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TYPHOID FEVER IN CHILDREN IN THE PAST AND PRESENT MULTI-DRUG RESISTANT TYPE WITH SPECIAL REFERENCE TO NEUROLOGICAL COMPLICATIONS
PM Udani, Vimla Purohit, Paresh Desai
Dept. of Paediatrics, Bombay Hospital Institute of Medical Sciences, Mumbai - 400 020.
Typhoid fever has been a major health problem in children from the time it was described in India. In the past before the advent of chloramphenicol it was a very serious disease and morbidity and mortality was high particularly affecting the school age group children. The treatment with chloramphenicol was so effective that morbidity and mortality due to typhoid came down dramatically. However, with the use and abuse of chloramphenicol for other infections, the typhoid bacilli developed resistance to various antibiotics like chloramphenicol, ampicillin and other drugs. The new multi-drug resistant typhoid emerged and posed a great challenge to medical profession particularly paediatricians as the multi-drug resistant typhoid only responded to the new antibiotics like norfloxacin, amikacin etc. The present communication deals with the problems of typhoid fever before any specific drug was available in the past, chemotherapy with chloramphenicol with excellent results and now the multi-drug resistant typhoid fever. The article gives not only the newer clinical emerging pictures and various complications of multi-drug resistant typhoid but especially highlights the large number of neurological complications affecting the central and peripheral nervous systems. It also reviews several complications affecting the central and peripheral nervous systems. It also reviews several studies on many aspects of typhoid fever not only from Indian Literature, but also studies from other developing countries. Though some of the neurological complications like typhoid encephalopathy of various types were known in the past various other neurological manifestations are being detected and have been detailed in the article. It also gives the case examples which are quoted to emphasise conditions like typhoid meningitis (serous and pyogenic), radiculopathy, post typhoid recurrent episodes of cerebral involvement, hemiplegia, quadriplegia, ophthalmoplegia, typhoid cerebellitis and sensory motor neuropathy, isolated cranial nerve involvement, polyneuritis, parkinsonism etc. Some of the conditions which are simulating typhoid or precipitated by typhoid are Reye’s syndrome, subacute sclerosing panencephalitis (SSPE), subdural effusion, post typhoid reactivation of neurotuberculosis or other clinical types of tuberculosis etc. The mechanism of resistance has been reviewed. Some of the non-neurological important complications like renal involvement, myocarditis, hepatitis and change in clinical pictures have been described in brief. Emphasis has been given to the use of new anti-typhoid drug when the routine drugs fail, use of steroids and the plea to include typhoid vaccine in the national schedule of immunizations, at the same time pointing out the importance of hygiene, sanitation, clean water and safe food supply.
INTRODUCTION
Typhoid fever in children though known as periodic fever from antiquity to people and health professionals has been reported of great magnitude, from the time paediatrics was started in India in 1928. [1] However, Willis2 described typhoid about 240 years back in English medical literature. [2] Before the chemotherapy for typhoid was available the morbidity and mortality of typhoid was significantly high. In 1944-45 BJ Hospital for Children the first independent children’s hospital in the country having 75 beds had 10-15 cases of typhoid fever at one time. During the epidemic of typhoid from June to September the typhoid fever constituted almost 10% of total admissions. It is interesting to note that the children with good nutrition usually had a better prognosis than those who had poor nutrition. Late Dr. Coelho, the father of paediatrics in India observed that as the nutrition was the most important factor affecting the prognosis of typhoid, usually advised well cooked soft, full diet with good calorie intake. [1] Most of the children tolerated diet very well except those with hepatitis and severe abdominal distension. The recovery occurred within 2 to 4 weeks or longer. Children who were often starved as was the practice before chemotherapy era, developed further progressive malnutrition with high morbidity and mortality.
Salmonella Typhi
The genus salmonella consists of more than 1700 sero types. Of these about 100 are pathogenic to man. However, the most common of them is S. Typhi which is pathogenic to man.
Criteria for the diagnosis of multi-drug resistant typhoid fever (MDRT)
- Persistent pyrexia in a child with typhoid fever inspite of adequate dose of conventional antimicrobial drugs like chloramphenicol, ampicillin, amoxycillin, cotrimoxazole, furazolidon etc.
- Poor clinical response of other symptoms like abdominal distension, hepatomegaly, persistence of splenic enlargement, when present and development of complications inspite of treatment.
- Persistence of positive blood cultures for 2 weeks or longer inspite of routine treatment.
- There was good response to newer antimicrobial agents to which S. typhi was sensitive as per our study.
MATERIAL
Material presented in this communication provides :
Morbidity and Mortality with the use of various antibiotics
Cases of typhoid reported from this hospital are of all age groups but mostly children. The diagnosis was proved by isolation of S. typhi from the blood or clot culture or by strongly positive widal or rising widal titre. Fig. 1 gives the data of typhoid in children in a period of 16 years admitted at Kasturba Hospital between 1976 and 1991. In the first epidemic of 1977-80 (Fig. 1) the typhoid bacilli were not resistant to chloramphenicol and ampicillin which were used in the treatment. The fatality rate was 0.6%. However, during the second epidemic between 1987-90 and early 1991 the overall fatality rate in all age groups in this multidrug resistant typhoid fever ranged from 5.5% to as high as 27%. Fig. 2 also shows the number of admissions and overall fatality rate in all age groups from 1987-1991 August. It shows that between 1987 and 1988 the number of admissions for typhoid was 6 times higher between 1989-90 and fatality rate was 14%. Table 1 shows the fatality rates in all age groups between 1987-90. It can be seen that the mean fatality rate in adults was 15.1% as opposed to low fatality rate of 3.2% in 297 children. Table 1 also shows that the fatality rate was high in malnourished children in general hospitals where often children are admitted late with a number of complications. It may be emphasised that the fatality rate was 8 to 30 times higher between 1987-90 than the period 1981-86. Typhoid is much more serious disease in adults than in children.
Fig 1 : Typhoid fever in Kasturba Hospital ( K.H ) - 1966 to 1986 - 11 yrs
Fig 2 : Typhoid fever in KH 1987 to 1990 / 91 (Aug)
Table 1 Fatality rates (FR) from 1987-1990 in Kasturba General Hospital for infectious diseases, Mumbai No. of cases All ages FR% Paediatric
No.Age groups (0-14 yrs)
FR in (%)1987 165 (15.1) 46 (2.1) 1988 137 (27.1) 24 (4.1) 1989 163 (5.5) 44 (2.1) 1990 814 (14) 183 (2.1) 1279 (15.1 ) 297 (3.2)Mean
Table 2 Typhoid fever Bom. Hosp. Inst. Med. Sciences
(BHIMS-PGI) total cases in BHIMS (ID + OPD) in 18
months (June, 1990 to Dec., 1991)1. Widal test +ve Rising titre > 125 or - +ve 250 or more (O and H) 440 Total cases 440 No. Paediatric < 15 yrs
Adolescents ) ) =302 and Adults ) > 15 yrs
(for comparison)
Laboratory studies and the results at various centresBombay Hospital
Table 2 gives the results of widal test carried out in 440 cases in indoor and outdoor services of the Bombay Hospital Institute of Medical Sciences (BHIMS). In a period of 18 months from June 1990 to December 1991 widal test was positive in 440 patients. It was positive more than 1:250 titre to O and H or there was rising titre above 125 in others. Of the total 440 cases, children under 15 year constituted 302 cases. Fig. 3 shows positive blood cultures in 251 patients, 150 children and 97 young adults between July 1990 and December in BHIMS. It can be seen that the amikacin, cefotaxamine, fluroquinolone were the most effective drugs as 93 to 97% of S. typhi strains were sensitive to these three drugs. But the next in order was ceftazidine as S. typhi was sensitive in 85% while the sensitivity of S. typhi to amoxycillin, gentamycin, ampicillin, chloramphenicol varied between 30 and 50%. It was least sensitive to cotrimoxazole, it being 12.3%. With these results of sensitivity studies, we preferred two of the first 3 drugs, usually amikacin and norfloxacin with excellent results (Fig.4).
Fig 3 : Positive blood cultures ( T.98, PT 2 %) and drug sensitivity
Calcutta (Table 3)
Anand et al3 reported multidrug resistant typhoid fever in Calcutta between August and October 1989 and found that in 201 young adults culture was positive in 175 cases i.e. 84%. In their cases of typhoid fever the temperatures persisted for a period of 3-4 weeks to 6 to 7 weeks unless chemotherapy was given with drugs to which S. typhi was sensitive. They reported that the S. typhi strains in Calcutta were 100% sensitive to ciprofloxacin, norfloxacin and gentamycin while they were re sistant to trimethoprim and cotrimoxazole to 89.1% to chloramphenicol 78.3% and to ampicillin 49.1%.
Fig 4 : Typhoid Encephalopathy
Table 3 Resistance and sensitivity studies of S. Typhi to various antimicrobial drugs Resistance Sensitivity (%) N (%) Good MOD 1 Ampicillin 88 49.1 34 55 2 Chloramph 137 78.3 32 6 3 Trimethoprim (T.M.P.) 156 89.1 19 0 4 SMX (Cotrimoxazole) 156 89.1 19 0 5 Gentamycin Ciprofloxacin Norfloxacin Nil 0 100% sensitive
(Anand et al, Lancet, Feb., 1990; 10-352)Wang et al[4] reported the sensitivity of S. typhi to antimicrobial contents in Shanghai. They found that 80% of S. typhi strains were resistant to chloramphenicol, ampicillin and cotrimaxozole.
Shanghai (China)New Delhi
Gupta et al[5] studied sensitivity / resistance of 10 strains of S. typhi isolated from cases of typhoid admitted in AIIMS in New Delhi. They found that there was resistance to ampicillin, cotrimoxazole, chloramphenicol, amoxycillin, cloaxacillin while the strains were most sensitive to amikacin, ciprofloxacin, norfloxacin and cefotaxime as well as ceftazine.Vellore
Jesudasan and Jacob John[6] reported resistance of S. typhi to 4 antimicrobial agents. They isolated 115 strains of S. typhi and they found that 11% were resistant to chloramphenicol, ampicillin and cotrimoxazole.
Gulati et al[7] used oral ciprofloxacin (10/20 mg/kg/day in 2 divided doses in 30 children with MDRT and found it very useful in all the cases. They observed transient arthropathy of terminal interphalangeal joints in one child 15 days after the drug was stopped. Hence they suggested that the drug is safe, effective an economical antimicrobial treatment of MDRT.
Age specific incidence of typhoid in children
30% children in Bombay Hospital series diagnosed as typhoid were admitted in hospital and others treated in outpatient services, Table 4A shows that 32.6% of cases of typhoid fever occurred in children under 5 years while 66.4% or almost two-thirds occurred between 5 and 15 years. It may be emphasised that nearly 14% of cases occurred in the first 3 years of life. Pandey et al[8] reported 353 cases of typhoid in children and 13.5% were below the age of 5 years. Kapur et al from New Delhi[9] reported very high incidence of 52.5% in children below 5 years. In the underprivileged paediatric patients admitted in Institute of Child Health, JJ Group of Hospitals from 1990 to 1991 (Table 4B), it was found that of the total 120 cases with strongly positive widal in 63 (52%) and culture positive 47 (39%), 34.9% of children were under the age of 5 years, while 64.1% were between the age of 5 and 15. The maximum number of cases were seen between the age of 5 and 10 years. However, 16% of cases were below the age of 3 years, the youngest child being of 3 months.[9]Neurological complications (Table 5)
Neurological complications of typhoid reported by some Indian and foreign authors are given in Table 5, to get the comparative incidence of various complications.Encephalopathy
The encephalopathy of different types is the most common complication among the total 446 neurological complications. The encephalopathy could be of different types. It can occur at the onset of the height of the illness due to toxaemia or septicaemia while in others it can occur during defervescence and improvement in toxaemia with treatment. While the post-typhoid encephalopathy though uncommon is important as it may manifest weeks or months after the acute illness and can be missed easily if the prior history and other data are not available. It may be also mentioned that typhoid may produce a picture of acute encephalopathy particularly during the acute phase in the absence of toxaemia and septicaemia. However, though rare, one of them most difficult situations is encephalopathy due to mixed infections like tuberculous encephalopathy and typhoid encephalopathy. The evidence for both may be present like intrathoracic tuberculosis, tuberculous contact or presence of TB antigen by Elisa technique in CSF. On the other hand, blood culture and widal are also positive in these cases. Such mixed cases, though rare, should be kept in mind. With the complication of encephalopathy the prognosis was much more serious in the past even though typhoid fever was not resistant to chloramphenicol. Although encephalopathy is uncommon in multidrug resistant typhoid fever (MDRT), but when it occurs prognosis is guarded as the child may recover with severe residual neurological sequelae. It is specially so in post-typhoid encephalopathy but not so in acute encephalitic picture. Table 5 shows that meningism is an extremely common finding during the acute stage and it constitutes 42.8% of neurological complications. CSF is normal in these cases. It responds well to chemotherapy.
Table 4 (A) Age specific incidence of typhoid in children Total - 302 (BHIMS OPD + INDOOR) No. % *1/7 th-under - 3 yrs Infancy 8 26 } *Almost 1/3 rd 1-3 yrs 34 11.2 } 32.6 Under 5 yrs 3-5 yrs 57 18.8 } 5-10 yrs 122 40.3 } 10-15 yrs 81 26.8 } 66.4 * (2/3rd 5 - 15)
Table 4 (B) Typhoid fever in children of underprivileged population
ICH - JJH 1990-1991 (Nov.) (")Courtesy - (RB Patel et al) (Widal +ve - 63 (52%) - Culture +ve - 47(39) Age groups No. (%) Infancy 2 (1.6) } % 1-3 yrs 18 (1.5) } 34.9 (upto 5 yrs) 3-5 yrs 22 ( 18.3) } % 5-10 yrs 53 (44.1) } 10-15 yrs 25 (20.8) } (64.9)
Table 5 Neurological complications of typhoid reported by some
Indian and foreign authorsTypes of Neurological Complications
No.due toTyphoid/Total No. ofTyphoid
% of total Typhoid % % of total Nuerological
Complications of
Typhoid in (%)Encephalopathy 176/2107+ 803 60.2( ) Meningism 125/1297 9.6 42.8 Meningitis (not meningism) 26/192 13.5 8.9 Convulsions 29/1222 2.3 9.9 Spastic paralysis cerebral origin 49/539 9.0 16.7 Cerebellar Involvement 14/187 7.4 4.79 Parkinsonian syndrome 17/539 3.1 5.8 Aphasia 6/282 2.1 2.05 Cranial Nerve palsy (Isolated) 4/1101 0.3 1.3 Radiculitis/ Polyneuritis 3/352 0.8 1.02 Sensory Motor Neuropathy 17/534 3.1 5.8 Schizophrenic Psychosis 13+/397 3.2 4.4 Scholastic Deterioration (Episodic) 1/42 0.7 0.3 Spinal cord Lesions Lateral Column Involvement (General) 1/142 Delirium - Confusional state in acute stagenot included
Pyogenic Meningitis
Pyogenic meningitis due to S. typhi is a rare complication. It mainly occurs in neonatal period and infancy though some older children have been reported from NIMHANS. The material from NIMHANS consists of children and young adults as it is from an Institute of Neurology. [10] The pathology and pathogenesis has all been described in brief later. Serous type of typhoid meningitis is not common. The child presents with meningeal signs and increased protein and cells or only cells in the CSF but absence of S. typhi from the CSF. Prognosis in these children with serous meningitis is good.Convulsions
Among the neurological complications generalised convulsion is one of the important features of the disease but is not common and usually associated with other complications. However, it was focal in one child and 2 children presented with status epilepticus.Spastic Paralysis of Cerebral Origin
This is not uncommon complication and child may have hemiplegia, quadriplegia or generalised spasticity as was described in Nigerian series. [11] Hemiplegia which occurred in 15 out of 45 cases in NIMHANS series was associated with pyogenic meningitis in 3 and in nonmeningitis cases in 12 probably due to infarction. Quadriplegia occurred in pyogenic meningitis in one and nonmeningitis patients in 2 while in our series of Bombay Hospital one child had demyelination of the white matter as proved by MRI with hemiplegia. While generalised spasticity was reported by Osuntokun in 30 out of 352 neurological complications.
Schizophrenic Psychosis
Following typhoid this complication has been reported particularly in adolescents and young adults in Nigerian series. [11] In our series we have not found this complication. However, an older child or an adolescent presenting only with schizophrenic psychosis, S. typhi as a cause should be kept in mind. It was striking in the Nigerian series as in the patients presenting with schizophrenic psychosis the diagnosis was made at autopsy in which characteristic typhoid lesions were found in the intestinal tract. In a recent study on Schizophrenia, Shenton et al[21] carried out new generation of neuroimaging technique and quantitative MRI measurement, of volume described three major findings. First there was a lateralized (left sided) decrease in volume of gray matter in the anterior hippocampus, amygdala, parahippocampal gyrus and superior temporal gyrus and a concomitant increase in the volume of temporal horn of the lateral ventricles. Secondly, there was a strong correlation between the degree of thought disorder, a cardinal neurobehavioral symptom of Schizophrenia and the decrease in the volume of the left superior temporal gyrus a region long considered important as a neuroanatomical substrate of language. In the patients, there was statistical significant correlations among volume reductions in neuroanatomically interconnected temporal-lobe regions that may be important in forming auditory associative links. Such changes could be suspected in MRI of the brain.
Scholastic deterioration
This is one of the most interesting findings which we came across in one of our cases in whom the whole family had typhoid. The parents and other children recovered but this child of 10 years who was brilliant in studies before, deteriorated in his scholastic performance. He had typhoid in May 1991 from which he recovered. He deteriorated in his scholastic performance in August 1991. He improved and had second episode of deterioration following in November 1991. Fortunately he recovered fully. Such a scholastic deterioration following typhoid is likely to be missed particularly when it occurs after weeks and months of attack of typhoid. The authors from France[14] reported 10 cases of post-typhoid encephalopathy in which children had scholastic deterioration and also developed various neurological complications like mild to severe mental retardation. Personality and behaviour disorder, epilepsy, choreic symptoms etc.Aphasia
Aphasia is a well known complication and occurred in one of our cases and has been reported in 5 other cases. Fortunately it is rare and is probably due to typhoid neurotoxin causing damage in the speech area. In most of our cases there is recovery. However, in some cases the sequelae may persist for a long time. [17,18]Parkinsonian Syndrome
It is essential to keep in mind that the characteristic clinical picture of Parkinsonism can occur as happened in one of our patients who developed Parkinsonian tremors, rigidity and typical shuffling gait.
Cerebellar Involvement
This is not a rare complication. It could be isolated in a number of cases and hence in a child with midline cerebellar lesion or generalised hemispheric cerebellar lesion, typhoid should be suspected as the cause and necessary investigations carried out to establish or exclude the diagnosis of S. typhi infection.[11-16]
It was described in 10 cases (1%) of all patients with neuropsychiatric manifestation of typhoid fever in 959 cases. [11] Swamy10 described it in 6 cases, out of 40 patients (15%).Cranial Nerve Palsies
This is rare. However, child can present with isolated cranial nerve palsies like facial paralysis, palatal paralysis and even retrobulbar neuritis. [14,18,19] Vyas reported a case of typhoid with paralysis of facial, glossopharyngeal, hypoglossal nerve and aphasia. Child made complete recovery with treatment.Spinal Cord Lesions
Significant motor involvement due to spinal cord lesion though rare has been seen by us as an isolated manifestation in one case along with cerebellar signs. In all our cases of typhoid we also look for sensory motor neuropathy described earlier and evidence of spinal cord lesions like lateral column involvement.
Radicultis and Neuritis
Radiculitis and Neuritis are rare complications but it is important to keep in mind that the characteristic Guillain Barre syndrome can occur in a child with typhoid fever as has been reported by Jhanmugan. [20]Sensory Motor Neuropathy
This is not an uncommon complication of typhoid, it is noted in 5 of our 142 cases (2.38%), Osuntokun et al [11] reported 7 in his 352 children and Swamy10 reported 5 out of 40 cases (12.5%).Delirium and Confusion
These symptoms which occur in acute stage of typhoid are not included in neurological complications of typhoid.
Neurological complications of typhoid in and underprivileged communities in JJ Hospital
Of the 120 cases admitted in the JJ Hospital neurological complications occurred in 10 (i.e. 8.3%). Three had encephalopathy with hemiplegia, one had cerebellar involvement, five had meningism in which there was presence of meningeal signs and the CSF was normal and one had serous meningitis. This child had typhoid, meningeal signs and pleocytosis and 10 cells of normal biochemistry. Typhoid bacilli were not found in CSF.
Table 6 gives incidence in general of typhoid encephalopathy by various authors from all over the country between 1954 and 1990. [8-11,15,23,20,32] It was found that encephalopathy occurred in 10.2% of cases with a range of 3 to 20.3% the highest being in the series of Manchanda et al from Amritsar. [24]
Swamy et al[10]reported neurological complications in typhoid fever excluding typhoid meningitis from their experience in NIMHANS (Table 7). In their series of 46 cases with neurological complications 28 were children under 18. There were 6 cases of typhoid meningitis, one with cerebral abscess. Many of them had neurological signs like coma, quadriplegia, bilateral pyramidal signs, hemiplegia and focal fits. It shows wide varieties of neurological complications. It is interesting that hemiplegia or hemiparesis occurred in 25% of cases (10 out of 40). Cerebellar signs occurred in 22.5%, seizures in 20% and 2 of them had status epilepticus. Parkinsonian features were seen in 15% and encephalomyelo-radiculopathy in 12.5%. Table 7 also shows the eye signs like conjugate deviation, nystagmus and upward gaze palsy in 12.5% of cases. 3 children had papilloedema because of cerebral oedema, while psychosis occurred in 15% of cases. Some of rarer complications were quadriplegia, pseudobulbar palsy and polymyositis. It may be pointed out that there were multiple signs in many of these cases. Sharma and Gathwala described high incidence of encephalopathy of 42.9% in the past from Rohtak in Haryana in a series of 42 cases, while in a recent series of MDRT it was 26.5%. [47]
Typhoid meningitis (Table 8)
This includes cases in which there was frank pyogenic typhoid meningitis and does not include cases of meningism. The incidence of complications of typhoid meningitis in children is very low and there are occasional cases described by various authors mentioned in Table 8. The youngest age of a child with typhoid meningitis was 3 months while we have seen typhoid meningitis in a neonate in autopsy material in JJ Hospital. In 5 children with typhoid in our present series, we had three with tuberculous meningitis which is a rare occurrence and poses problem in diagnosis. Pal et al [9] reported 5 cases of meningitis, two in neonates caused by S. typhi and three caused by S. typhimurium. Swamy et al [10] in his study of subjects of all age groups reported 6 cases of typhoid meningitis one of whom had an abscess. Even though in our country typhoid meningitis is rare, Handerson33 reported 3 cases of typhoid meningitis with a review of 144 children from the literature. Meningitis can be frank purulent (pyogenic) meningitis or serous meningitis. In the latter the child has with meningeal signs, increased proteins and cells but no organisms.
Table 6 Various clinical types of diffuse cerebral involvement (Encephalopathy) during convalascent or post typhoid No./Total CNS involvement (%) Diffuse encephalitis (23)
Verma et al (1972)7/100 Diffuse Encephalopathy (24)
Pohwala et al (Indore) (1957)13/155(8.6%) (55) (23.6%) ICH JJH (Udani et al, 1990) 3/120 Different Types (25)
(Udani, 1991, Textbook of Paediatrics)3+1/142 Pohwala J et al (Indore) 1954) (26) 3/155 (55) (23.6%) Diffuse mixed types (27
)Silhar A et al (Rajkot) (1957)6/60 Diffuse mixed types (28)
Manchandana et al (Amritsar) (1959)(20.3) Diffuse encephalopathy (29)
Bhandari + Pohwala (Indore) (1960)38/450 (8.44) Diffuse encephalopathy (30)
Kaul KK (Jabalpur) (1963)(16.66) Joshi HD (Mumbai) (1963) (31) (13.5) Seth and Puri (Delhi) (1963) (32) 21/683 (3.09) Pandey et al (Pondy) (1990) (8) (7.6) Swamy et al (Bangalore) (1990) (10)
Encephalo Myeloradiculopathy5/45 (11.1) Kapoor et al (Delhi) (1985) (9) 3 (9.7) Osuntokun et al (Nigeria) (1972) (11) 35/352 (8.6)
Bombay Hospital Series (Table 9)
Table 9 gives neuro-complications of typhoid in children in Bombay Hospital in a period of 18 months from June 1990 to December 1991. Of the 144 cases of typhoid widal was positive in significant high titre in all children while the culture was positive in 56 of them. It gives neurological complications in 23 children i.e. almost 16%. Of these 23 cases, meningism was common and occurred in 28.6%, encephalopathy 14.28% and neuropathy both sensory and motor in 23.5%. This also included children with bilateral radiculopathy. The Table 9 also gives the complications which were uncommon like cerebellar syndrome, convulsions, subdural empyema and lateral column involvement etc. As mentioned also in Table 8 earlier, both typhoid and tuberculous meningitis occurred in 3 children.Post Typhoid Neurological Syndrome
This is a rare condition. However, it should be kept in mind as child may present with mental retardation, scholastic deterioration, some weeks or months after the attack of typhoid fever. In these children if seen early have strongly positive widal and/or culture. Even though the temperature came down to normal in this case of ours and widal was positive in May 1991, mild mental retardation and scholastic deterioration occurred in August 1991. He had second episode of neurological deterioration in November 1991. Similar 10 cases have been described by Schachter in 1954 from France. [14] The importance of such complications though rare is that if the child is seen later, aetiological cause of typhoid may be missed unless proper history, clinical data and investigations are available from the past records. It also shows that in a child with severe typhoid who might have recovered should be periodically seen for any neurological complications. Even though these cases have followed typhoid fever a possibility of chronic slow viral infection of the brain should be kept in mind. From the available data of our case and those from France it appears to be a neurological complication of typhoid only.
Table 7 Neurological complications in Typhoid Fever(Neurology Institute -
Experience - NIMHANS)(Swamy et al, 1990)Total.........46 (Ped Ado 8 Young Adults) 18 years and under 28 19 to 25 years 18 Typhoid Meningitis (PYM)6 A - 4 B - 2 Coma 5 Quadriplegia 1 Bilat Pyr Signs 3 Hemiplegia 2 Focal Fi 1(Ty Abs) Typhoid Neuro-Signs Without Meningitis Total 40 No. % Hemiplegia / Hemiparesis 10 (25) Cerebellar Signs 9 (22.5) Seizures (2 - Status) 8 (20) Parkinsonian Features 6 (15) Encephalo - Myeloradiculopathy 5 (15) Polyradiculopathy
(Myelo-Radiculopathy) (8 Years)5 (12.5) Eye Signs - (NYST.V + H (R))
- Conjugate Deviation
Upward Gaze Palsy -5 (7.5) Papilloedema (Probably - Cer. Oed.) 8 Psychosis (Schizo - 1)4} 6 (15) Catatonia2 }
(Schizo - Behaviour + Over Excitement)Quadripledge 2 Semicoma 2 Asphisia 1 Psuedo. Bulbar Palsy 1 Polymyositis 1
Spinal Cord and Neuromuscular Complications in Typhoid
These are various rare complications like transverse myelitis, myeloradiculopathy, radiculopathy, polyneuritis (Guillain Barre syndrome) sensory or sensory motor neuropathy and polymyositis.
Pathology and Pathogenesis of purulent meningitis in Typhoid
Swamy et al have reported the autopsy findings from NIMHANS in 6 children who had pyogenic meningitis due to typhoid. [10] There was characteristic purulent exudate over the supero-lateral surface of the brain which also extended at the base. There was a pressure effect on the vessels with the resultant infarction in the brain and isolated compression of cranial nerves with multiple cranial nerve palsies. They also described cortical vein thrombosis. In some of these children there was ventriculitis. Involvement of 3rd ventricle can produce hypothalamic damage.
Possible Pathogenetic Mechanisms of other neurological complications
This has been confirmed in experimental animals by Sriramachari. [34] Hyperpyrexia above 107o to 108o F may be responsible for brain damage. Though other mechanisms like fluid and electrolytes disturbances, typhoid septicaemia have been postulated, the most likely cause is typhoid neurotoxin which is responsible for the brain damage. However, with evidence of vasculitis, there could be perivenous myelinoclysis or para or post infectious encephalopathy with demyelination. In children with post-typhoid encephalopathy which may be progressive or recurrent for weeks and months, autoimmune mechanism may be responsible for progressive damage of the brain as in some cases of progressive tuberculous encephalopathy. [35,36] Immune origin of inflammatory reaction must be considered in view of perivenous myelinoclysis described above and vasculitis reported by Ramchandran et al. [37] However, there could be activation of silent neurological disease as happened in one of our cases who developed subacute sclerosing panencephalitis (SSPE). Swamy also described in his cases of typhoid encephalomyelopathy, pathological mechanisms for damage to the brain and spinal cord. In children with classical purulent meningitis, the meningeal exudate can extend into the cranial nerves specially the optic nerve. In these patients there was oedema of the brain, with neuronal loss, astrocytic proliferation in the dentato-olivary pathway. In the cervical spinal cord there was softening and focal necrosis of the grey horns in lateral columns. In 3 of Swamy’s cases even though brain was unremarkable on naked eye examination except for mild oedema there was no significant inflammatory reaction. However, there were histological changes in the cerebellum, damage to dentate nucleus and Purkynye’s cells which showed neuronal loss. Also there was damage to inferior olivary complex of medula oblongata and olivary dentate cerebellar pathway. Histological changes indicate neuronal chromatolytic cytoplasmic degeneration, neuronal destruction with astrocytosis and pallor and spongy degeneration of myelin tracts.
Table 8 Neurological complication in typhoid fever Typhoid Pyogenic Meningitis : (except one case mentioned in 3) 1. Verma et al (New Delhi) Meningitis 1/100 35 2. ICH JJH (Udani et al) Se. Meningitis 1/120 3. Bombay Hospital (Udani et al) TBM and Typhoid 3 Typhoid with probably Serious Typhoid Meningitis1 5/142 1/142 4. Arora and Kumar (Mumbai) (1964) 1/Case Report 5. Kundiya (Aurangabad) (1979) 1/Case Report 6. Phadke et al (Poona) (1980) 1 7. Fule et al (Sholapur) (1990) 4/153 8. Pal et al (Mumbai) (1990) 5 in Infants 9. Ramaswamy et al (1990) with
Autopsy Findings in Frank Pyo6 10. Osuntokun et al (1972) (Nigeria) 2/352 11. Henderson (1948) 3 (144, Reviewed)
Table 9 Neuro-complications of typhoid in BHIMS-PGI Indoor patients - Period 18 months (June 1990-Dec. 91) 1. Total admissions:(culture positive 56) 142 (all widal +ve) Complications No. % Neurological 3 (15.9) almost 16% No. % No. % 1. Meningism 6 (23.6) 2. Meningitis
(Mixed Typhoid + TB -1)4 (19) 3. Encephalopathy 3 (14.28) 4. Neuropathy 5 (23.8) i) Sensory,
iii) S.M.
iv) Radiculopathy (Bilat)
ii) Motor5. Cerebellar Synd 1 (4.8) 6. Convulsions (only) 1 (4.8) 7. Subdural empyema 1 (4.8) 8. Lat. Column Involvement 1 (4.8) (18 months spasticity - Hyperreflexia, Ankle Clonus)
Various neurological syndromes caused by TAB Vaccine
Miller [38] described neurological syndromes complicated by TAB vaccination. Mono or poly-radiculitis occurred in 12 children six in each group, polyneuritis (Guillain Barre’ syndrome) occurred in 8 children, Landry’s paralysis in 9 and transverse myelitis in one. 15 children had cerebral symptoms while 5 had meningeal symptoms and signs. The idea of presenting neurological syndromes complicating TAB vaccination is that these complications are likely to be due to autoimmune mechanism because TAB vaccine does not contain any neurotoxin.
Non-neurological manifestation of TyphoidAbdominal
In our study of 142 children at the Bombay Hospital the hepatomegaly from 3 to 5 or below coastal margin was found in almost all cases. The liver was tender in majority and the liver enzymes particularly SGPT was above 70 m per ml or more in 56.3% of cases. Hepatic scan done in proved cases with Technetium 99 showed diffuse hepatopathy with poor areas of uptake. Liver histology of biopsy specimens and autopsy studies in JJ Hospital revealed characteristic focal necrosis in the liver. It should be emphasised that typhoid is a common cause of usually a mild hepatitis. In a child with persistent pyrexia of 5-7 days or more with tender hepatomegaly, typhoid should be suspected and excluded by proper investigations.Splenomegaly
Mild to moderate enlargement of spleen was characteristic particularly between 5 and 12 days of typhoid in the past. In the present series only 1 to 3 cm enlargement of spleen occurred in majority of cases. However, when the splenic enlargement was more than 4 to 5 cm there was a strong possibility of a complicating malaria which has become endemic in this region. The spleen regressed fully after antimalarial therapy.
Gall Bladder
In our study gall bladder involvement or tenderness over the gall bladder specially on Murphy’s point was unusual. The usual finding on abdominal sonography was distended gall bladdar with suspicious cholecystitis. Even in the material at JJ Hospital gall bladder was involved in 5 out of 120 cases i.e. 4.1% cases.
Gastro Intestinal Complications
Diarrhoea was the most common complication and occasionally child presented with picture of acute gastro-enteritis and S. typhi was isolated from the stool culture in these cases. In children with diarrhoea we usually use furazolidone as it is antityphoid drug as well as controls the diarrhoea. In the old days in 40s and 50s in children with typhoid the large yellowish watery stools were described as pea soup stools which were not usually seen in the present study. Meteorism uncommon in the present series was seen frequently in children in the past. Moreover, it was one of the serious complications often with bad prognosis. Paralytic ileus occurred in 3 out of 142 cases i.e. 2.08%. The prognosis was serious with such complication in the past. None of these children died.
Haematemesis
Haematemesis is rare in typhoid but we have seen two cases.
Intestinal Haemorrhage
As per our experience in the past as well as the present intestinal haemorrhage is very rare. We have seen only 4 cases of haemorrhage in the last four decades. This is because intestinal ulcers in typhoid are shallow in children.
Intestinal perforation and peritonitis
Typhoid perforation is rare in children as ulcer is shallow. In 4 decades we have seen 3 proved cases of typhoid perforation in children. This may be partly so because some children with perforation are directly admitted on the surgical side. Taneja et al [39] between 1957-1960 also reported that perforations were rare while in a series of typhoid fever in children in JJ Hospital perforation occurred in 1 out of 120 cases (0.8%).9 However, in the series of Gupta and Gupta from Banaras Hindu University [40] in a period of 3 years typhoid perforation occurred in 65 children between the age of 5 and 15 years and the fatality was as high as 25%.
Respiratory Complications
In the past when the chemotherapy was not available for typhoid. bronchitis was part and parcel of typhoid during the second week of the disease. However, bronchitis was noted in a small percentage cases in the present series. Nontuberculous pneumonia occurred in 15.4% of cases.
Typhoid and Tuberculosis
In the series of JJ Hospital with 120 cases 11 developed intrathoracic tuberculosis, 10 having parenchymal lesions and enlarged mediastinal nodes. One child developed disseminated tuberculosis. However, there were no cases of tuberculous meningitis in the series of JJ Hospital. [9] It may be pointed out that in the past tuberculous meningitis often presented with typhoid like temperature and children were usually treated with chloramphenicol till they developed convulsions and coma. CSF examination helped in the diagnosis of tuberculous meningitis along with other investigations for evidence of tuberculosis.
Typhoid and Tuberculosis in Bombay Hospital
Amongst the 142 cases of typhoid, tuberculosis was detected in 35 (24.3%) of cases. Such a high incidence is because both conditions are common in our situation. However, reactivation of tuberculous focus may follow typhoid often because the patients are starved or not given adequate nutrition which is a traditional practice with some physicians with the result that both typhoid fever per se and its consequence of undernutrition lead to reactivation of tuberculous focus in any organ. We have found that almost all of them and intrathoracic tuberculosis while in 3 children there was mixed infection, with typhoid and tuberculous meningitis. It is important to keep this complication in mind as it may not be easy to distinguish between typhoid and tuberculous encephalopathy or serous meningitis as presence of meningeal signs as well as increased protein and cells without change in sugar and chloride values may occur in both. Encephalopathy following typhoid and/or tuberculosis may be distinguished on circumstantial evidence, and by special immunodiagnostic test e.g. by Elisa, and detection of Tb. Antigen in the C.S.F. Presence of Tb. antigen in the C.S.F. is diagnostic of tuberculous aetiology but a negative result does not exclude TB. Positive polymerase chain reaction (PCR) in CSF confirms tuberculous aetiology.
Neurological Complication of Typhoid Fever
It may be desirable to review some of the neurological complications of typhoid in children described in past (Table 10) and complications encountered in the recent series of ours as well as others between 1987 and 1990.
Complications described in the past 3 1/2 decades
Fig. 4 describes the CNS involvement in 55 children in a total of 155 cases of typhoid reported by Pohowala and Ghai in 1957. [23]
Typhoid Encephalopathy
This was described in 13 cases. The characteristic encephalopathy in these series occurred after the fever settled down or responded to chloramphenicol and then child progressed from semicoma to coma. The duration of encephalopathy varied from days to weeks. The results in their case were either recovery, death or residual brain damage like mental retardation, hemiplegia, ataxia and choreiform movements. One of the interesting findings in this series was absent abdominal reflexes (Fig. 4). Table 10 shows the neurological complications of typhoid as reported by various authors. [32] In the series of Seth and Puri,32 45 out of 683 children developed neurological complications. Table 11 gives the detailed description of the various neurological signs in their serious. Overall mortality in this series was 17.7%. It can be seen that typhoid was a serious disease in the past even though S. typhi was sensitive to chloramphenicol.
Neuropsychiatric manifestations in Typhoid Fever
Osuntokun et al [11] reported a study of 959 cases of typhoid fever with neuropsychiatric manifestations, a study which was carried out over a period of 6 years from 1966 to 1971 in Nigeria. Though the data included subjects of all the age groups there were 352 cases in children and young adults under 20 years. He reported encephalopathy in 35 cases i.e. 3.6% of total patients or almost 10% of the neuropsychiatric manifestations (Tables 5 and 6). The confusional states or delirium was most common while semicoma and coma which are manifestations of encephalopathy occurred in 35 subjects as mentioned above. The motor neuron disease, temporary amnesia, and schizophreniform psycho is occurred in subjects who were prone to these diseases. [11] The neurological complications of typhoid in the past 3 to 4 decades by various authors in India have been listed in Table 6. In this period S. typhi was sensitive to chloramphenicol and ampicillin. However, as shown in Table 6 CNS involvement occurred in 36.4% of cases of Bhandari and Pohowala. [29] Taneja and Sood in 33.3% of cases and 30.3% of cases in the series of Seth and Puri. [32] Verma et al reported 100 culture proved cases of typhoid fever in whom CNS involvement occurred in 35% and encephalopathy 20% (Table 10). These authors classified the cases of encephalopathy on the basis of onset, duration and whether there were meningeal signs or not along with CSF findings. They described them as meningo-cerebral with normal CSF, diffuse encephalitic in those who had no meningeal signs, acute encephalitic type and acute meningitic type which are rare. However, in these latter cases of serous meningitis there was pleocytosis in the CSF.
Table 10 Neurological complications of the typhoid in the past 3-4 decades(Sensitive to Chloramphenicol and Ampicillin) Authors Year Total Mental changes and Neurological Findings 1. Taneja and Sood 1957 60 DelirumInvolantry Movements 33.3(%)
(6.6%)2. Bhandari andPohwala ( 1960
(1954,ENC)155 CNS Involvement 57(36.4)(%) 3. Seth and Puri 1963 683 CNS Involvement 45(30.3)(%) 4. Verma et al
(Typhoid Fever -
Culture Proved)1972 100 CNS Involvement
Encephalopathy35 (%) Types of Encephalopathy No. of Cases No. of Deaths 20(%) 1. Meningocerebral 11 2 2. Diffuse Encephalitis
(No Meningeal Signs)7 3 3. Acute Encephalitic 1 3 4. Acute Meningitic 1 Nil
Table 11 Neurological complications (Not MDRT) Total Cases - 683 - Neuro - Complications - 45)
(Seth and Puri - 1963)
Total Neurological Complications : 45/683Neurosigns (A) No. % Neurological Signs (B) No. % 1. Delirium 16 (35.5) 1. Hyperreflexia 21 (46.2) 2. Disturbance in Sensorium (Drowsiness - Coma) Encephalopathy 21 (46.6) 2. Extensor Plantar 12 (26.4) 3. Convulsions 3 (6.6) 3. Meningism 66 (13.2) 4. Hemiplegia 3 (6.6) 4. Facial Palsy 2 (2.2) 5. Chorea 1 (2.2) 5. Papilloedema 1 (2.2) 6. Tremor 1 (2.2) 7. Blindness 1 (2.2) . Cardiovascular complications particularly myocarditis in Typhoid
In the past cardiac complications were common and it was thought that these children had toxic myocarditis. As a matter of fact before the days of chemotherapy when the typhoid was considered a very serious disease, myocarditis was considered a common occurrence to such an extent that we used to take electrocardiograms (ECG), whenever child had well marked tachycardia, unusual bradycardia or more commonly weak heart sounds, tick tack rhythm or gallop rhythm. Even though enlargement of heart was not common, ECG changes were very common and often we discharged the child when the ECG became normal. In 1960 typhoid constituted almost 13.2% of the various communicable diseases in the BJ Hospital for children. [41] Moreover, chloramphenicol was not available freely at that time with the result that we had to keep these children for a longer time in the hospital. Frank myocarditis with cardiac enlargement and cardiac failure was rare and is rare even today. Singh and Singhi [42] reviewed the cardiovascular findings in enteric fever and found that it occurred from 1 to 80% of cases of typhoid. ECG changes occurred in 30 to 80 per cent of patients. Their ECG criteria for diagnosis of myocarditis were prolonged PR interval, lengthening of Q-Tc interval, conduction defects and ST and T wave changes often associated with low voltage. However, these ECG changes alone did not correlate with the clinical toxicity. Moreover, cardiac failure may be present with minimal ECG changes. A significant rise of SGOT was observed in 30 per cent of enteric myocarditis by Khosla et al. [43] In most of our cases SMA 12 was done and it revealed varying degrees of increase in SGPT and mild increase in SGOT which may be related to myocardial involvement. However routinely ECG was not done. When clinical myocarditis was present with evidence of cardiac enlargement, feeble heart sounds and gallop rhythm and evidence of cardiac failure the prognosis was poor. Mortality was 77% in the series of Rowland. [44] Mujumdar et al[45] reported cardiac involvement in typhoid fever in children in Calcutta and reiterated that cardiomyopathy may result as a long term sequelae of typhoid myocarditis.
In a recent study of multi-drug resistant typhoid fever in Calcutta. Arora et al[46] reported relative bradycardia in 11.6% of cases while in another study. Sharma and Gathwala[47] reported the complication of myocarditis in 14.3% in a series of 42 cases in the past when S. typhi was sensitive to chloramphenicol. While in their recent series of multi-drug resistant typhoid no case of myocarditis was detected.
Renal involvement
In many ill children in the past and recent series, urine examination, often revealed presence of albumin, occasional pus cells, red blood cells and granular casts indicating mild toxic nephropathy but this was asymptomatic and usually of no significance. However, overall renal involvement considering all cases of typhoid it is rare, 2 to 3%. [48] We have seen typhoid fever presenting with clinical features of acute glomerulonephritis in the past and we described this type of onset of typhoid as nephrotyphoid. [25] However, frank acute glomerulonephritis with severe renal failure due to MDRT has been reported in a child of 10 years by Dhawan and Marwah.[49]The patient recovered with peritoneal dialysis and ciprofloxacin. Sitprija et al [50] carried out renal biopsies in 3 unselected cases of typhoid fever with no clinical and laboratory evidence of renal dysfunction and were able to demonstrate immune-complex glomerulitis in all. However, in a recent report, same authors have suggested a direct role of S. typhi in the pathogenesis of renal lesion. They observed deposition of immunoglobulin and complement on the glomerular basement membrane besides detection S. V1 antigen in the glomerular capillary wall. Similar case has been described by Amerio et al. [51] Khosla and Lochan[52] correlated the disappearance of circulating immune-complexes with recovery of renal function.
MECHANISM OF RESISTANCE OF S. TYPHI TO CONVENTIONAL DRUGS
The strains of multi-drug resistant S. typhi have been increasing in India for the last 5 to 6 years. However, earliest reports of S. typhi resistance to chloramphenicol was first published in 1950. [53] Since then a number of outbreaks of typhoid fever due to resistant strains of S. typhi have been described in different parts of the World [54] as well as in India. [55] However, as mentioned earlier the epidemic proportion of resistant typhoid has been widely reported in the last 5 to 6 years or so. Various authors from India have reported increase in multi-drug resistant typhoid fever to an extent of 10 to 50% to the conventional chemotherapy. [56] Koul [57] reported a series of 48 bacteriologically proved cases of enteric fever in whom 35% were resistant to conventional drugs. They also reported that the incidence of complications such as shock, myocarditis, encephalopathy and paralytic ileus was high among these children which has not been the experience of ours and many others.
Meherban Singh[56] has reviewed briefly the mechanism of resistance. Jesudasan and John6 described in Vellore study that of the total 115 isolates. 13 or about 11% were resistant to chloramphenicol, ampicilin and cotrimoxazole. From conjugate experiments with 10 out of 13 strains using E coli, K 12 (J 62.2) response, they found that in every case E coli acquired resistance to all the 4 drugs. They suggested that the antimicrobial resistance was through plasmin mediation. Plasmids are small extrachromosomal genetic elements to which bacteria act as hosts. Plasmids are indispensable to cell under ordinary conditions of growth. Presence of plasmids is detectable, when genes they carry confer new properties on the hosts. [58] A resistance may develop by mutation or as mentioned earlier by acquisition of plasmid mediated R factor. The resistance (R) factor carry genes conferred on the host cell to various antimicrobial agents such as antibiotics. Single plasmid for example may carry separate genes for resistance to streptomycin, chloramphenicol and sulphonamides. In some cases it is possible to dissociate the plasmids into several smaller ones, an element called resistance transfer factor (RTF) carrying the genes to intracellular transfer process and separate elements called R determinants carrying the resistance genes while in others as various elements remain tightly linked, the entering plasmid is referred to as R factor. Plasmids are of major clinical significance not only because they may carry genes for resistance to therapeutic drugs but also because some of them mediate bacterial recombination a process that leads to emergence of strains with new combinations antigenic and virulence factors. The R factor appears to have originated from nonpathogenic enterobacteria like E coli or Shigella pathogens. The R factor transfers from the resistant S. typhi to E coli, E 12 at a frequency of about 10 x 4 and from E coli, K 12 to VI type S. typhi at a rate of about 10 x 6 in and overnight crosses.
Drug resistance in gram negative bacterial genes governing resistance to various drugs like neomycin, kanamycin, streptomycin, chloramphenicol are found on one or another plasmid with various combinations. Most plasmid-governed resistance is mediated by enzymatic inactivation of the drug, for example by acetylation or phosphorylation. While chromosomal mediated resistance usually reflects a lowered affinity of its target molecule for the drug. Bacteria can become resistant to drugs by any one of the three genetic mechanisms, mutation, recombination or acquisition of plasmid carrying drug resistance genes. 60 to 90 per cent or resistance genes in the gram negative pathogens are carried on transferable plasmids. This is of clinical significance as plasmids can transfer from cell to cell with ease and strong selection which chemotherapy has exerted on drug resistance have combined to produce striking results. Plasmid genes for antimicrobial resistance often control the formation of enzymes capable of destroying the antimicrobial drugs. Chloramphenicol resistance is due to destruction of the drug by an enzyme chloramphenicol acetyltransferase.
The high incidence of typhoid fever and misuse, overuse and abuse of various antibiotics has led to the present problem of resistant S. typhi. For example combination of chloramphenicol and streptomycin was extensively used in infants and children for gastroenteritis some of whom were due to viral infections while others due to E coli. [59] Similarly cotrimoxazole has been used extensively in gastrointestinal tract infections. In our study of sensitivity and resistance of S. typhi to various antimicrobial agents (Fig. 3) it was found that the 95% to 97% of the strength of S. typhi were sensitive to amikacin and norfloxacin. Similarly cefaxone and some of the 3rd generation cephalosporins have been used because sensitivity to S. typhi to these drugs was over 90% and the cure rate was satisfactory.
THERAPEUTIC IMPLICATIONS AND RESPONSE
After realising that large number of cases of typhoid fever admitted in 1990-91 were sensitive to amikacin and norfloxacin, we have routinely used these drugs in multi-drug resistant typhoid fever. In almost 95% of cases high temperature settled down within 3 to 5 days of the use of these two drugs. In some of these cases even though the temperature was present, the toxaemia reduced remarkably. In some children in whom inspite of improvement in general condition and toxaemia often high fever persisted causing anxiety. However, in these cases we have used steroids particularly parenteral dexamethasone along with other antibiotics and fluid therapy given by intravenous route. Response was almost dramatic and within 24-48 hours of starting of therapy temperature came down to normal. Symptoms and signs regressed and the child became alert and playful with improved food and fluid intake. It may be emphasised that in none of the cases in which steroids have been used along with appropriate antimicrobial therapy any complications like perforation, haemorrhage, abdominal distension have occurred. Almost 35 years back when chloramphenicol alone was used in the treatment of typhoid and temperature was not responding satisfactorily the use of steroids was advocated as a routine in ill children with excellent results. [39,60] As mentioned earlier these complications are extremely rare because in children typhoid ulcers are shallow. Apart from the improvement in general condition with amikacin and norfloxacin there was regression of enlarged tender liver, improvement in heart sounds and meningeal signs. There was not a single death in the series of 142 cases treated in Bombay Hospital in a period of 2 years. Similar results have been described by others. [61] In children who had diarrhoea as a symptom of typhoid fever or gastroenteritis due to S. typhi steroids were not used. In these children over and above two drugs mentioned above, furazolidone was used as it acts on S. typhi as well as it is useful in the control of diarrhoea. In our experience the cotrimoxazole was rarely useful as was borne out by the studies that organisms were sensitive to it only in 13% while in the series of other resistance to cotrimoxazole has been less than in our study. This is probably so as in practice often cotrimoxazole is much more commonly used in various infections in children in Mumbai.
The conventional drugs chloramphenicol, amoxycillin, ampicillin, cotrimoxazole may be tried initially in children with typhoid and if response is satisfactory the other newer drugs may not be used. However as our experience has been mainly with referred cases, who had already received a number of these drugs over a period of one or two weeks, our routine was to use amikacin and norfloxacin or ciprofloxacin in these children. With the use of the first two drugs the response rate was excellent and there were no complications or fatality as opposed to the comparatively high case fatalities in children treated in general hospitals like Kasturba Hospital with multi-drug resistant typhoid fever.
There has been some objectives against the use of quinolone group of drugs including norfloxacin, ciprofloxacin or ofloxacin and others. Though these drugs are the drugs of choice for adults, in children often there is objection to use them because of their potential irreversible damage to the cartilage of weight bearing joints of immature animals like rats, rabbits etc. Such results in experimental animals are likely to be due to a very large dose of the drug used in animals. Though it is too early to say in a period of 2 to 3 years there has not been a single case in which any adverse effects are noted. It may be pointed out that nalidixic acid which is being used for over 2 decades particularly for urinary infection has not produced any adverse effects in children inspite of its adverse effects of arthropathy in experimental animals. It appears that quinolone associated arthropathy may be species specific and dose dependent. In animals the dose used is 10 times more than that with therapeutic dose used in children. Hence it should be our routine of using two drugs namely amikacin and norfloxacin along with fluid therapy, multivitamins and micronutrients including zinc and in some cases steroids. High calorie, soft, well cooked nutritious family diet has been rewarding as there been no complications and no fatalities in our cases with this treatment.
Prevention
With the availability of large number of chemotherapeutic agents particularly for enteric infections, various public health measures like disposal of sewage, clean sterile water atleast by boiling have been neglected. At the personal and hospital level, washing hands, cleanliness, measures to reduce the menace of flies, disposal of excreta, a separate ward and separate staff for these patients have been neglected with the result that enteric infections have widely spread.Typhoid Vaccine
Realising the epidemic proportion of multi-drug resistant typhoid fever it is essential that the newer and effective vaccines should be included in the universal programme of immunisations (UPI) with primary and booster doses so as to provide at least some protection. An injectable V1 polysaccharide vaccine has been tried and found protective in 64% of children only by one injection. However for the present acetone inactivated vaccine should be included in the UPI.
Syndromes associated or due to Typhoid Fever and some precipitated by Typhoid (MDRT), some interesting case examples
i) Typhoid with reactivation of neurotuberculosis
This girl S. Nair of 13 years had a history of typhoid fever with strongly positive widal and was treated with antityphoid drugs. She was admitted in the Bombay Hospital with a history of high irregular fever and CSF showed mild increase of proteins and cells but sugar and chlorides were normal. Because of persistence of temperature tuberculin test was done. It was strongly positive and chest X-ray revealed massive paratracheal adenopathy on the right side with apical mottling. Child was treated with antituberculous drugs INH, RMP and PZ along with amikacin and norfloxacin. However, the temperature persisted even though child clinically improved remarkably, meningeal signs disappeared and she was conscious, alert, walking about and was normal except for irregular high fever. Suspecting pyrexia of central origin an MRI of the brain was done and it revealed infarction in the region of the thalamus and caudate nucleus indicating that pyrexia was central in origin. Central fever is due to disturbance of heat metabolism due to damage to the roastal area of hypothalamus particularly of the preoptic nucleus. This girl made uneventful recovery and has been followed up for a period of 3 years without any complications.ii) Atypical Reye’s syndrome and other neurological complications following typhoid
Kuldip an 8 year old male child was admitted with atypical Reye’s syndrome with very high SGPT of 5000 mu/ml. Blood ammonia was also increased. Child had consistently positive widal in high titre and irregular high fever. This child developed Parkinsonian syndrome with characteristic rigidity, Parkinsonian tremors and shuffling gait. He also had frontal lobe syndrome with echololia, emotional lability and other characteristic symptoms like personality changes which have been described after leucotomy. This child improved with antityphoid drugs, steroids and mannitol. It is a very interesting case example of a child who came with strongly, positive widal, convulsions, vomiting, coma with markedly raised SGPT of 5000 m/ml increased blood ammonia and had persistent pyrexia. Child developed initially Parkinsonian syndrome which improved in a period of 3 weeks and later had evidence of symptoms suggestive of damage to the frontal lobe.iii) Post Typhoid CNS involvement
This occurred in a girl, Jyoti 6 years old who had typhoid like temperature about 6 to 8 weeks earlier. Her mother and also other sibs had typhoid and widal was strongly positive both in the mother and the other sibs. As Jyoti was admitted 6 to 8 weeks after the temperature settled down, her widal was negative because of 8 weeks of interval after typhoid. Moreover, antityphoid drugs were given. Her CSF was normal. She had spastic quadriplegia, pseudobulbar palsy, emotional lability and had seizures. It was interesting that the child was conscious, alert, recognised the mother and distinguished the strangers. But later she developed aphasia. This child was diagnosed as a case of post-typhoid CNS involvement with severe cerebral damage. An MRI revealed periventricular leucomalacia indicating demyelination of the white matter. This child was kept on long term steroid therapy and there was only mild improvement in her condition. A follow up of one year later revealed that the child was conscious, alert, had spastic quadriplegia, and emotional lability but aphasia had improved and she could speak a few words.
iv) Subacute Sclerosing Pan Encephalitis (SSPE) following typhoid or precipitated by typhoid
Mehboob Alam, an 11 year old male child was BCG vaccinated. He developed typhoid in January, 1990 and widal was positive 1:250. His tuberculin test was positive. Chest X-ray was positive for intrathoracic tuberculosis. An MRI was suggestive of tuberculoma in the brainstem with hypodense area around due to oedema. Child was given amikacin injection, norfloxacin tablets, anti tuberculous drugs and steroids. He improved so remarkably that he walked out of the hospital and appeared normal. However, he was readmitted with a relapse after 3 months. EEG showed a characteristic picture of SSPE. A second MRI showed extensive area of demyelination in the brain. The CSF measles titre was high and it also showed increased gammaglobulins. This was one of the most unusual case as he presented with typhoid, had meningeal signs and because he was conscious, alert and had quadriplegia an MRI was done which was suggestive of tuberculoma in the brain stem. During the first admission he was also seen by a neurologist and he ruled out the possibility of SSPE. However, three months later when he was readmitted, he had characteristic EEG of SSPE and high measles antibody titre in CSF. Child deteriorated rapidly and he was discharged at request because of his hopeless condition. This child had typhoid, probably tuberculoma as he improved remarkably with anti TB drugs and steroids but finally he died of SSPE.
v) Subdural Effusion with Typhoid
Kum. Pervin Ali Ibrahim a 12 year old girl had enteric fever with proved strongly positive widal and developed cerebellar ataxia. She also had tingling and numbness in limbs and EMG and nerve conduction showed sensory motor neuropathy. The girl improved remarkably with chemotherapy and steroids.
vi) Subdural Effusion with Typhoid
Master R. Jadhav, 8 year old male child was admitted with typhoid fever, strongly positive widal, both 0 and H (1:250) and developed paralysis of the left lower limb. CT scan showed subdural effusion. CSF showed increased proteins and cells. Subdural effusion in typhoid has not described but it is possible that child had vascular damage during septicaemia, which might have resulted in subdural effusion. CSF findings were suggestive only of serous meningitis.
vii) Typhoid with Serous meningitis and bilateral radiculopathy
Cyrus Pinherio, a 10 year old male child was admitted with a history of persistent pyrexia with difficulty and pain on walking. Widal was strongly positive (1:250). A CSF revealed increased proteins and cells. The nerve conduction study revealed bilateral radiculopathy. The child recovered fully with anti typhoid drugs and steroids.
The above mentioned cases are examples of typhoid complicated with tuberculous meningitis, associated with other conditions like SSPE and picture simulating atypical Reye’s syndrome, cerebellar ataxia and sensory motor neuropathy which have been described in typhoid but not the subdural effusion. These cases point out to the unusual complications of typhoid associated with neurotuberculosis and some were probably precipitated by typhoid like SSPE. Moreover, at times it is difficult to make out whether the child had tuberculous encephalopathy or typhoid encephalopathy or both as this boy had miliary tuberculosis which improved with treatment, but later developed encephalopathy and died.viii) Post typhoid recurrent episodes of cerebral involvement
Aqdus Tatli, an 11 year old girl had typhoid in May, 1991 with strongly positive widal in a titre of 1:250. The girl was brilliant in studies before the illness. In the hospital she had positive tuberculin test. After the attack of typhoid in May, 1991 she recovered fully with treatment. She was readmitted in 13th August, 1991 for behaviour disorder and mental regression. She became dull, had mental changes, irritability and had no interest in studies. She improved with anti tuberculous drugs, isoniazid, rifampicin and steroids. During her 2nd visit she was hospitalised for 4 weeks and she improved remarkably. She was readmitted 3rd time in December, 1991 when she had relapse. She had mental change, abnormal behaviour and loss of memory. Her handwritings had deteriorated. She improved with anti tuberculous drugs as well as antityphoid drugs and steroids. This is one of the unusual cases of typhoid with post typhoid recurrent episodes of cerebral involvement and was complicated by tuberculosis. In such a case it is difficult to distinguish cerebral involvement due to typhoid from chronic or recurrent tuberculous encephalopathy. [35,36]
SUMMARY AND CONCLUSIONS
This communication deals with the problem of typhoid fever in the past 3 to 4 decades and recent epidemic outbreak of multidrug resistant typhoid all over the country. It provides an incidence of resistance / sensitivity of S. typhi to various conventional and newer antimicrobial agents so that rational drug therapy can be used in children. Typhoid used to come in an epidemic proportion in the past. However as the organisms were sensitive to chloramphenicol, fatality rate even in the past was low. It may be emphasised that fatality rate in the past was higher in adults than in children.
The present paper particularly emphasises the neurological complications of typhoid fever described by various Indian and foreign authors in the past and the present and our experience both personal as well as of other Indian authors. Various neurological complications not emphasised in the past have been emphasised in the present series of ours and describes complications like subdural fluid collection though rare, fairly high incidence of sensory motor neuropathy, cerebellar complications and various types of encephalopathies. Often these encephalopathies could be missed if typhoid fever as the cause is not kept in mind. Number of cases of mixed infections of tuberculous and typhoid encephalopathy, mixed meningitis and conditions like Reye’s syndrome and other unusual manifestations have been stressed. Moreover, conditions like SSPE may be activated in isolated cases. The SSPE might be incidental, associated or precipitated. Similar silent conditions have been reactivated in the experience of others particularly in Nigeria.
Other interesting features are very common involvement of liver usually mild hepatitis almost forming part and parcel of typhoid fever, but at times it was severe and the initial picture simulated viral hepatitis. A number of non-neurological manifestations or complications of typhoid involvement respiratory, cardiac, renal and other systems have been briefly described. It may be emphasised that as typhoid and tuberculosis both are common conditions in our country, in children who have persistent pyrexia due to typhoid, there may be activation of various clinical types of tuberculosis. This is likely to occur much more so in underprivileged population. In the experience of majority of paediatricians, perforations and/or haemorrhage is rare.
A s a routine, initially drugs like chloramphenicol, ampicillin, cotrimoxazole may be tried but as
