J Neurol (1991) 238 : 299-303

Journal of

Neurology

© Springer-Verlag 1991

Is progression in postencephalitic Parkinson's disease late and age-related? P. Vieregge 1, V. Reinhardt 2, and B. H6ft 3 1Klinik ftir Neurologie, Medizinische Universit~t zu Ltibeck, Ratzeburger Allee 160, W-2400 Liibeck, Federal Republic of Germany 2Institut ftir Neuropathologie, Klinikum der Gesamthochschule, W-4300 Essen, Federal Republic of Germany 3Psychiatrische Klinik der Heinrich-Heine-Universit~t, W-4000 Dtisseldorf, Federal Republic of Germany Received July 19, 1990 / Received in revised form December 13, 1990 / Accepted December 21, 1990

Summary. Follow-up data are presented of ten patients with autopsy-proven postencephalitic Parkinson's synd r o m e (PEP) (mean age at death: 56.0 years) with regard to m o t o r and psychic deterioration over a period of institutional observation between 3 and 30 years. Four patients showed deterioration of their H o e h n - Y a h r score of at least one grade. These patients did not differ statistically with respect to age of occurrence of lethargic encephalitis, interval to PEP, age at start of PEP, duration of survival with PEP, and age at death. M o t o r deterioration in these patients seems to be attributed m o r e to inherent disease progression, rather than to an age-related process. Clinical and pathological evidence for this conclusion is presented. Key words: Postencephalitic parkinsonism - Aging Basal ganglia - Encephalitis lethargica

Introduction Until recently, lethargic encephalitis (EL; von Economo's disease) and its sequelae have been mainly regarded as a matter of medical history. Its leading clinical consequence, i.e. postencephalitic parkinsonism (PEP) has, however, attracted renewed interest in recent years for several reasons: 1. Single encephalitic cases with parkinsonism as their leading clinical feature raise the question whether sporadic E L still exists [11, 16]. 2. Midbrain involvement in P E P may today serve as one heuristic access to the understanding of disorders presently attributed at least in part to midbrain pathology, i.e. obsessive-compulsive disorder [18], tic disorders, especially Gilles de la T o u r e t t e ' s syndrome [4, 21], and features of tardive dyskinesia or tardive dysphrenia [6]. Offprint requests to: P. Vieregge

3. The main interest, however, lies in the comparison between P E P and the parkinsonian syndrome caused by M P T P [8]. In both conditions, a single pathogenetic incident afflicts the substantia nigra (SN), resulting clinically in a parkinsonian syndrome. The time t a k e n to establish parkinsonism i.e. the "free interval", is, however, sometimes considerably longer in P E P than in M P T P Parkinsonism [8]. It has been suggested that in idiopathic Parkinson's disease (IPD) subclinical damage to the SN may, after many years, be followed by an age-related attrition of the nigral neurons leading to parkinsonism in the later decades of life [2]. In support of this hypothesis of age-related attrition, a previous clinical report found progressive m o t o r deterioration in 10 of 11 P E P patients over at least 66 years of age, when rated retrospectively [3]. On the other hand, counts of pigmented cells of SN in P E P and I P D did not indicate an age-related decrease of this p a r a m e ter, when disease durations between P E P and I P D of early and late onset were c o m p a r e d [8]. H o w e v e r , the m e r e consideration of nerve cell numbers m a y somewhat neglect their functional capacities. In order to restudy this issue of progression in P E P the following clinico-pathological investigation was undertaken.

Patients and methods Hospital records A review of case records was made from a total of 29 patients with the definite or presumed diagnosis of postencephalitic parkinsonism at postmortem examination. All patients were treated in the Rheinische Landesklinik - Psychiatrische Klinik der HeinrichHeine-Universit~tt Dtisseldorf, a large mental hospital, for varying numbers of years. Nineteen patients had to be excluded either because of a lack of sufficient clinical documentation, or too short an observation period for the scope of the present study. Thus, ten patients were included in this study. The pertinent case records were reviewed for data relevant to previous EL, for observations on the clinical course prior to admission, for the observations dur-

300 ing the whole in-patient stay regarding parkinsonian and psychopathological symptoms, drug treatments, and for behavioural and social observations. The ten patients were admitted because of psychiatric disturbances or social conflicting behaviour: exogenic psychoses (2 cases), obsessive-compulsive behaviour (2 cases), episodes of agitation (1 case), helpless and often unmarried state, not able to care for themselves (5 cases). The patients were housed in wards of this mental hospital. Five of them participated, at least sometimes, either in minor household or gardening work, or even occupational therapy at a subindustrial level. None of the patients received a special diet. After admission, the patients were in the hospital for treatment and custodial reasons for between 3 and 30 years.

Motor assessment Since the study was retrospective from postmortem diagnoses, none of the patients could be assessed clinically for the purpose of this study by any of the authors personally. As frequencies of postmortem examinations have fallen considerably in recent decades [20], no patient could be included in a prospective way to permit his or her follow-up until the postmortem examination in the last 15 years. Clinical and especially motor evaluation therefore had to rely completely on the notes about the long-term observations on the patients, as written in the patients' records. Changes in behaviour, psychopathology, drug treatment, occurrence of intermittent diseases or even new aetiopathogenetic aspects were found listed for the individual patients to a varying degree, dependent on the experience of the respective neuropsychiatrist in charge. Most of these physicians, however, were on duty for several years, thus becoming intimately acquainted with their patients and their clinical problems. Aside from the historical data all symptoms relevant to parkinsonism were recorded. Staging according to Hoehn-Yahr scale criteria was done for every patient following the record's admission data [10]. Any change of motor state, when leading to a different score on the Hoehn-Yahr scale, was listed for the age indicated in the records. A detailed motor score, as for instance in scale III of the UPDRS, was not possible in this form of case evaluation [7].

Pathological evaluation Autopsies were done at most 48 h after death in a special autopsy suite. General autopsy findings were taken from the autopsy records. Mid-brain and brain-stem slices were taken from formalinfixed brain tissue or from the neuropathological archives for review. Detailed cell counts were not possible. More detailed pathological findings from this review have been presented elsewhere [19].

Results

Patients Seven m e n and three w o m e n were studied. Their age at the d e v e l o p m e n t of E L r a n g e d f r o m 4 to 29 years with a m e a n of 17.0. T h e free interval after E L until the first s y m p t o m s of P E P was 1 - 2 6 years with a m e a n of 14.3. A g e at incipient P E P ranged f r o m 20 to 39 years with a m e a n of 31.3. T h e patients were in-patients in this institution for at least 3 up to a m a x i m u m of 30 years (mean 14.4). Survival with P E P was b e t w e e n 15 and 36 years with a m e a n of 24.7. O n admission, all patients had considerable m o t o r , vegetative and psychic disturbances due to P E P . N o n e was d e m e n t e d . T h e r e were no close-

ly associated illnesses in any of the patients except for no. 3, who had diabetes. No signs of a c c o m p a n y i n g neurological disease other than sequelae of E L were enc o u n t e r e d in any of the patients prior to their immediate death. Seven patients had had the s o m n o l e n t - o p h t h a l m o plegic form of EL. In three cases the exact course was not stated. Residual signs of E L were o c u l o m o t o r in six (also oculogyric crises) and pupillomotor in five patients (lack of convergence reaction, spurious and/or delayed pupillary reactions towards light). F o u r patients had had sleep disturbances, two of t h e m narcolepsy. All patients had definite P E P according to the criteria of Duvoisin and Y a h r [5]. The cardinal features of parkinsonism were asymmetrical in four cases. Resting trem o r was present in chin (3 cases), tongue (7 cases), hands and arms (7 cases) and legs (3 cases). Nine patients had hypomimia; nine had hypokinesia. Rigor was detected in eight patients. Six patients had pro- or retropulsion. Small-stepped, shuffling gait was r e c o r d e d in seven patients. Speech difficulties were observed in three patients with palilalia in a n o t h e r two. Five patients had a bent-forward posture of the trunk. T w o patients had dystonic foot postures, one a dystonic laterocollis, and one a thalamic hand. Sebaceous skin changes were n o t e d in five patients. All patients had hypersalivation; three suffered from attacks (or crises) of profuse sweating. All patients had psychic disturbances to a varying degree: irritability (6 cases), p o o r affectivity (4 cases), m o o d changes (5 cases), reduced impulse (6 cases), attacks of obsessive-compulsive b e h a v i o u r (4 cases) - in two cases in a time-locked association with oculogyric crises, hallucinations (2 cases), sudden attacks of crying and agitation (2 cases). All patients received anticholinergic drugs at different doses for between 3 and 29 years with at least partially sustained i m p r o v e m e n t . N o n e had received L-dopa preparations.

Analysis of disease course F r o m the case records a clinical staging of the patients was carried out regarding data at admission and prior to death using the H o e h n - Y a h r Scale [10]. The relevant data are shown in Table 1. A m o t o r deterioration was described in four patients (nos. 2 - 4 , 6), their H o e h n Y a h r score b e c o m i n g one grade worse during the observation period. The other six patients did not show m o t o r deterioration. These two groups with and without m o t o r deterioration did not statistically differ in m e a n values for age at suffering from E L , years of interval until P E P developed, age at incipient P E P , years as in-patients in this institution, years of survival with P E P , and age at death. N o n e of the patients had b e c o m e d e m e n t e d prior to death.

Pathological observations The m e a n age at death of all patients was 56.0 years. Causes of death were acute p u l m o n a r y disease in eight cases (e.g. tracheobronchitis, p n e u m o n i a , p u l m o n a r y embolism), cachexia in one, and stroke in one case.

301 Table 1. Clinical and pathological data of ten patients with postencephalitic parkinsonism (PEP), EL, Encephalitis lethargica; SN, substantia nigra; LC, locus coeruleus; A P D , acute pulmonary disease. + , mild; + + , marked; + + + , severe; - , absent Patient

1

2

3

4

5

6

7

8

9

10

Sex

M

F

M

F

M

M

M

M

M

F

Date of birth

1907

1909

1904

1913

1910

1903

1902

1904

1904

1910

Date of admission

1946

1952

1952

1950

1941

1938

1950

1934

1054

1965

Age at E L (years)

27

12

18

13

4

22

29

16

17

12

Internal to P E P (years)

1

24

21

20

16

10

2

8

20

21

Age at incipient P E P

28

36

39

33

20

32

31

24

37

33

Age at deterioration

47

-

52

44

-

-

60

-

-

-

Survival with PEP (years)

21

15

18

15

32

29

31

36

25

25

H o e h n - Y a h r score at admission

3

3

3

4

3

2

3

3

3

3

H o e h n - Y a h r score prior to death

4

3

4

5

3

2

4

3

3

3

Date of death

1956

1960

1961

1961

1962

1964

1964

1964

1966

1968

Age at death

49

51

57

48

52

61

62

60

62

58

Cause of death

Stroke

APD

APD

APD

Cachexia

APD

APD

APD

APD

APD

Nerve cell loss SN LC

+++ +++

++ ++

+++ +++

+++ +++

++ ++

+++ +++

++ ++

++ ++

+++ +++

+++ +++

Phagocytosis of melanin pigment SN LC

+++ +++

+ +

++ ++

+++ ++

+ +

++ ++

+ +

+ +

+++ +++

+++ +++

Neurofibrillar tangles SN LC

-

+ +

+ +

+ +

-

-

-

+ +

-

+ +

Gliosis SN LC

++ ++

+ +

+ +

+ +

+ +

+ +

+ +

+ +

++ ++

++ ++

Microglial reaction SN LC

+++ +++

-

-

++ ++

+ +

. .

Neuronophagia SN LC

+ +

+ +

+ +

++ ++

+ +

+ +

+ +

+ +

++ ++

+ +

Lewy bodies present SN LC

No No

No No

No No

Single No

No No

No No

No No

No No

No No

Single Yes

Similar changes of other pigmented brain-stem nuclei

Yes

No

Yes

Yes

Yes

No

Yes

No

Yes

Yes

Examination of brain histology disclosed the known f e a t u r e s o f P E P i n t h e S N ( T a b l e 1): a m a j o r p r o p o r t i o n o f n e u r o n s , i n s o m e c a s e s e v e n all, w e r e m a r k e d l y d e p i g mented. Likewise a considerable loss of neurons was s e e n , w h i c h i n s o m e c a s e s a l s o a f f e c t e d t h e l a t e r a l cell groups. Occasionally single preserved neurons were encountered. Similar changes were seen in the locus coeruleus with both areas showing a mostly dense fibrillary gliosis in the affected regions. Neurofibrillary tangles were seen in SN and locus coeruleus to a varying degree.

. .

. .

. .

. .

Single Lewy bodies in two typical PEP cases did not rule o u t t h e d i a g n o s i s [9]. M i c r o g l i a l r e a c t i o n s w e r e m i n o r ( c a s e s 1, 4, 5 ) , b u t p r e s e n t i n t w o c a s e s w i t h m o t o r d e t e r i o r a t i o n w h o d i e d a t a g e 4 9 a n d 48 y e a r s r e s p e c t i v e l y .

Discussion T h i s s t u d y w a s o f 10 c a s e s o f P E P , all h a v i n g s u f f e r e d f r o m d e f i n i t e E L [5]. A l l w e r e p r o v e n t y p i c a l c a s e s o f

302 P E P when examined histologically. Since the investigation was retrospective, it had to rely completely on clinical records dating back to the mid-1930s, when rating scores regarding parkinsonian motor and other symptoms were not used. Clinical observation was, however, always done by several experienced neuropsychiatrists. As all cases were in-patients in the institution for many years, close observation by doctors and nurses was maintained. Thus, non-clinical information on the behaviour of the patients, e.g. in household or gardening activities, could also be provided. It had not been possible to have the patients filmed. All patients were admitted because of psychic or behavioural disturbances. This could have led to minor appreciation of motor signs. The case records gave no indication in any case that deterioration in psychopathology took place. We were specially alerted to this, since such signs may be missed by application of simple motor scores. We could, on the other hand, not evaluate whether motor impairment itself would be less in our patients than in cases with minor psychopathological changes, since a control sample could not be set up. With such restraints in mind, it was quite possible to define a circumscribed parkinsonian syndrome following an acute E L in all cases and to follow up their clinical course. P E P may start even years after E L with about 80% of patients having a "free interval" of equal to or less than 15 years [5]. Mean "free interval" in our sample was 14.3 years. Also the mean age of onset of PEP was comparable with that of the series of Duvoisin and Yahr [51. It has been inferred by Calne and Lees [3] that PEP may further deteriorate when the patient reaches advanced age. This was observed in 10 out of 11 PEP patients of the study from a London long-term care unit. All patients were 66 years and older [3]. In our study the observation of progressive motor deterioration was made in four out of ten patients. The two groups in our study, with and without clinical deterioration, did not differ statistically when compared for means of several age parameters: age at suffering from EL, "free interval" duration to PEP, age at start of PEP, survival time with PEP, or age at death. None of our patients had intellectual decline or degenerative changes in special senses (e.g. eye, ear). It has been suggested that age-related neuronal attrition may play a role in several neurodegenerative conditions [2]. P E P has been proposed to be an "ideal disorder" to study the issue of age-related attrition of previously damaged nerve cells. Therefore, it may be useful to compare the findings of the present study with those of the London patients, who, however, could be observed prospectively [3]. Most obvious, at first, is the disparity of age distribution among the patients investigated. The older patient group from L o n d o n is most likely a sample of PEP patients having survived until old age as the fittest from a larger P E P population. This is substantiated by the comparatively low disease affliction, as represented by the scores of the 1979 motor evaluation. This would, consequently, mean that a proportion of the more severely

impaired patients from that sample has already died. The average distribution in our patients was considerably younger (mean age at death: 56.0 years). So, if age changes played a major role in motor deterioration, such deterioration should either not have been observable in our younger age group, or should be due to causes other than simple aging. Conversely, if the motor deterioration in the London group were not due to mere aging, other causes must have accounted for that deterioration. Age, as one factor contributing to progression of a given disease, has to be differentiated from other possible contributors, if the clinical state of individual patients is considered. 1. The severity of symptoms at the start of the disease, i.e. symptoms of EL, may be different in degree, evolution and duration in different patients. The age at which the encephalitogenic illness occurs may also be different, and all factors may affect the type of disease progression. While these issues were not mentioned in the London report, there was no indication in our study that these parameters were different for the patient groups with and without motor deterioration. 2. Intercurrent medical or surgical illness may interfere with an underlying disease, as also well known for PEP [13]. Older age groups are prone to multimorbidity. While age at death in our study was comparably low and signs for atherosclerosis, for example, elsewhere in the body were scarce at autopsy, such findings were only mentioned in part from the clinical viewpoint of the London study. 3. Environmental factors, such as diet, drinking habits, or life style, may have changed and may also change an underlying disease (e.g. alcohol abuse). All of our patients (except one diabetic) received the same diet while under institutional care, and the same can be assumed for the London sample, which was also from an institution. These factors, therefore, can be disregarded for the present discussion. 4. Most important, however, is the issue whether pathology and/or pathophysiology of a given disease may itself be enrolled in the progressive disease course [14]. It has long been known clinically that a proportion of patients with PEP have slow and insidious progression after the onset of disease, while another group have not. In the series of Duvoisin and Yahr [5] 10 out of 28 definite, and 3 out of 7 probable PEP cases showed such deterioration. This corresponds fairly well to the proportion in our study (40%), all the patients being aged 60 years or younger. Also pathologically, a proportion of cases do not merely show nerve cell loss and subsequent fibrillary gliosis in the areas involved. Some cases also exhibit microglial reactions or neuronophagia, indicating more recent tissue changes by various causes [8, 9]. Formation of neurofibrillary tangles occurs in some cases irrespective of age to a quite variable degree in a distinct topical distribution, but it is not a universal finding [8, 9, 12]. Occurrence of neurofibrillary tangles indicates metabolic changes after and beyond the encephalitogenic nigral

303 l e s i o n [9]. T w o o f o u r d e t e r i o r a t i n g b u t fairly y o u n g p a tients h a d these m i c r o g l i a l changes. T h e o t h e r t w o , s o m e w h a t o l d e r , h o w e v e r , d i d n o t s h o w active i n f l a m m a t o r y c h a n g e s . T h e p a t h o l o g i c a l c h a n g e s i n h e r e n t in the prim a r y p a t h o g e n i c e v e n t thus v a r y . T h e y m u s t b e conside r e d , h o w e v e r , b e f o r e " a g i n g " p e r se is i n c l u d e d in an e x p l a n a t i o n o f t h e clinical v a r i a b i l i t y in P E P a n d also p r o g r e s s i o n l a t e r in t h e d i s e a s e c o u r s e . 5. A s p o i n t e d o u t b y C a l n e a n d L e e s [3], n e w s y m p t o m s a n d signs e m e r g i n g d u r i n g t h e c o u r s e of P E P h a v e to b e e v a l u a t e d , if t h e y a r e p e r t i n e n t to t h e d i s e a s e s p e c t r u m , or if t h e y a r e signs o f m o t o r i m p a i r m e n t as f o u n d in " n o r m a l a g i n g " . It has b e e n e m p h a s i z e d t h a t in P E P d y s t o n i c o r p o s t u r a l a b n o r m a l i t i e s m a y e m e r g e in t h e d i s e a s e c o u r s e [15]. I n o u r o p i n i o n t h e y s h o u l d n o t b e e v a l u a t e d as d u e to the aging m o t o r s y s t e m . P u r e l y senile d y s t o n i a , even w h e n c o n s i d e r e d d e g e n e r a t i v e , is r a r e [1]. W e w o u l d r e g a r d d y s t o n i a in P E P to b e m o r e l i k e l y a p a r t of the inh e r e n t d i s e a s e p r o c e s s . Its a t t r i b u t i o n to m e r e aging s e e m s unjustified. I n o u r s t u d y t h e d y s t o n i c a b n o r m a l ities in f o u r of o u r cases w e r e a l r e a d y n o t e d o n a d m i s sion, a n d n e i t h e r p r o g r e s s e d n o r e m e r g e d at a l a t e r d a t e . T h e p r e s e n t s t u d y , d e a l i n g with a g r o u p o f P E P p a t i e n t s , i n d i c a t e s t h a t d e t e r i o r a t i o n o f p a r k i n s o n i a n signs in s o m e p a t i e n t s s e e m s to b e d u e to an i n h e r e n t d i s e a s e p r o c e s s in the p r e s e n i l e a g e g r o u p . W h e t h e r this i n h e r e n t d i s e a s e p r o c e s s also acts in t h e o l d e r p a t i e n t g r o u p s r e m a i n s o p e n to d e b a t e . F o r P E P , a conclusive a n s w e r r e g a r d i n g the l a t t e r a n d o t h e r issues s e e m s , at p r e s e n t , i m p o s s i b l e , since it n o w r e p r e s e n t s an e x a m p l e o f m e d i cal h i s t o r y , an " u n d i s c o v e r ' d c o u n t r y , f r o m w h o s e b o u r n n o t r a v e l l e r r e t u r n s " [17].

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