Rickettsial meningitis

Abstract

Rickettsial infections are common in southern Europe and the most frequent and lethal type is Mediterranean spotted fever, caused by Rickettsia conorii. The disease is usually characterised by the classical triad of fever, eschar and rash, and is generally a mild disease in children. Complications including neurological involvement are rarely described. We report an unusual case of meningitis in an 18-year-old man, presenting during summer with fever and persistent headache. The cerebrospinal fluid analysis revealed increased cellularity (107 cells/μL), hypoglycorrhachia (50% of glycaemia) and hyperproteinorrhachia (284 mg/dL). Rickettsial infection was confirmed by serology and the patient was treated with doxycycline, with a favourable outcome. The patient's pet squirrel and/or associated vectors might be involved in the transmission of Rickettsia spp. This case underlines the importance of a high clinical suspicion and the benefits of early empirical treatment when facing compatible epidemiological contexts.

Background

Rickettsial infections are caused by obligate intracellular organisms, carried by arthropods, and are divided into two main groups: the spotted fever group and the typhus group.^{1 2}

In the Mediterranean basin, the most common disease-causing Rickettsia species within the spotted fever group are Rickettsia conorii, Rickettsia sibirica mongolitimonae and Rickettsia slovaca, although several other species of Rickettsia have been identified over the years, including Rickettsia raoultii, Rickettsia rioja, Rickettsia helvetica, Rickettsia massiliae, Rickettsia monacensis and Rickettsia felis.^3–5

In Portugal, as in the remaining southern Europe, the most prevalent rickettsiosis is Mediterranean spotted fever.^{6 7} Reported incidence was 8.4/10 000 inhabitants between 1989 and 2005.⁷ The classical presentation is fever, headache and rash that are caused by a process of generalised microvasculitis, usually associated with an eschar.^{1 8 9} Most symptoms are non-specific and the severity of presentation varies widely.¹ The mortality rate is 2.5% on average, although in Portugal reports indicate a much higher rate (20–30%).^{7 9}

Besides variation in severity, there is an increasing number of reports describing infections by diverse Rickettsia spp with atypical presentations such as acute myocarditis and atrioventricular block, interstitial pneumonitis, meningitis and encephalitis.^10–15 We report a rare case of meningitis in the absence of the typical general symptoms.

Case presentation

A previously healthy 18-year-old male adolescent presented at a paediatric hospital in Lisbon with an 11-day history of progressive biparietal headache refractory to symptomatic therapy (paracetamol and ibuprofen). The patient also had low-grade fever (axillary temperature of 37.5°C). He had been medicated as an outpatient with clarithromycin 500 mg every 12 h during the previous 5 days.

The patient reported contact with a dog and a pet squirrel but did not recall any recent tick or flea bite.

Physical examination on admission revealed arterial pressure of 125/75 mm Hg, heart rate 75 bpm, axillary temperature 37°C and a normal neurological examination (including absence of meningismus). No lymphadenopathy, rash or eschar was noted.

Investigations

Laboratory studies showed 5700/μL leucocytes (4500–11000/μL), 53.9% neutrophils, normal haemoglobin and platelet count, negative sedimentation rate and C reactive protein (0.07 mg/dL; reference value <2 mg/dL), no renal dysfunction and normal transaminase values.

Cerebrospinal fluid (CSF) analysis showed pleocytosis (107 cells/μL with lymphocyte predominance; reference value <10 cells/μL), hypoglycorrhachia (36 mg/dL for a glycaemia of 84 mg/dL; reference value ≥60% of glycaemia) and hyperproteinorrhachia (284 mg/dL; reference value ≤45 mg/dL).

Head CT and MRI showed right frontal inflammatory sinusopathy and were otherwise normal.

Cerebral spinal fluid and blood cultures were negative. Investigation for herpesvirus, enterovirus, arbovirus, Borrelia and Mycobacterium tuberculosis was negative. Serological blood studies including HIV, venereal disease research laboratory, Mycoplasma, Brucella and Bartonella excluded acute infection. Chest radiography was normal and the tuberculin intradermal reaction was negative.

Intravenous ceftriaxone was administered for 1 week with no improvement.

The diagnosis was confirmed by serology (immunofluorescence assay) that showed a seroconversion, with an eightfold increase of IgG antibodies for R conorii in 2 weeks (with titres of 128 and 1024). PCR for Rickettsia in the blood specimen was negative.

The squirrel's blood was also tested for the presence of rickettsial infection by PCR and serology. No rickettsial DNA was detected but serology revealed an IgG titre of 64, considered positive. No fleas or ticks were collected from the squirrel.

Treatment was changed to doxycycline.

Differential diagnosis

Our patient presented with meningitis and was empirically treated with ceftriaxone with no improvement. At this time, other less frequent aetiologies were considered.

M tuberculosis, a relatively common agent in Portugal, can cause insidious meningitis with hypoglycorrhachia. However, the normal imaging studies, the negative tuberculin intradermal reaction, CSF amplification and culture did not support this diagnosis.

Viruses can also cause meningitis, namely enteroviruses and arboviruses, especially during summer months, but these were also ruled out by laboratory tests. Borrelia and Brucella infections were also excluded.

Treatment

Recommended treatment for rickettsial infections is doxycycline 100 mg twice a day for 5–10 days (or at least 3 days following defervescence).^1–9 Our patient completed 10 days of doxycycline.

Cephalosporins and penicillins are ineffective as observed in this case.⁹

Outcome and follow-up

The patient evolved favourably with remission of symptoms 24 h after starting doxycycline and had no sequelae.

Discussion

The atypical presentation and the paucity of additional symptoms (no high fever, myalgias, rash or eschar) in this case challenged the diagnosis. Nonetheless, the epidemiological context raised the suspicion of a zoonotic infection and the positive serology for Rickettsia confirmed the diagnosis and led us to change the antibiotic therapy to doxycycline, with improvement.

The patient presented during summer and lived in a rural setting (two factors associated with the highest incidence of rickettsioses)⁶ and he had a history of exposure to several animals, including a squirrel and a dog. Transmission of Rickettsia might have occurred directly by one of the pets or by their vectors, such as ticks or fleas. Although no vectors were tested, the squirrel had a positive serology for Rickettsia spp. Furthermore, the lack of improvement under therapy with cefthriaxone was suggestive of infection with an atypical agent.

Owing to the presence of shared protein and lipopolysaccharide antigens, it is extremely difficult to distinguish closely related agents within the rickettsial spotted fever group by serological methods.¹⁶ Only successful isolation of the agent or molecular detection in blood or tissue can determine the Rickettsia species.⁷ However, this was not achievable in this case, which might be related to treatment with clarithromycin prior to admission.

Central nervous system involvement, namely rickettsial encephalitis, is characterised by confusion and obtundation due to increased intracranial pressure and has been associated with a worse prognosis.⁷ Our patient did not show signs of cerebral parenchymal disease.

In general, rickettsial meningitis behaves like a viral meningitis but responds only to doxycycline or chloramphenicol instead of symptomatic therapy.^{14 17} Our patient was medicated with clarithromycin which has demonstrated efficacy in rickettsial infections^{18 19}; we hypothesise that the lack of response was due to the short duration of therapy and the erratic central nervous system penetration.

Milder presentations, such as the one described, have been reported in association with R felis and R helvetica.^{14 15} Thus far, in Portugal, R felis has only been isolated in fleas.^{20 21} R helvetica, although common in ticks, is rarely isolated in humans; it may be associated with a short-lived bacteriaemia.²²

We conclude that aseptic meningitis and encephalitis should elicit the hypothesis of rickettsial infection, given its high incidence in endemic areas and diverse symptomatology.¹⁷

Learning points.

• Rickettsial infection may present as meningitis and should be included in the differential diagnosis in endemic countries.

• Definitive diagnosis of rickettsial infections relies mainly on serological methods that can be limited in an initial phase (due to latency in antibody response), emphasising the need for a high clinical suspicion.

• Early treatment should be instituted empirically, since it improves prognosis, diminishes mortality and sequelae associated with rickettsioses.

• There are an increasing number of reports regarding emerging Rickettsia spp responsible for incomplete and atypical presentations that should be considered.