part II

Japanese encephalitis (JE) part II: 14 Years’ follow-up of survivors

N. B. S. Sarkari, A. K. Thacker, S. P. Barthwal, V. K. Mishra, Shiv Prapann, Deepak Srivastava & M. Sarkari Journal of Neurology Official Journal of the European Neurological Society ISSN 0340-5354 J Neurol DOI 10.1007/ s00415-011-6131-9

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Author's personal copy J Neurol DOI 10.1007/s00415-011-6131-9

ORIGINAL COMMUNICATION

Japanese encephalitis (JE) part II: 14 Years’ follow-up of survivors N. B. S. Sarkari • A. K. Thacker • S. P. Barthwal • V. K. Mishra • Shiv Prapann • Deepak Srivastava • M. Sarkari

Received: 10 November 2010 / Revised: 14 May 2011 / Accepted: 21 May 2011 Ó Springer-Verlag 2011

Abstract Japanese encephalitis, the commonest Arbovirus encephalitis, has been endemic in many parts of Asia, the Pacific Islands, and India; also, there have been many epidemics. Most of the post JE cases have been associated with neurological and neuropsychiatric deficits but have not been properly classified and followed. Practically all the previous studies were in children or young adults. The aim of this study, involving only adult cases, the largest ever being reported, has been to follow the 688/1,199 survivors of JE patients out of 1,282 of acute cases admitted during four epidemics for a period of 14 years after properly classifying the sequelae. This prospective study was conducted in B.R.D. Medical College Gorakhpur N. B. S. Sarkari A. K. Thacker V. K. Mishra S. Prapann M. Sarkari Department of Medicine, B.R.D. Medical College, Gorakhpur 273013, India e-mail: [email protected] V. K. Mishra e-mail: [email protected] S. Prapann e-mail: [email protected] M. Sarkari e-mail: [email protected] S. P. Barthwal Department of Medicine, M.L.N. Medical College, Allahabad, India e-mail: [email protected] D. Srivastava Bharat Diagnostic Centre, Gorakhpur, India e-mail: [email protected] N. B. S. Sarkari (&) Maya Bazar, Gorakhpur 273001, UP, India e-mail: [email protected]; [email protected]

(India), involving 665/688 post JE cases with neuropsychiatric deficits from four epidemics of 1978, 1980, 1988 and 1989 which were properly classified in nine groups. While the first epidemic of 1978 was being studied, more disastrous episodes flared up and the patients were subsequently added. Hence, the total duration of this prospective study was from November 1978 to December 2003. There were 14 defaulted initially from 688 followed (23/688 without sequelae and 665/688 with neuropsychiatric deficits), and later 130 were lost from time to time at various stages of follow up. Four out of 23/688 discharged without any deficit had to be readmitted for bizarre movements, assaultative behaviour and euphoria without fever and altered sensorium. All of them improved by symptomatic treatment. Progressive improvement occurred in all the parameters consisting of psychological disturbances, higher cerebral dysfunction, speech disorders (dysphonia, dysarthria, dysphasias, apraxia and agnosia), extra pyramidal, pyramidal features, and hypothalamic disturbances, cranial nerves including pupils and fundi and seizures. Maximum cases improved between 6 months (55%) to 1 year (78%). Only some features improved between 5 to 14 years. Four patients of hemiplegia remained bed ridden. Some non disabling features like dysarthria and corticospinal features without paralysis persisted in 5% (95% improved) and 74% (26% improved) respectively. One patient with bizarre movement and nine with marked tremors could not regain normalcy. A large number of patients of JE are left with several minor or gross residual neuropsychiatric and neurological features after the acute phase. In this series also the discharged patients with neurological deficits who were quite disabled initially and needed constant care by family members and also those who required some help intermittently improved with passage of time and eventually returned to normal life.

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Author's personal copy J Neurol

Some of them were left with non-disabling residual neurological signs even after 14 years. Fourteen of 544 (3%) could not return to their livelihood. Keywords Japanese encephalitis Neuropsychiatric sequelae Extra pyramidal disorders Speech disturbances and hypothalamic features Abbreviations GCS Glasgow coma scale JE Japanese encephalitis

Introduction The acute phase of Japanese encephalitis, the commonest Arbovirus encephalitis, has been extensively studied [12, 14–18, 20, 26, 30, 33]. In India, there have been many studies of small and large epidemics [2, 3, 28, 35] which mainly dealt with children. Long term studies regarding the natural history following the acute phase have not been so well conducted. The neuropsychiatric disturbances were noted in 38 patients followed for 10–12 months only after the onset of the disease [29]. Eleven had various types of neuropsychiatric disturbances. The remaining 27 also showed a relatively milder degree of neurological disturbances and mental retardation. The records of 567 cases of JE in Korea were reviewed and it was noted that at the time of discharge there were many with residual neurological and neuropsychiatric deficits and the Korean physicians believed that continued improvement in most cases could be safely expected [17]. A real long term follow up was carried out in 143 survivals (mostly children) out of 690 patients for a period of 5–17 years [10, 11] and the disorders were classified in four groups ranging from mild neuropsychiatric disturbances, gross psychosis, mental impairment and residual pyramidal symptoms. The children below 5 years showed more intellectual impairment and neurological deficits than the older children. One hundred forty-one Thai patients were studied for 1 year after the onset of JE and neurological abnormalities were observed in more than 30% of the survivors [27]. All the neurological signs improved but lesser in subjects below 10 years than those of more than 11 years. Ninety-one out of 141 survivors in another study were followed up to 9 months only and almost all of them had complete recovery but slower in patients with contractures and gross mental deficiency [28]. Several studies were reviewed on short term sequelae of JE and the neurological deficits were reported in 25–75% which continued to improve over the years [23].

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In 2007 85 JE patients were traced, 6–27 years after hospitalization. The study showed that significant neurologic and overall functional disability were evident in a high proportion of JE survivors many years after their index hospitalizations [6]. One hundred eighteen children of JE were studied and followed over an 8.3 year period. Forty-four (41%) of the 108 patients who survived had apparent full recovery; Three (3%) had mild, 28 (26%) moderate, and 33 (31%) severe neurological sequelae. More than one-half of the patients continued to experience neuropsychological and behavioral disorders [19]. There are many important features, which appear from the above studies. (1) Almost all the studies have either been in children and/or young adults; (2) The number of post JE cases was small. (3) The types of neuropsychiatric disorders have been variable and not properly classified. Aim of study The aim of this prospective study of adult survivors (688/ 1,199) from four epidemics, the largest ever reported so far, was to follow them for 14 years after properly classifying the sequelae to record the ultimate natural course. Such detailed and lucid classification of the deficits of JE after the acute phase and such a long term continuous follow up has also not yet been reported. Patients and methods Adult cases, numbering 1,282, were admitted to the medical wards of Nehru Hospital, B.R.D. Medical College during the acute phase of the disease. Since the first epidemic of 1978 was studied, more disastrous episodes flared up and were subsequently included. Hence, the total duration of this prospective study of the follow up was from November 1978 to December 2003. The overall mortality of acute cases was 511/1,199 (43%) and 688/1,199 (57%) survived. Twenty-three of 688 (3.3%) patients were initially discharged without any neurological deficits (GCS-15) and 665/688 (96.7%) with deficits (GCS-8 to 14) [31]. These were classified in nine groups, of course with a lot of overlap. Some of the important features included extra pyramidal features (589/ 665), speech disturbances (528/665), pyramidal features including limb paralysis (495/665) and various psychological disturbances 467/665 (Table 1) and Fig. 1. The study protocol was approved by the scientific and ethical committee of the college. Written consent was taken from the relatives for studying the cases. The follow up was focused on the deficits/clinical features at the time of discharge. A separate ‘‘Post Encephalitis’’ outpatient clinic was established and all the survivors were contacted through the nearest primary health centres or

Author's personal copy J Neurol Table 1 Deficits of J.E. at the time of discharge (n = 665/ 1,199) and number followed (n = 651/665) after initial defaulters (14)

Types of deficit

Initial

Followed

Psychological disorders

467

453

Higher cerebral dysfunction

395

381

Speech disturbances

528

514

Extra pyramidal features including abnormal posture

589

575

Parkinsonian feature

200

200

Hyperkinetic movements

347

338

Dystonic postures

42

37

Impaired muscle tone

396

386

Pyramidal feature including paralysis

495

485

Hypothalamic disturbances.

355

350

Cranial nerve and eye changes

213

210

Seizures

263

253

Fig. 1 Japanese Encephalitis (Acute Phase)

Result of acute phase n=1282

Left against medical Advice N=83

Final number of cases during the acute phase n=1199

Survivors Expired 511/1199 (43%) 688/1199 (57%)

320/511 (63%) Died within 3 days

Survivors with Deficits 665(97%) GCS-8to14 Initially without deficit 23/688 (3 %) GCS-15

4 Re-hospitalised 19 Remained well

Became normal after 1yr

the health workers. Each patient was given a separate number and was examined to record the details on a standard format/proforma. Those who could not be traced were sent

All 23 remained normal

postal reminders. The neurological findings were confirmed at least by one of the neurologists. As far as possible, subsequent follow up was carried out by the same examiner.

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Basic assessment was carried out in 89 relatives of the patients at the time of discharge/at first visit using local dialect of Hindi, i.e. Bhojpuri, keeping in mind the socioeconomic and occupational status of the rural poor population with low basic education (maximum education up to VIII standard). The tests, therefore, were modified which was considered suitable by the scientific and ethical committee of the college. Each answer was verified from the relatives. Psychological disturbances Assessment of mood, personality and behaviour was done. Hallucinations and delusions were recorded as informed by relatives. Patient’s attitude during examination was noted. The patients were thus grouped as psychotic and nonpsychotic. Higher cerebral functions Memory (past and recent) was assessed by standard questionnaire. Past memory Past memory questions, pertaining to well known events in the history of India and of their respective villages, e.g. dates of India’s independence and Republic Day, name of the first Indian Prime Minister and murderer of Mahatma Gandhi; the names of present and previous Graam Pradhan (Head of Village administration), birth dates and marriage dates of the patients and of their children were asked and verified from the relatives. Recent memory Recent memory was tested on the basis of what the patient had eaten at breakfast or lunch, description of journey from the village to hospital, forgetfulness concerning marketing, repetition of 4–5 digit number given 5 min earlier. Intelligence test Intelligence test was difficult to quantify due to marked variation in the socio-educational background; however, tests were carried out broadly on the modified guidelines of ‘‘Stanford Binet Intelligence Scale’’ [5, 32]. Thus, a rough guide to intelligence consisted of (1) Serial subtractions of 3 from 100 as quickly as possible. The time taken and number of mistakes were recorded. (2) Use of local currency (Rupees and coins of different denominations) for different tests, e.g. to count, add and subtract after recognizing them. This test was also useful for nominal dysphasia, dyscalculia, and agnosia. (3) To speak or write tables of 2, 5, 6 and 9 as quickly as possible. A global disturbance in the higher mental function was labeled as confusional state. Test for apraxia and agnosia were carried out in the patients who were alert.

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Apraxias Apraxias were tested by asking patients (I) to undress and to dress themselves (II) to light beedi/cigarettes (III) to copy images made (IV) to construct a watch and depict a particular time (V) to write name and addresses. Agnosias Patients of nominal dysphasia were excluded from the test. To maintain uniformity of tests and to keep them simple (1) we used simple color charts, letters of Hindi and simple words. (2) Patients were asked to name commonly used objects, e.g. keys, pens, teaspoons, watches, jugs, glasses and cups of different shapes and sizes, and to compare/or match them with the duplicates. (3) They were asked to touch, feel and describe shapes, sizes, and textures of common objects and name them with closed eyes. (4) They were asked to recognize the sounds produced by ringing bunch of keys, shaking a bag of coins or tearing papers with closed eyes. Speech defects Various speech disorders were classified as dysphonia, dysarthria, and dysphasia. The findings were confirmed at every visit by at least one of the neurologists. Extra pyramidal features Extra pyramidal features were classified as parkinsonian, hyperkinetic movements and dystonic postures. Cranial nerves Cranial nerves including the pupils and fundi were examined in detail at each visit. Complete motor, sensory and reflex examinations were carried out to identify any limb weakness or presence of corticospinal sign only. Hypothalamic disturbances Hypothalamic disturbances were carefully recorded and classified. Sexual behaviour was evaluated by queries made for male patients through their wives by female nurses in isolated cabins. For female patients their husbands and female attendants were interviewed. In females disorders of libido was not recorded. Seizures The diagnosis of seizures was made by the description of eye witness or as documented by a medical personal. Laboratory data The study was basically clinical on the survivors of the four epidemics of JE (1978, 1980, 1988, 1989) and during follow up no further tests were carried out. Viral and immunological tests were done during the acute stage. Only a representative number of samples from each epidemic were confirmed for recent JEV infection by immunological tests

Author's personal copy J Neurol Table 2 Result of Serological studies of JE 649/1,282 (IgM in 402 and IgG in 247) Year

Total admissions

Cases

IgM estimation

IgG estimation

Single serum Cases

Positive

Paired sera %

Cases

Single serum

Positive

%

Cases

Positive

Paired sera %

Cases

Positive

% 41.4

1978

222

110

19

10

52.7

47

21

44.7

15

6

40

29

12

1980

260

131

67

35

52.2

17

8

47.1

32

14

43.8

15

6

1988 1989

476 324

244 164

92 72

53 42

57.6 58.3

61 27

31 14

50.8 51.9

51 49

22 27

43.1 55.1

40 16

18 6

45 37.5

Total

1,282

649

250

142

56.8

152

77

50.7

147

69

46.9

100

42

42

40

Positivity of IgM in 51–56% and IgG in 42–47% of samples in high titers suggested recent infection

1978

222

29

27

93.11

1980

260

34

30

88.24

fever, headache, altered sensorium or paralysis. They had assaultative behaviours, euphoria, and delusions of grandeur with mirror writing. They improved with symptomatic treatment but needed full constant care for 6 months and intermittent help for further 6 months before becoming normal. The rest 19/23 remained normal (Fig. 1).

1988 1989

476 324

36 24

31 21

86.12 87.5

Psychological disturbances

Total

1,282

123

109

88.75

Table 3 CSF IgM estimation of JE during acute stage (single sample in 123/1,282) Year

Total admissions

Number of cases

Positive cases

%

Positivity of IgM in CSF in 109/123 samples (88.75%)

in blood and CSF (Tables 2, 3 brought from part I); virus isolation was from CSF and brain.

Result There were 688/1,199 (57%) patients (450 males and 238 females) who survived and were followed up every 15 days for 3 months, every month for 1 year and every 3 months for 14 years. The patients who had recovered fully during follow up were asked to report after 1 year. Of the 23/688 patients who were discharged with no overt neurological deficits, seven females defaulted initially. A further 16 patients did not return after 2 years although they had become normal and resumed normal life. The 14/665 patients with deficits defaulted from the beginning and 107/665 failed to return in spite of reminders during various periods of follow up. The total number of patients not available for the 14 year follow up period was 144/688 (21%) (Table 4) and Fig. 2. Because of socioeconomic and travel problems, and as many of them had regained normal livelihood, they had possibly decided not to attend. In those who survived, 688/1,199 (57%) neurological deficits were found in 665/688 (97%). Only 23/688 (3%), 18 females and five males, were discharged without any deficit. Of the 23, four males had to be readmitted within 2 months for bizarre movements of the limbs without

The group in Table 5 consisted of 453/651 patients with psychotic and nonpsychotic features. The majority [353/ 453 (78%)] of them improved by 1 year after discharge particularly those with delusions, hallucinations, euphoria and emotional instability. One hundred thirty-nine of 453 cases (31%) were restless, agitated and hyper-excitable, and even aggressive at discharge. They had to be prescribed chlorpromazine 150–200 mg/day along with diazepam 15–30 mg/day in divided doses. They started to improve right from the first visit which continued. Doses of both were reduced to half after 3 months, which were continued for 1 year, and then withdrawn gradually by ensuing 2 years. One hundred thirty-six of 139 (98%) improved by 5 years and only 3/139 (2%) were left until the end of study with mild occasional restlessness. Psychopathic, anti-social disorder with loss of moral values was a dominant feature in 46/453 (10%) male patients only. This consisted of inappropriate removal of clothes, abusive behavior, speaking indecent words and exhibiting obscene gestures (showing erect penis to public, sometimes started masturbating, and showing sexual signals/signs). They were also prescribed chlorpromazine 150–200 mg/ day along with diazepam 15–30 mg/day in divided doses. There were four patients who had phases of impulsion to eat burning wood or coal; one patient developed kleptomania. Improvement was observed in 35/46 (76%) by the end of 1 year and in 45/46 (98%) after 5 years. One continued with occasional outrage only. Visual hallucinations, delusions of persecution and grandeur suggestive of diffuse involvement of frontal and temporal lobes were noted in 13/453 (2.9%), 6/453 (1.3%)

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Author's personal copy J Neurol Fig. 2 survivors JE (688)

Patients with

Patients without

Deficits (665)

Deficits (23)

7 Defaulted Initially

14 Defaulters Initially

651 Followed

16 Lost after 2 years

1O7 Defaulted during Various periods of follow up. Supposed to have become normal

544 Followed for 14 yrs.

Table 4 Total defaulters = 144 (including initial loss of 21) Discharged

Initial loss

6 Months

1 Year

3 Years

4 Years

5 Years

14 Years

M

F

M

F

M

F

M

F

M

F

M

F

M

F

M

F

450

238

2

19

0

6

5

41

7

20

2

20

2

13

0

7

Followed (n = 667) Initial followed

6 Months

1 Year

3 Years

M

F

M

F

M

F

M

F

M

F

M

F

M

F

448

219

448

213

443

172

436

152

434

132

432

119

432

112

and 7/453 (1.6%), respectively. Visual hallucinations which consisted of visualising one of the close relatives standing or moving around him without fear and aggression, improved by 6 months (100%). Delusions of persecution and delusion of grandeur were detected in 6/453 (1.33%) and 7/453 (1.6%), respectively. Those with delusions of persecution developed fearful feeling of being killed by their close relative; by cutting of throat or slaughtering by axe, sickle or long knife. Delusions of grandeur in seven consisted of patients behaving like a big merchant or king posing to buy the whole village market, distributing money, clothing and other domestic belongings to charity. All patients with delusions started to

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4 Years

5 Years

14 Years

improve within 1 month following discharge and ceased in all by 1 year (100%). Classical features of depression were observed in 155/453 patients (34%). They were treated with amitriptyline 75–100 mg/day which was gradually withdrawn as improvement continued from the very first visit after 15 days. 99/155 (64%) had improved after 6 months and 56/155 (36%) remained with depression at 1 year although by 5 years 153/155 (99%) had improved. Two of 155 (1%) had occasional vacant look and were rather withdrawn. Emotional instability in the form of spontaneous laughing and crying was present in 180/453 (40%). It improved in 108/180 (60%) by 6 months and in 176 (98%)


by 5 years. Four were left with phases of loud laughter up to 14 years. Euphoria was noted in 20/453 (4%). They all improved by the end of 1 year (Table 5). Higher cerebral dysfunction Higher cerebral dysfunction was present in 381/651 with a fair amount of overlap. The candidates with impaired

intelligence 381/381 were associated with general lack of concentration, impaired capacity for reasoning and judgment. They were also unable to do subtraction, addition and money transactions correctly. Intelligence continued to improve; 35.7, 68 and 96% improved by 6 months, 1 year and 5 years, respectively. Memory improved rather slowly. Obvious progress was witnessed after 6 months in 93 (25%). Two hundred thirty-

Table 5 Progressive improvement of psychological disturbances (n = 453/651) Features

Total no. of patients

Initial deficit in

Number of improved cases 6 Months

1 Year

5 Years

Finally improved (%)

453

247

353

440

97.13

139

79

110

136

97.84

Psychotic features Restless, agitated and hyper excitable Psychopathy/assaultative behaviour

46

22

35

45

Hallucination-visual

13

13

13

13

100

Delusion-persecutive

6

3

4

6

100

Delusion-grandeur

7

3

5

7

100

Non psychotic features Inattentive

97.83

120

94

116

117

97.5

Depressed

155

99

125

153

98.71

Emotional instability

180

108

143

176

20

14

18

20

Euphoria

97.78 100

353/453 (78%) of them improved by 1 year after discharge particularly delusions, hallucinations, euphoria and emotional instability where as by 5 years 98–100% had improved which continued up to 14 years Table 6 Progressive improvement of Speech disturbances, Aphasia and Agnosia (n = 514/651) Features

Total no. of patients

Deficit in

Number of improved cases

Finally improved %

6 Months

1 Year

5 Years

514

269

381

504

Dysphonia

81

70

79

81

Dysarthria

203

89

165

193

21

18

21

21

100

Jargon dysphasia Expressive dysphasia

98.05 100 95.07

70

27

43

69

100

Nominal dysphasia

175

134

160

175

100

Automatic speech

131

101

125

131

100

Echolalia Agraphia

51 69

51 54

51 62

51 69

100 100

Acalculia

466

307

376

466

100

82

57

69

82

100

Paraphasia and neologism Mirror writing

40

37

38

40

100

Ideo-motor and ideational apraxia

173

110

133

173

100

Constructional apraxia

487

262

286

471

75

59

72

75

100

131

129

131

131

100

Dressing apraxia Agnosia (visual and tactile)

96.71

Rapid improvement in 269/514 (52%) to 381(74%) occurred by 6 months and 1 year respectively and continued up to 5 years (100%) in all types of speech disorders. Ten cases of Dysarthria did not get clear speech without any functional disability. Sixteen were left with constructional apraxia even after 14 years

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Author's personal copy J Neurol Table 7 Progressive improvement of Extra pyramidal features (n = 575/651) Features

Deficit in


1 Year

Finally improved % 5 Years

Parkinsonian 200/575 Mask like face and Bradykinesia

199

109

150

191

97.49

Cogwheel rigidity

170

81

109

161

96.47

Monotonous speech and Dysarthria

174

50

71

93

56.32

153

3

41

142

13 99

3 72

11 98

13 99

100 100 100

Tremors Slow Fast Excessive salivation Hyperhydrosis Gait

96.08

32

32

32

32

114

58

72

112

98.25

Hyperkinetic movements (n = 338/575) Bizarre Tremor (Coarse)

71

48

58

69

98.59

267

122

190

253

96.63

Dystonic postures (n = 37/575) Opisthotonus

10

8

10

10

100

Bizarre posture

27

21

23

27

100

Maximum clearance of various extra pyramidal features was noted between 6 months (55%) to 1 year (82%) and continued up to 14 years. Dysarthria, bizarre movement and coarse tremors persisted in 44, 2 and 3%, respectively, up to 14 years

four (63%) and 354 (96%) had become normal after 1 year and after 5 years, respectively. Sixteen of 370 (4%) were left with mild impairment of memory not affecting daily living activity. They were, however, fit enough to look after themselves and help in farming. Confusional state became normal by 6 months. Speech disturbances Speech disturbances including dysphasia, dyscalculia, apraxia, agnosia and constructional apraxia were noted initially in 514/651 (Table 6). There were cases of dysarthria in 406/665. It was present in 203/514 (40%) with speech disorders (Table 6) and was slow to clear; 187/203 (92%) and 193/203 (95%) had become normal at 5 and 14 years, respectively, but 10/203(5%) did not improve. Dysarthria and monotonous speech as a part of parkinsonian syndrome could be detected in 174/575 (30%). There was little improvement and only 98/174 (56%) returned to pre-morbid speech after 14 years (Table 7). Twenty-nine of 334 (9%) had spastic dysarthria as a part of corticospinal features without any improvement but could carry out all the routine including employment. Extra pyramidal features Parkinsonian features were observed in 200/575 patients while hyperkinetic movements in 338/575 and dystonic

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postures in 37/575. Follow up of the extapyramidal features revealed persistence of monotonous speech and dysarthria in 76/174 (44%) and only 98/174 (56%) improved by 14 years, while other parameters started to improve rapidly after 1 year and continued till 14 years with an overall improvement in 96% (Table 7). Hyperkinetic movements in the form of bizarre movement and tremors were detected in 71/338 and 267/338 respectively. Bizarre movements consisted of a combination of dystonic, athetoid or arrhythmic jerky movements of the limbs. Sometimes one limb moving in one fashion and the other in different, producing peculiar combination of movements and posture, which was difficult to group in the known types. These features progressively improved, 48/71 (68%) became normal by 6 months. 69/71 (97%) and 70/71 (99%) recovered by 5 years and 14 years respectively. The improvement of tremors was slow and only 122/267 (46%) became normal by 6 months, 253/267 (95%) by 5 years and 258/267 (97%) by 14 years. They remained well and could return to their daily activities satisfactorily. Only one patient with bizarre movements and nine with marked tremulousness were unable to return to their livelihood even after 14 years but needed no help for the routine. Dystonia consisted of ophisthotonous 10/37 and bizarre postures 27/37. The latter presented as mixture of dystonia of body and limbs. Ophisthotonous improved in all 10/37 patients by 1 year. Twenty-one of 27 (78%) patients with bizarre postures became normal by 6 months and all 27 after 5 years (Table 7).

Author's personal copy J Neurol Table 8 Progressive improvement of hypothalamic disturbances (n = 350/651) Features

Deficits in


1 Year

Finally improved % 5 Years

Hyper somnolence

45

16

26

45

Insomnia

63

44

57

63

100

Altered sleep rhythm

29

25

29

29

100

Increased appetite

48

25

37

48

100

Decreased appetite

63

25

56

63

100

Increased thirst

74

34

63

74

100

Polyuria Increased libido

67 11

31 3

56 9

67 11

100 100

Decreased libido

101

48

85

101

100

6

6

6

6

100

65

55

65

65

100

Loss of diurnal variation of temp. Hyperhydrosis

100

Hypertension

30

26

27

27

90

Glycosuria and hyperglycaemia

26

26

26

26

100

Almost all the hypothalamic disturbances cleared by 6 months to 1 year Improvement of libido was observed in 51/112 (46%), 94/112 (84%) and 112/112 (100%) after 6 months, 1 year and 5 years, respectively, and continued up to 14 years

The disorders of muscle tone consisted of increased muscle tone of plastic type in 359/386 and decreased tone in 27/386 respectively. Those with decreased tone improved completely by 1 year whereas 16 with mild increased tone remained as such until the end of the study without any disability, i.e. 96% improved. Hypothalamic disturbances Almost all the hypothalamic disturbances cleared by 6 months to 1 year. Improvement of libido was observed in 51/112 (46%), 94/112 (84%) and 112/112 (100%) after 6 months, 1 and 5 years, respectively (Table 8). Pyramidal features and motor paralysis Motor paralysis was found in 151/485 (31%) patients though corticospinal signs only were noted in 334/485 (69%). Initially there were 86 cases of hemiplegia and 65 with monoplegia. By 6 months, 38/86 (44%) of the former improved and 60/86 (70%) and 82/86 (95%) recovered completely by 1, 5 years and up to 14 years, respectively. Four patients with hemiplegia remained bedridden. Two of them had associated marked intellectual disturbances, seizures and bizarre movements on either side of the body. Similarly, 33/65 (50.77%) patients of monoplegia improved by 6 months. Of the remaining patients 56/65 (86%) and 59/65 (91%) recovered by 5 and 14 years, respectively. Therefore, total recovery in the paralysis group was 141/151 (93%). Six of those with monoplegia were left with mild clumsiness only without interfering with their routine and farming.

Corticospinal features consisting of generalized hyper reflexia including exaggerated jaw jerk, Hoffman’s sign and ankle clonus were detected in 334/485 patients. However, plantars were extensor in 151 only, equivocal in 133 and flexor in 50 without paralysis. Unilateral pyramidal features were present in 133/334 (40%). It improved only in 76/133 (57%) and continued in 57 (43%) from 5 years onwards. Bilateral pyramidal features, however, were noted in 201/334 (60%). Overall, the features, without causing any disability, persisted in 191/201 (95%) after 1 year, i.e. only 10/201 (5%) had improved. Twenty-nine of 201 with bilateral signs had dysarthria. Overall, in 248/334 (74%), the pyramidal features continued until the end of the study and only 86/334 (26%) had improved. Seizures Two-hundred sixty-three of 360 patients (73%) at discharge were put on 120 mg of phenobarbitone and 200 mg of phenytoin for maintenance. But only 253/263 patients (238 with generalized and 15 with partial) could be followed (Table 1). All of them received anticonvulsants which were continued for 3 years and later reduced to 60 and 200 mg, respectively, for a further 2 years. In 215/238 of patients with generalized seizures, it was possible to discontinue the drugs after 5 years. In 23/238, the generalized seizures were rather difficult to control and they were, therefore, given 120 mg phenobarbitone and 200 mg of phenytoin for 14 years. In patients with generalized seizures, focal neurological deficits were present in 60

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patients (48 had hemiplegia and 12 monoplegia), while only two patients with focal seizures had monoplegia.

Discussion We describe the largest series of follow up of 665/688 discharged adult patients of JE with various neurological and neuropsychological deficits.

dysarthria and 16/487 (3%) with constructional apraxia were left with improvement of 95 and 97%, respectively. We have not been able to find such details about apraxia, agnosia, dyscalculia and other varieties of speech disturbances in the literature. Apraxias and agnosias indicate diffuse involvement of parietal and occipital areas and their sub cortical association fibres. These can occur in any diffuse brain disease [4]. Extra pyramidal features

Psychological disturbances Nine types of psychological disturbances, psychotic and nonpsychotic, were present in 453/651 patients initially with overlap of features (Table 5). Such description has not been reported. All disorders in this series showed good recovery and by 1 year 353/453 (78%) had improved. None of them had severe disability but could not be back to work at 1 year. The progress continued for 5 years in 440/453 (97%) but all returned to normalcy by 3 years in spite of mild disturbances in some. Many workers have followed the survivors with various neuropsychiatric deficits consisting of intellectual, memory and behaviour disturbances. All of them noted rapid improvement, more in patients over 11 years with some non-disabling residual features. The earliest features to disappear were restlessness, agitation and confusion [7–11, 13, 24, 28].The psychological disturbances of psychotic or non psychotic nature suggest diffuse involvement of frontal, temporal lobes and their association fibres linking with thalamus, hypothalamus and limbic system [1, 21]. Higher cerebral dysfunction This group consisted of 381/651 patients with impairment of intelligence in all 381, memory disturbance in 370/381 and state of confusion in 25/381 with fair amount of overlap. Confusional state became normal by 6 months whereas intelligence and memory took some time to improve and after 5 years only 12/381 and 16/370 were left indicating improvement in 97 and 96% respectively. All of them were, however, fit for their livelihood. Disturbances of intelligence and memory, along with many psychotic features with good recovery (more in patients above 5 years), were observed by many [7–11, 13, 22, 34], although they had only small number of cases with variable periods of follow up. Speech disturbances Speech disturbances including dysphasia, dyscalculia, apraxia and agnosia were noted initially in 514/651 (Table 6). After 5 years only 10/203 (5%) patients with

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Table 7 various extra pyramidal features were recorded in 575/651 patients. Two hundred of 575 had pankinsonian features. Three hundred thirty-eight 575 and 37/575 had hyperkinetic movements and dystonic postures, respectively. They all showed progressive recovery without any physical disability; maximum clearance of various extra pyramidal features occurred between 6 months (55%) to 1 year (75%). Almost all of them could resume their normal routine life by 5 years. However, those with bizarre postures, i.e. 27/37, needed total care for 6 months and intermittent care from 1 to 3 years, and became normal by 5 years. There is a paucity of such details in the literature. Some such features have been reported in very small number of cases [9, 25]. Pyramidal features Motor paralysis and only pyramidal signs were present in 485/651 patients initially with hemiplegia in 86/151 and monoplegia in 65/151. They improved progressively by 5 years and at 14 years only 6/65 with monoparesis were left, that too without functional disability, i.e. (91%) completely improved. Eighty-six of 151 had hemiparesis/ hemiplegia. Four of 86 of them remained bed-ridden and needed constant care. After 6 months, 1 and 5 years, 38/86 (44%), 60/86 (70%), and 82/86 (95%), respectively, had become normal. In the earlier part from 6 months to 1 year they required intermittent help and watch particularly during bathing, clothing and some assistance during walking. Various paralytic features have been reported at variable periods of follow up [10, 11, 27]. Hypothalamic disturbances In 350/651 patients various hypothalamic disturbances could be recorded (Table 8). Besides sleep and appetite, libido was interestingly disturbed in 112, out of which 101 had initially decreased libido but 11 had increased libido. These features became obvious at the first visit. All the features tended to improve and by 6 months to 1 year became normal. Transient hypothalamic disturbances in such a diffuse brain disease are quite likely. We have not

Author's personal copy J Neurol Fig. 3 Final outcome after 14 years follow up

Discharged=688 Defaulters=144 Followed=544

402 (73.9%) Needed help)

142 cases (26.1%) No help for ADL* Resumed normal work after 1Yr 170 (42.3%Needed constant help)

232 (57.7% Intermittent help 3 to 6 months)

86 Hemiplegic **4 remained Bed ridden 82 Improved by 5 years 108 normal with some guidance

124(53.45%) Normal work with guidance

84cases Full care for ADL

for 6 months

for 6 months

for 6 months

100% Normal by 5 years

**1 case of Bizarre movement

74 Normal after 5 years

&** 9 cases of Coarse Tremors did not improve * Activity of Daily Living Total improvement 530/544 (97%) **No improvement in 14/544 (3%)

come across such classification of hypothalamic disturbances in literature. Some hypothalamic disturbances like insomnia, hyper somnolence and hyperhydrosis have been reported by few workers [10, 13, 34]. Pupillary and cranial nerve changes Two hundred ten of 651 had eye and cranial nerve involvement. Pupillary abnormalities could be recorded in 147/210 including Argyll Robertson pupil in 30/197 and papilloedema in 50/197. All cleared by 6 months. Such detailed pupillary abnormalities have not yet been reported following JE possibly because most of the studies were in children. Palsy of VI and VII nerves was in 13/210 and cleared within 6 months.

mostly nocturnal. They (23/238) were, therefore, given phenytoin 200 mg and phenobarbitone 120 mg daily for life. Few long term studies are available regarding seizures. It was reported in four out of 68 with other neurological deficits 5 years after the acute infection [10], whereas in five out of 56 after 10 years [13]. However, it was observed in 4% of adults after 1 year [27]. As almost all the neuropsychiatric and neurological deficits in this series cleared up by 5 years, it is indicative of severe neuronal oedema rather than degeneration/ damage. None of the patients (with or without neurological deficit) could return to normal working life at 6 months. Even if they were apparently normal, they needed rehabilitation in the form of some help in dressing, calculation, construction and marketing. Fig. 3.

Seizures It is expected that seizures, focal or generalized, might persist after such a diffuse brain disease but only 23/238 (9.67%) of generalized seizures had some attacks even after 5 years. These were not incapacitating and were

Conclusion It is, therefore, concluded that a large number of patients of JE who were discharged with several minor or gross

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residual neuropsychiatric and neurological features after the acute phase, were quite disabled and initially needed constant care by family members and also those who required some help intermittently improved with passage of time and eventually returned to normal life. Some of them were left with non-disabling residual features even after 14 years, although they were fit enough for all practical purposes. Practically all of them returned to their daily working between 3 and 5 years, hence the burden on family, society and the exchequer has been very negligible. Acknowledgments We are grateful to Prof. J. Farrar, Oxford University Clinical Research Unit. The Hospital for tropical Diseases, Ho Chi Minh City Viet Nam for his guidance and criticism, Dr. Avijit Sarkari and Mr. Jitendra Kumar for their help in preparing the manuscript. Conflict of interest

The authors declare no conflict of interest.

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