studied clinical symptoms before and after the onset of MS, the cause of MS, treatment, and clinical outcomes.
1353-8020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1353-8020(02)00124-4
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T. Harada et al. / Parkinsonism and Related Disorders 9 (2003) S15–S23
Fig. 1. The incidence of malignant syndrome (MS) as a complication of Parkinson’s disease (PD) and early-onset parkinsonism (EOP).
Although the patients demonstrated marked autonomic symptoms at the onset of MS, we were particularly interested in investigating the presence of autonomic symptoms before the onset. We also examined other neurological diseases associated with MS in a similar way as in patients with PD and EOP.
3. Results 3.1. Incidence The overall incidence of MS as a complication of PD and EOP in our department was 3.1%, 8 of 260 patients (Fig. 1, Table 1). The age at the time of examination was 62.4 ^ 11.7 (mean ^ SD) years in the PD and EOP patients without MS ðn ¼ 252Þ; and 56.3 ^ 12.7 years in the patients with MS ðn ¼ 8Þ: The duration of illness was 5.8 ^ 5.0 years in the group with PD and EOP without MS, and 13.2 ^ 11.2 years in the group with MS. The Hoehn and Yahr (HY) stage was 2.6 ^ 0.8 in the group without MS, and 3.5 ^ 0.5 in the group with MS. In the patients with MS, the duration of illness was significantly longer, and the HY stage higher than that in the patients without MS. The incidence of complications of MS was 2.1% (5 of 239 in PD patients) and 14.3% (three of 21 in EOP patients), showing a significantly higher value in the EOP group than that in the PD group (Fig. 1, Table 1). The age at the time of the examination was 61.2 ^ 11.0 years in the PD patients with MS, and 64.1 ^ 11.3 years in the PD patients without MS. The duration of illness was 7.9 ^ 3.9 years in the PD group with MS and 5.0 ^ 3.3 years in the group without MS. The HY stage was 3.4 ^ 0.5 in the PD group with MS and 2.7 ^ 0.8 in the group without MS. In the PD patients with MS, the duration of illness was significantly longer, and the HY stage was significantly higher than that in the PD
patients without MS. The age at the time of examination was 48.0 ^ 12.5 years in the EOP patients with MS, and 42.1 ^ 11.0 years in the patients without MS. The duration of illness was 22.2 ^ 14.8 years in the EOP group with MS and 12.6 ^ 7.3 years in the group without MS. The HY stage was 3.7 ^ 0.6 in the EOP group with MS and 2.6 ^ 1.0 in the group without MS. In the EOP patients with MS, the duration of illness was not significantly longer and the HY stage was not significantly higher than that in the EOP patients without MS, but the EOP patients with MS showed comparatively longer duration and a more advanced stage of illness (Fig. 1, Table 1). 3.2. Clinical characteristics of parkinsonism Table 2 shows the clinical features before the onset of MS in PD and EOP. All PD and EOP patients with MS had Table 1 Demographic data on the patients studied
Total No (PD þ EOP) Age Duration of illness Hoehn & Yahr No with PD Age Duration of illness Hoehn & Yahr No with EOP Age Duration of illness Hoehn & Yahr
Without MS
With MS
252 62.4 ^ 11.7 5.8 ^ 5.0 2.6 ^ 0.8 234 64.1 ^ 11.3 5.0 ^ 3.3 2.7 ^ 0.8 18 42.1 ^ 11.0 12.6 ^ 7.3 2.6 ^ 1.0
8 56.3 ^ 12.7 13.2 ^ 11.2** 3.5 ^ 0.5** 5 61.2 ^ 11.0 7.9 ^ 3.9* 3.4 ^ 0.5* 3 48.0 ^ 12.5 22.2 ^ 14.8 3.7 ^ 0.6
MS: malignant syndrome, PD: adult onset patients with Parkinson’s disease (age of onset above 40), EOP: early onset patients with Parkinson’s disease (age of onset before 40), *P , 0:05; **P , 0:01:
T. Harada et al. / Parkinsonism and Related Disorders 9 (2003) S15–S23
‘wearing-off,’ and showed comparatively longer duration of illness and advanced stages of PD and EOP compared to those patients without MS. Psychiatric disorders such as hallucinations and delusions were noted in four patients, and dementia was found in two. PD patients exhibited various autonomic dysfunctions, such as constipation, urinary disturbance, oily face, orthostatic hypotension, impairment of peripheral circulation, dyshydrosis, and edema, while EOP patients demonstrated only mild autonomic symptoms, consisting of mild constipation and urinary disturbance.
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in two patients (Table 2). L -dopa, trihexyphenidyl hydrochloride (THP HCl), amantadine HCl, bromocriptine, droxidopa (L -DOPS), and tolcapone (a catechol-o-methyl transferase inhibitor: COMT inhibitor) were reduced or discontinued simultaneously in some patients. A reduced dosage or discontinuation of L -dopa was one of the most frequent causes of MS. It occurred within three or four days following a reduction in dosage or discontinuation of the drugs, and in six patients, MS developed during hot weather, i.e. from June through September in Japan. 3.4. Clinical features at the onset of MS
3.3. Cause of onset The causes of onset of MS included reduced dosage or discontinuation of anti-parkinsonian drugs in six patients, dehydration in three, and a reduction of oral intake in two. In addition, an infection and treatment with a major tranquilizer was noted in one patient each. These causes overlapped
Clinical features at the onset of MS are shown in Table 3. Most patients demonstrated hyperthermia, muscle rigidity and high levels of serum creatine kinase (CK), whereas some demonstrated an incomplete type such as patient 7, who had a normal body temperature without any notable autonomic symptoms. Patients manifested pronounced
Table 2 Clinical features before onset of malignant syndrome in Parkinson’s disease and early-onset parkinsonism Case Age*sex Diagnosis Duration Duration Hoehn and Wearing-off Phychiatric Dementia Autonomic of disease of therapy Yahr stage symptoms dysfunction (years) (years) 1
35*F
EOP
11.0
0.8
IV
þ
þ
2
urinary dusturbance, constipation
2
49*F
EOP
16.5
3.6
III
þ
2
2
constipation
3
51*F
PD
4.2
2.0
IV
þ
2
2
4
52*F
PD
11.1
10.5
III
þ
þ
þ
constipation urinary disturbance, orthostatic hypotension, disturbance of peripheral circulation constipation, decrease of skin temperature, orthostatic hypotension, CVR-R #
5
57*F
PD
3.1
3.0
III
þ
2
2
6
60*M
EOP
39.0
10.0
IV
þ
2
2
7
72*F
PD
10.2
9.3
III
þ
þ
2
8
74*M
PD
10.8
10.6
IV
þ
þ
þ
Cause of onset
intramuscular injection of haloperidol reduced dosage of antiparkinsonian drug dehydration
infection, reduction of oral intake, dehydration, reduced dosage or discontinuation of antiparkinsonia drug pollakisuria, hypersalivation, discontinuation of oily face antiparkinsonian drug constipation reduced dosage of antiparkinsonian drug constipation, oily face, discontinuation of hypohydrosis, tolcapone disturbance of peripheral circulation, pretibial edama constipation, oily face, reduction of oral orthostatic hypotension, intake, dehydration, pretibial edema discontinuation of antiparkinsonian drug
EOP: early-onset parkinsonism, PD: Parkinson’s disease, *CVR-R # : coefficient of variation of R-R interval.
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Table 3 Clinical features at onset of malignant syndrome in Parkinson’s desease and early-onset parkinsonism Case Diagnosis Body Muscle Serum Disturbance of Variation of Tachycardia Hyperhidrosis Change of Outcome temperature rigidity CK level consciousness blood pressure Hoehn and Yahr stage (8C) (IU/l) 1 2 3 4 5 6 7 8
EOP EOP PD PD PD EOP PD PD
37.8 37.2 39.2 38.2 37.4 38.2 36.3 39.0
þþ þþ þþ þþ þþ þþ þ þþ
222 11,013 2517 216 121 555 625 324
2 2 2 þþ 2 2 2 þ
2 2 þ þ 2 2 2 2
þ þ 2 2 þ þ 2 þ
þ þ 2 þ þ þ 2 þ
IV ! V III ! IV IV ! V III ! V III ! IV IV ! V III ! IV IV ! V
recovery recovery recovery recovery recovery recovery recovery deterioration
EOP: early onset parkinsonism, PD: parkinson’s disease, *normal range of serum CK: 30 t 120.
autonomic signs such as hyperthermia, hyperhidrosis, tachycardia, fluctuation in blood pressure, abnormal respiration and urinary disturbance. Some autonomic symptoms were observed even in EOP patients, who usually showed milder autonomic symptoms. Increased muscle rigidity was observed, and the HY stage progressed by 1 or 2 stages in all patients. An altered level of consciousness was noted in two patients and generalized convulsions in one patient,. The serum CK level, (normal range 30– 120 international unit/l (IU/l)), ranged widely between 121 and 11,013 IU/l. Rhabdomyolysis developed in two patients who showed serum CK levels of 2000 IU/l or more, but acute renal failure or disseminated intravascular coagulation (DIC) did not follow. Treatment consisted of adding or resuming anti-parkinsonian drugs, cooling the body, and fluid replacement. Only patient 2, who showed a serum CK level higher than 10,000 IU/l, received dantrolene (100 mg/day) in addition. An intramuscular injection of haloperidol to prevent hallucinations and delusions was discontinued in patient 1. MS resolved in all patients, and their parkinsonism recovered to the former state in all but one patient. 3.5. Case presentation Patient 7 was a 72-year-old woman with PD. Her parkinsonism began with a movement disorder in the fingers at 59 years of age, and gradually progressed. The following year, treatment with THP HCl was initiated, and then L dopa was added and gradually increased. Eight years later, she was in a debilitated state; drug-induced hallucination appeared, and her parkinsonism became uncontrollable. In 1995, 13 years after the onset, 300 mg/day of tolcapone, a COMT inhibitor, was administered orally. Because the patient felt so well, the drug was suspended for 3 days. Subsequently, her muscle rigidity, freezing gait, and hypokinesia worsened. After the tolcapone was discontinued, there were no marked autonomic symptoms such as hyperthermia, hyperhidrosis or tachycardia, although there was an aggravation of her parkinsonism. However,
the serum CK level increased to 625 IU/l. The attending physician believed that she had incomplete MS and told the patient to resume tolcapone. The patient recovered without further difficulty. In patient 7 (PD patient), autonomic dysfunctions such as constipation, oily face, hypohidrosis, and orthostatic hypotension were noted before the onset of MS. Cutaneous blood flow was decreased in the peripheral part of the limbs. Fig. 2 shows the results of gastric emptying assessed by an acetaminophen (AAP) test [7,8]. Since AAP is not absorbed by the stomach but rapidly absorbed by the duodenum or more distal parts of the intestine, the time course of the blood level after oral administration of AAP reflects the gastric emptying time. In patient 7, the AAP level remained low until 60 min after ingestion, suggesting a gastric emptying disorder. Fig. 3 shows the circadian rhythm of blood pressure and pulse rate (PR) in patient 7. A non-dipper type circadian rhythm was observed, and the correlation between systolic blood pressure (SBP) and PR disappeared (Fig. 3). In parkinsonian patients and patient 7, the correlation coefficient between SBP and PR was significantly lower than that in healthy controls [9,10] (Fig. 3). Fig. 4 shows the clinical course of patient 6 (EOP patient). This patient was diagnosed as ‘autosomal recessive EOP [11] with diurnal fluctuation (AR-EPDF)’ reported by Yamamura et al. [12]. In January 1996, about 40 years after the onset, the oral dose of L -dopa was decreased from 600 to 400 mg on the patient’s own initiative in order to suppress dyskinesia. This reduction of L -dopa led to the development of MS several days later. Increasing the L -dopa dose, cooling the body, and fluid replacement resulted in a rapid recovery. An AAP test before the onset of MS was performed. The plasma AAP levels between 15 and 45 min were low, indicating a gastric emptying disorder with an autonomic dysfunction. Circadian rhythms of the blood pressure and PR before the onset of MS were studied. The circadian blood pressure rhythm was characterized as the dipper type. However, there was a negative correlation between the blood pressure and PR, showing a minus number as the correlation coefficient. Changes in plasma
T. Harada et al. / Parkinsonism and Related Disorders 9 (2003) S15–S23
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Fig. 2. Time course of plasma acetaminophen concentration after oral administration in healthy controls, parkinsonian patients and patient 7. In patient 7 and parkinsonian patients, the plasma acetaminophen level remained low until 60 min after ingestion compared with that in healthy controls, suggesting a gastric emptying disorder.
dopamine and L -dopa levels were examined during the recovery period from MS (Fig. 5). Despite being treated with frequent and divided doses of anti-parkinsonian drugs, pronounced circadian variations of plasma dopamine and L dopa levels were noted. Thereafter, incomplete MS comprised of increased muscle rigidity, hyperhidrosis, mild fever, and high level of serum CK, developed twice without any reduction in the dose of anti-parkinsonian drugs. These symptoms were also treated by cooling the body and with fluid replacement. The clinical features of other neurological diseases before and at the onset of MS are summarized in Tables 4
and 5. At the onset of MS all three patients demonstrated hyperthermia, high levels of serum CK, extrapyramidal tract signs, and various autonomic symptoms (Table 5). Patient 9 was treated for schizophrenia at another hospital and had taken several major tranquilizers including haloperidol (21 mg/day) by mouth over the previous 5 years. A cerebral infarction occurred in an extensive region of the left middle cerebral artery territory (left putamen, internal capsule, temporal lobe, parietal lobe, and hypothalamic feeding arteries), which was then complicated by aspiration pneumonia. During the recovery period (5 days after the cerebral infarction), a nasal administration of
Fig. 3. Circadian rhythm of blood pressure and pulse rate in patient 7. A non-dipper type circadian rhythm was observed (a), and the correlation between Systolic blood pressure (SBP) and pulse rate (PR) disappeared (b). In parkinsonian patients and patient 7, correlation coefficient between SBP and PR was significantly lower than that in healthy controls (c).
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Fig. 4. Clinical course in patient 6 (EOP patient). The reduction of L -dopa led to the development of malignant syndrome (MS). Thereafter, incomplete MS developed twice without reducing the anti-parkinsonian drug dosage. These episodes of MS were treated by cooling the body and with fluid replacement.
haloperidol (2.25 mg/day) was resumed at a low dose. MS developed the next day. Patient 10 was a 55-year-old man with Shy-Drager syndrome. MS was triggered by a reduction of his L -dopa dose and a urinary tract infection. Shy-Drager syndrome had developed at 49 years of age, with autonomic symptoms such
as orthostatic hypotension, impotence, edema, urinary disturbance, paridrosis, and Horner’s syndrome. Cerebellar ataxia and extrapyramidal tract signs were also noted. The patient had taken L -dopa orally for extrapyramidal tract symptoms since 54 years of age. A head-up tilt test resulted in severe orthostatic hypotension before the onset of MS.
Fig. 5. Circadian variation of plasma dopamine and L -dopa level in patient 6. Despite being treated with frequent and divided doses of anti-parkinsonian drugs, pronounced circadian variations were noted.
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Table 4 Clinical features before onset of malignant syndrome in other neruological disorders Case
Age*sex
Diagnosis
Duration of disease (years)
Duration of therapy (years)
Neurological findings
Autonomic dysfunction
Cause of onset
9
52*M
Sch
30
5.3
hallucination and delusion
unknown
10
55*M
SDS
6
0.7
cerebeller ataxia extrapyramidal tract sign
11
67*F
Dep
9
9.0
2
orthostatic hypotension, impotence, pretibial edema, pollakisuria, urinary incontinence, residual urine, dyshidrosis Horner’s syndrome unknown
cerebral infarction, aspiration pneumonia, haloperidol p.o. reduction of L-dopa dose urinary tract infection
operation of colon cancer intramuscular injection of haloperidol
Sch: Schizophrenia, SDS: Shy-Drager syndrome, Dep: depression.
Although pronounced orthostatic hypotension developed, the heart rate was not increased. The autonomic dysfunction was prominent. A glucose tolerance test revealed alimentary hypotension. A 123I-methaiodobenzylguanidine (MIBG) scintigraphic image in this patient showed a defect in the myocardial part. The uptake in the overall cardiac muscles was markedly decreased, indicating an extensive impairment of cardiac sympathetic nerve endings. With respect to circadian rhythm in blood pressure and heart rate, the day and night blood pressures were reversed, and the correlation between blood pressure and PR had disappeared. In addition, autonomic function tests such as a cold pressor test, Valsalva maneuver, measurements of the coefficient of variation in the R-R interval of ECG (CVR-R), noradrenaline test, drug instillation test, sympathetic skin response (SSR), and cystometry were performed. As a result, an extensive and pronounced autonomic dysfunction was revealed from the center to the periphery in both the sympathetic and parasympathetic nerves. The first MS appeared with a gradually decreasing dosage of L -dopa. Cooling the body, fluid replacement and increasing the L -dopa dosage facilitated recovery (Fig. 6). Thereafter, a second episode of incomplete MS, comprised of increased muscle rigidity, hyperhidrosis, mild fever, and high levels of serum CK developed without any reduction in the antiparkinsonian
drug dosage. These symptoms were also treated successfully by cooling the body and with fluid replacement (Fig. 6). In patient 11, MS developed 3 days after undergoing surgery for colon cancer, following two intramuscular injections of haloperidol (5 mg) given for insomnia. Extrapyramidal tract signs including marked dystonia in the neck, shoulder, and upper limbs as well as muscle rigidity and hypokinesia with mild fever were observed. Cooling the body and fluid replacement, discontinuation of haloperidol, and administration of dantrolene sodium (40 mg/day, intravenous injection, 3 days), and biperidine were effective in this patient.
4. Discussion The incidence of MS was five of 239 PD patients (2.1%) and three of 21 EOP patients (14.3%), showing a higher rate in the EOP group. All PD and EOP patients with MS showed HY stage of III or more, prolonged duration of illness, as well as a debilitated state. The episodes were triggered by a reduced dosage or discontinuation of antiparkinsonian drugs, reduction in oral intake, dehydration, infectious disease, cerebral infarction, and the postoperative
Table 5 Clinical features at onset of malignant syndrome in other neruological disorders Case
Diagnosis
Body temperature (8C)
Muscle rigidity
Serum CK (IU/l)
Unconsciousness
Variation of blood pressure
Tachycardia
Hyperhidrosis
Clinical course
Prognosis
9 10 11
Sch SDS Dep
38.2 38.8 37.8
þþ þþ þþ (with dystonia)
273(N:18 t 86) 567(N:30 t 120) 434(N:40 t 240)
þþ þ 2
2 þ þ
þ þ þ
þ þ þ
deterioration deterioration deterioration
recovery recovery recovery
Sch: schizophrenia, SDS: Shy-Drager syndrome syndrome, Dep: depression, N: normal range.
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Fig. 6. Clinical course of patient 10. The first episode of malignant syndrome (MS) appeared with a gradually decreasing dosage of L -dopa. Cooling the body, fluid replacement and increasing the L -dopa dosage facilitated recovery. Thereafter, a second episode of incomplete MS developed without a reduction in the anti-parkinsonian drug dosage. The MS was also treated by cooling the body and with fluid replacement.
state and treatment with a major tranquilizer, with some overlap of causes in some patients. The autonomic dysfunction had developed before the onset of MS in many cases. The time course of the blood level after oral administration of AAP reflects the gastric emptying time because AAP is not absorbed by the stomach but rapidly absorbed by the duodenum or more distal parts. The AAP level was significantly decreased 15 –60 min after oral administration in the PD group compared to that in the control group, indicating a prolonged gastric emptying time due to a reduced gastric emptying ability in the PD patients (Fig. 2). Each AAP level between 15 and 60 min correlated well with the CVR-R, and is generally considered a good index of parasympathetic function [7,8]. We investigated the circadian rhythms of the blood pressure and PR in healthy humans. Both blood pressure and PR showed a constant day-night rhythm in which the values were higher during the day and lower during the night (dipper-type rhythm). Thus, there was a significant correlation between the blood pressure and PR. The correlation coefficient was significantly lower in PD patients than that in healthy humans [9,10] (Fig. 3). Patient 7 also demonstrated an extremely low correlation coefficient. These abnormalities in circadian rhythms of the blood pressure and PR in PD patients are believed to impair the central autonomic nervous system [9,10]. Such
abnormalities in the biological rhythm are thought to be associated with the impairment of the supraoptic nucleus in the hypothalamus [13]. We therefore, suspect that there may be a relationship between MS and abnormalities in the circadian rhythms of the blood pressure and PR. We speculate that measurements of circadian rhythm of blood pressure and PR would be able to provide some clues in investigating the conditions in which MS occurs. There have been some reports demonstrating that imbalance among neurotransmitters and their receptors in the center for autonomic control, mainly the hypothalamus, is implicated in the development of MS. Namely, the dopamine-noradrenaline imbalance hypothesis [14] and dopamine-serotonin imbalance hypothesis [15] in the thermoregulatory center of the hypothalamus have been reported to be responsible. Even EOP patients, who are usually considered to demonstrate milder autonomic symptoms, showed abnormalities in the correlation between the circa the autonomic dysfunction does exist in EOP. Patient 6, an EOP patient, was treated with frequent and divided doses of antiparkinsonian drugs. This patient had pronounced circadian variations of blood L -dopa and dopamine levels while recovering from MS. Intracerebral dopamine kinetics are believed to demonstrate a marked circadian variation. Thus, it is speculated that there are conditions in which MS is more likely to develop, such as when changes in the receptor
T. Harada et al. / Parkinsonism and Related Disorders 9 (2003) S15–S23
sensitivity occur. Changes in the kinetics and neurotransmitter receptors such as dopamine, serotonin, and noradrenaline may also lead to conditions similar to those caused by altering the drug dosage. In addition, patients with conditions such as Shy-Drager syndrome (SDS) who show extensive and pronounced autonomic dysfunction, may be predisposed to MS. Changes in the kinetics and receptors of neurotransmitters such as dopamine, serotonin, and noradrenaline may also lead to conditions similar to those caused by altering drug amounts in patients with SDS. It is for these reasons therefore, that it is postulated that incomplete MS developed without a reduction in the antiparkinsonian drug dosage in patient 6, an EOP patient, and patient 10, an SDS patient. In conclusion, the factors in clinical background associated with the development of MS in PD, EOP and other neurological diseases associated with parkinsonism include high HY stage, long duration of disease, diurnal fluctuations such as ‘wearing off’, early-onset (EOP), the acute phase following organic or functional brain damage such as the acute stage of cerebrovascular disease or after general anesthesia, and overt or latent autonomic dysfunction. In patients with these background factors it is particularly important that levedopa should not be reduced or discontinued abruptly for any reason. Testing autonomic nervous system function may be useful for determining a patient’s susceptibility to MS. Cooling the body, fluid replacement, resuming or increasing the dosage of antiparkinsonian drugs and administering dantrolene helped all patients in overcoming MS. Thus, even when MS develops, the prognosis is good if it is detected and treated early by the appropriate methods. Because some patients demonstrated an incomplete pattern of MS, the possibility of MS should be considered when reducing the anti-parkinsonian drug dosage or administering major tranquilizers.
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