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Spotted fever group (SFG) rickettsial infections are increasingly detected in Sri Lanka. We describe 17 patients with SFG who developed neurological manifestations.
Methods
The cases were studied prospectively from 2008 at the Teaching Hospital, Peradeniya. An immunofluorescent antibody assay (IFA) was used to confirm the diagnosis.
Results
All had an IFA IgG titer ranging from 1/64 to 1/4096 and a positive IFA IgM titer against Rickettsia conorii antigen; in 10 (59%) cases the IgG titers were ≥1/256 (definitive cases). The median age of the patients was 62 years (range 26–82 years); 10 were male and seven female. The median duration of fever was 12 days (range 4–35 days). Neurological manifestations on admission were drowsiness or confusion in 14 (82%) and a semi-comatose state in three (18%). Rigidity of the limbs occurred in 14 (82%), bradykinesia and resting tremors in 12 (71%), which persisted after defervescence, neck stiffness in seven (42%), weakness of the limbs in five (29%), deafness in two (12%), and stupor in three (18%). Electroencephalograms in three (18%) showed generalized slow waves. Cerebrospinal fluid examination showed a cellular reaction, predominantly lymphocytes, in three cases. Two patients died (fatality rate 12%).
Conclusion
We have documented for the first time the neurological features of SFG rickettsioses in the Central Province, Sri Lanka. These were predominantly extrapyramidal features in patients of older age.
The first recorded reference to rickettsial infections in Sri Lanka dates back to 1937–1945. Hospital-based studies carried out in 2001 and 2008 described the predominant prevalence of spotted fever group rickettsiae (SFG) in the hilly Central Province of Sri Lanka, and Orientia tsutsugamushi (scrub typhus) in the Western Province, the low country wet zone of Sri Lanka.
The emergence of SFG rickettsial infections in the Central Province was discovered among patients with clinically presumed rickettsial infections by immunofluorescent antibody assay (IFA) against Rickettsia conorii antigen. In the same region, IFA reactivity was found against Rickettsia helvetica, Rickettsia japonica, Rickettsia slovaca, Rickettsia asiatica, Rickettsia heilongjiangensis, and Rickettsia felis YH and TT118 antigens.
However, the rickettsial species that cause spotted fever in the region remain unknown. Rickettsial pathogens primarily infect endothelial cells causing disseminated vasculitis, which may subsequently lead to multiple-organ involvement.
Common clinical manifestations among SFG rickettsioses in the hilly Central Province include vasculitic skin rashes and arthritis, but clinical manifestations are sometimes obscure. However, since 2008 we have detected diverse neurological manifestations among spotted fever patients. The objective of this study was to summarize these manifestations in 17 such patients.
2. Methods
Data collected prospectively on patients admitted to the Teaching Hospital, Peradeniya since 2008 and who were later confirmed to have rickettsioses by IFA were analyzed, including history, clinical features, co-morbidities, laboratory investigations, and the presence of animal and insect bites. Those patients with an altered level of consciousness or those with other neurological manifestations such as unsteady gait, tremors, or focal neurological signs were identified as neuro-rickettsial cases. The initial clinical diagnosis of rickettsial infection was made based on three criteria: fever of more than 5 days, presence of a maculopapular rash, particularly involving palms and soles, and defervescence with anti-rickettsial antibiotics.
Blood samples for serology were obtained between day 8 and day 12 of the illness, and the IFA was carried out only on acute serum samples.
IFA assays were carried out to detect IgG and IgM antibody titers against prototype strains of O. tsutsugamushi (serotype Karp), Rickettsia typhi (Wilmington), and R. conorii (Malish) antigens. Antibodies were detected using fluorescein-conjugated goat anti-human IgG (γ-chain) or IgM (μ-chain) (KPL, Inc., Gaithersburg, MD, USA). The serum samples were screened at 1/32 dilution, and positive samples were titered to the endpoint using two-fold dilutions. Based on the published literature, an IFA IgG titer of 1/256 or more was considered positive for a definite diagnosis of SFG in this study.
This study forms part of the rickettsial studies that are currently being carried out, for which ethical approval was obtained from the Ethics Committee, Faculty of Medicine, Peradeniya University, Sri Lanka.
3. Results
A total of 134 patients fulfilled the clinical and serological diagnosis of rickettsial infection during the study period. Of these, we identified 17 patients who had neuro-rickettsioses. They had a positive IgM titer of 1/16 and positive IgG titers ranging from 1/64 to 1/4096 against R. conorii antigen. Ten patients (59%) had IgG titers ≥1/256 (definitive cases), whilst seven patients (41%) had titers <1/256 (presumed cases). All were non-reactive to R. typhi and O. tsutsugamushi antigens.
The median patient age was 62 years (range 26–82 years); 10 were male and seven female. The median duration of fever was 12 days (range 4–35 days). Out of the neurological manifestations, 14 (82%) were either drowsy or confused and three (18%) were in a semi-comatose state on admission. Fourteen patients (82%) had rigidity of the limbs, 12 (71%) had bradykinesia and resting tremors (which persisted even after defervescence), seven (42%) had neck stiffness, five (29%) had weakness of the limbs (a 33-year-old male patient developed flaccid quadriparesis and recovered), two (12%) had deafness, and three (18%) had stupor (Figure 1). Other manifestations were headache in 16 (94%), skin rash (Figure 2) in 17 (100%), fern leaf skin necrosis in seven (41%), conjunctival injection in 11 (65%), arthritis in seven (41%), and icterus in six (35%). Electroencephalograms (EEG) were done in four patients (24%), and three (18%) had generalized irregular slow waves suggestive of encephalitis (Figure 3). Of the seven cerebrospinal fluid (CSF) examinations, three had a cellular reaction in the form of pleocytosis.
Figure 1An elderly patient in a confused state with extrapyramidal rigidity.
Clinical and laboratory details are presented in Table 1, Table 2, according to the serology cut-off value of 1/256 (patients with titer ≥1/256 and patients with titer <1/256). Mean liver enzyme levels were high, and most patients had leukocytosis. The definitive cases had a mean platelet count of 97 × 109/l (range 4–194 × 109/l). The clinical details of the definitive cases are shown in Table 3. Two patients died (death rate 12%), but they had IgG titers <1/256. The remaining patients made a slow recovery with treatments such as doxycycline, chloramphenicol, and steroids.
Table 1Clinical features of patients based on IFA titer levels
Parameter
Titer ≥1/256 (n = 10)
Titer <1/256 (n = 7)
Age (years), median (range)
63 (33–79)
60 (26–82)
Gender, n (%)
Male
5 (50)
5 (71)
Female
5 (50)
2 (29)
Clinical features, n (%)
Fever
10 (100)
7 (100)
Headache
9 (90)
7 (100)
Myalgia
10 (100)
6 (86)
Vomiting
5 (50)
5 (71)
Cough
5 (50)
3 (43)
Icterus
3 (30)
3 (43)
Conjunctival injection
6 (60)
5 (71)
Skin rash
10 (100)
7 (100)
Necrotic rash
4 (40)
3 (43)
Arthritis
5 (50)
2 (29)
Diarrhea
3 (30)
1 (14)
Hepatomegaly
3 (30)
1 (14)
CNS clinical features, n (%)
Drowsy
1 (10)
2 (29)
Confusion
7 (70)
4 (57)
Semi-comatose
2 (20)
1 (14)
Hallucinations
1 (10)
0
Extrapyramidal rigidity
9 (90)
5 (71)
Tremors (Parkinsonism)
8 (80)
4 (57)
Stupor
1 (10)
2 (29)
Neck stiffness
5 (50)
2 (29)
Motor weakness of the limbs
2 (20)
3 (43)
Tinnitus
1 (10)
1 (14)
Deafness
1 (10)
1 (14)
IFA, immunofluorescent antibody assay; CNS, central nervous system.
Drowsy, mask-like face, rigidity, tremors of hands and bradykinesia
Arthritis, cough, icterus, thrombocytopenia; poor response to chloramphenicol; recovered with doxycycline
2
62, F
1/4096
Neg
Confused, neck rigidity, rigidity, tremors of hands and bradykinesia
Generalized skin rash, mild thrombocytopenia, high liver enzymes, normal CSF, EEG – slow waves suggestive of encephalitis; recovered with chloramphenicol/doxycycline
3
66, M
1/4096
Neg
Confused, rigidity, tremors of hands and bradykinesia, tinnitus, deafness
Generalized skin rash, arthritis, thrombocytopenia, high liver enzymes, normal CSF, EEG – slow waves suggestive of encephalitis; recovered with chloramphenicol/penicillin
4
60, F
1/2048
Pos
Confused, neck stiffness, rigidity, tremors of hands
Rash on the legs and feet, arthritis, CSF – high proteins, 100 × 106 cells/l (80% neutrophils); treated with doxycycline/penicillin/cefotaxime; recovered
5
63, F
1/2048
Pos
Semi-comatose, neck stiffness, rigidity and tremors, reduced power of limb muscles
Skin rash on the limbs, abdominal pain, icterus, mild thrombocytopenia, EMG – normal, CSF – 10 × 106 cells/l (60% neutrophils); treated with chloramphenicol and ceftriaxone; recovered
6
33, M
1/4096
Pos
Semiconscious, neck rigidity, flaccid motor weakness of limbs suggestive of Guillain–Barré syndrome
Skin rash, developed hepatic failure, icteric myocarditis, respiratory failure and required assisted ventilation, EEG – normal, EMG – motor axonal polyneuropathy; treated with many antibiotics including chloramphenicol and doxycycline; complete recovery
7
65, M
1/256
Pos
Confused, rigidity, tremors of hands and bradykinesia, weak right arm
Skin rash, thrombocytopenia, CT brain – left cortical infarction; recovered with chloramphenicol
8
72, M
1/2048
Neg
Confused, abnormal behavior, rigidity and tremors in the hands
Skin rash over feet, hands, and chest, mild thrombocytopenia, CSF – 5 × 106 cells/l, high proteins; treated as meningoencephalitis; recovered
9
79, F
1/512
Neg
Confused, mask-like face, rigidity, tremors of hands and bradykinesia
Skin rash on feet, normal blood counts; recovered with chloramphenicol/doxycycline
10
55, M
1/1024
Neg
Confused, neck stiffness, photophobia
Generalized skin rash, facial puffiness and leg swelling, arthritis, EEG – slow waves suggestive of encephalitis; recovered with chloramphenicol/doxycycline
Obscure neurological manifestations such as altered level of consciousness, extrapyramidal manifestations, tremor, rigidity, and dyskinesia were observed in a series of patients with SFG rickettsial infections, predominantly affecting those of older age. In most of the patients cure was possible by administration of anti-rickettsial antibiotics.
We used R. conorii antigen to diagnose SFG in these patients, as it has been used in previous studies in Sri Lanka.
This was based on the knowledge of the existence of wide cross-reaction between SFG rickettsiae, even though the exact local rickettsial pathogens of SFG remain unknown. According to the published literature on SFG, neurological manifestations in Rocky Mountain spotted fever caused by Rickettsia rickettsii are not uncommon. There is a report of neurological manifestations in a series of dogs infected by R. rickettsii.
However, neurological manifestations of Mediterranean spotted fever are limited to case reports, and common neurological problems in these cases have been alterations of the level of consciousness, headache, and CSF abnormalities such as pleocytosis and increased protein levels suggestive of meningoencephalitis.
In comparison, some patients in the current series had EEG changes compatible with encephalitis, whilst others had CSF changes. Computed tomography (CT) scans were done in only three patients, and one of these showed a cerebral infarction. However, the majority of patients had extrapyramidal manifestations along with an altered level of consciousness. Although magnetic resonance imaging (MRI) scans of the brain would have been more informative, none of the patients underwent an MRI scan of the brain due to limited availability.
In addition to neurological manifestations, all patients had a skin rash of varying severity and some patients developed a fern leaf necrotic skin rash. The development of arthritis, conjunctival injection, and icterus were detected in some patients. Thrombocytopenia and leukocytosis were common hematological findings and some patients had raised liver enzymes. Similar manifestations have been reported in the published cases of spotted fever with neurological manifestations.
This evidence suggests that involvement of the nervous system in spotted fever is not an isolated event and it may occur with the other clinical manifestations of rickettsiosis. Susceptibility to cerebral involvement in spotted fever was not clear in this study, however most of our patients were over the middle age.
Pathologically, direct infection or toxins should be the reason for inflammatory lesions in the vascular endothelium. A necropsy study in 1974 found both gray matter and white matter necrosis, and another study involving two cases of South African tick bite fever found foci of vasculitis in the brain with mononuclear leukocyte cell infiltration in the blood vessel wall and perivascular space.
However, further studies are needed to determine the pathogen and host factors that are responsible for nervous system involvement.
During the last two decades many novel rickettsial agents have been isolated and characterized. The emergence or reemergence of rickettsial infection are occurring in many regions of the world, thus clinicians should be vigilant to detect novel clinical manifestations. With this report, we draw attention to the importance of neurological manifestations in spotted fever group rickettsioses. These presentations may be infrequent, but awareness is essential as early treatment is important to save lives. Thus, a strong clinical suspicion and the establishment of rickettsial disease diagnostic facilities in endemic areas are the key determinants in achieving this final goal.
Acknowledgements
No funding was received to support publication, but the National Research Council of Sri Lanka (NRC grants, 0905) provided equipment to carry out the IFA tests at the Department of Veterinary Pathobiology, Faculty of Veterinary Medicine and Animal Sciences, University of Peradeniya, Sri Lanka.
Conflict of interest: The authors declare that they have no competing interests.
References
Edirisinghe J.S.
Kularatne S.A.
Rickettsioses in Sri Lanka.
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