Neurological Involvement in Acute Q Fever
A Report of 29 Cases and Review of the
Literature
Emmanuelle Bernit, MD; Jean Pouget, MD; François Janbon, MD; Hervé
Dutronc, MD; Philippe Martinez, MD; Philippe Brouqui, MD, PhD; Didier Raoult,
MD, PhD
Background Q fever is characterized by its clinical polymorphism;
neurological involvement has occasionally been described. In the course of
acute Q fever, neurological manifestations may include aseptic meningitis,
encephalitis or encephalomyelitis, and peripheral neuropathy.
Objective To review and evaluate cases of acute Q fever with neurological
symptoms diagnosed in our laboratory.
Methods A total of 1269 acute Q fever cases were recorded from January
1985 to January 2000 in our laboratory and were reviewed for neurological
complications. Patients were considered to have acute Q fever when serological
procedures showed Coxiella burnetii
phase II titers of 1:200 or higher for IgG and 1:50 or higher for IgM. Those
patients who underwent a lumbar puncture for cerebrospinal fluid analysis or
who had abnormal neurological symptoms were selected for this study. We
describe the clinical, epidemiological, and biological features of these cases.
We also review the literature and compare our cases with those previously
reported.
Results Among the 45 patients selected, 14 were excluded because they had
normal cerebrospinal fluid and no neurological symptoms. Two were excluded
because there were no clinical or epidemiological data. Three major clinical
syndromes were observed: meningoencephalitis or encephalitis in 17 cases;
meningitis in 8; and myelitis and peripheral neuropathy in 4. Encephalitic
signs were not specific, but behavior or psychiatric disturbances were common.
Conclusions Q fever should be included in the differential diagnosis of acute
neurological disease in a patient with a fever. Serological testing should be
performed in cases of meningoencephalitis, lymphocytic meningitis, and
peripheral neuropathy, including Guillain-Barré syndrome and myelitis.
Arch Intern Med.
2002;162:693-700
Q FEVER IS A worldwide zoonosis caused by Coxiella burnetii, a strictly
intracellular organism living in the phagolysosomes of the host cell.
Throughout the world, the most common reservoirs for C burnetii are cattle, sheep, and goats.1 Infection in animals
is not usually apparent, but the organism is found in urine, feces, milk, and
the afterbirth or aborted products of infected animals.2 Pets have also been
involved, mainly cats but also dogs.3 Moreover, as C burnetii can be transported by the wind,
a substantial proportion of patients have reported no direct contact with
animals.4 Human infection
occurs following inhalation of contaminated aerosols or ingestion of raw milk
or fresh goat cheese. A percutaneous route and vertical transmission from
mother to child have also been documented.
A main characteristic of C burnetii infection is clinical
polymorphism. Q fever is commonly categorized into acute and chronic forms, and
the clinical manifestations, serological profiles, and treatments for the 2
forms are different. Half of acute cases are asymptomatic. The most common
clinical syndromes of acute fever are a self-limited febrile illness, a flulike
syndrome, or pneumonia.2 Granulomatous
hepatitis may occur in association with an increase in liver enzyme levels.
Cases of prolonged fever, febrile eruption, myocarditis, and pericarditis have
also been reported. While the involvement of the central nervous system (CNS)
due to embolism from an infected valve during chronic Q fever endocarditis is
common,5 neurological
symptoms in acute Q fever have been reported less frequently, and their
incidence is probably underestimated. To our knowledge, only 17 well-documented
cases of meningoencephalitis,6-22 2 of Guillain-Barré
syndrome,23, 24 4 of peripheral
neuritis,25, 26 and 6 of aseptic
meningitis have been reported.26-29 Neurological
manifestations described in the course of the acute disease include aseptic
meningitis, encephalitis or encephalomyelitis, toxic confusional states,
extrapyramidal signs, dementia, behavioral disturbances, and multiple cranial
nerve involvement.30 Our laboratory has
recently reported the clinical and epidemiological features of 1614 cases of
acute and chronic Q fever, including neurological involvement in cases of acute
infection, without detailing cases reported or comparing them with cases from
the literature.31
We report herein 29 cases of Q fever with
diverse neurological symptoms from a series of patients diagnosed in our
laboratory between January 1985 and January 2000, including 5 previously
reported cases of meningoencephalitis.32 The prevalence of
neurological complications during acute Q fever was calculated. Neurological
manifestations associated with chronic Q fever were excluded. We also reviewed
the literature for all cases of acute Q fever with neurological involvement,
and their epidemiological and clinical features were compared with our cases.
PATIENT CHARACTERISTICS
Our laboratory is the French National Reference Center for Rickettsial Diseases
in Marseille, France, which receives 9000 samples annually from France and
other countries. A total of 1614 Q fever cases were recorded from January 1985
to January 2000 (1269 acute and 345 chronic infections); for most of these,
clinical information was available. Case records of patients with acute Q fever
were reviewed for neurological complications. Patients with meningitis
(cerebrospinal fluid [CSF] pleocytosis), encephalitic and/or medullar
involvement, and/or peripheral neuropathy were selected for this study. A
headache was considered a neurological symptom when it was severe enough to
prompt a lumbar puncture. However, of the cases where a lumbar puncture was
performed, we eliminated those where CSF was normal (cell count, <5/µL;
protein level, <0.5 g/L; and CSF glucose level, half the blood glucose
level) and there were no neurological symptoms. Exposure factors, age, sex,
presence of immunodepression, clinical presentation (occurrence of fever,
pneumonia, or hepatitis), and biological data such as increased erythrocyte
sedimentation rate (>20 mm/h), elevated liver enzyme levels (>40 IU/L,
which is twice the upper normal value), and thrombocytopenia (platelet count,
<130 109/L) were
studied.
DIAGNOSTIC PROCEDURES
Titers of IgG, IgM, and IgA antibodies in serum samples from each patient were
estimated by using the indirect immunofluorescent antibody test as previously
described.33 Serum IgG
antibodies were systematically removed before titration of IgA and IgM to avoid
rheumatoid factor interference (RF Absorbent, Dade Behring GmbH, Marburg,
Germany). Patients were considered to have acute Q fever when serological
procedures showed a C burnetii
phase II titer of 1:200 or higher for IgG and 1:50 or higher for IgM.33
Blood-CSF barrier permeability was evaluated by
the albumin quotient (plasma albumin level divided by the CSF albumin level; an
index of 0.0075 was considered the normal upper limit value).9 Coxiella burnetii antibody levels were
estimated in CSF by immunofluorescence, and intrathecal synthesis of
immunoglobulin was evaluated by IgG index (the ratio of CSF antibody titer
divided by serum antibody titer to CSF albumin level divided by serum albumin);
a ratio higher than 0.8 was considered suggestive of intrathecal synthesis.9
Blood and CSF samples (when available) were
inoculated onto human fibroblasts grown on a coverslip within a shell vial as
previously described.34 After 7 days of
incubation at 37°C, cultured bacteria were detected by using the direct
immunofluorescence test incorporating rabbit monoclonal antibody to C burnetii.35
DNA was extracted from CSF and/or blood samples
by using the QiAmp Tissue kit and the QiAmp Blood kit (QIAGEN GmbH, Hilden,
Germany) according to the manufacturer's instructions. These extracts were used
as templates in polymerase chain reaction amplifications as previously
described.36
REVIEW OF THE LITERATURE
We reviewed the English- and French-language literature on MEDLINE for all
cases of Q fever with neurological complications from 1946 to 2000 using the
following keywords: acute Q fever; Coxiella
burnetii; neurological involvement; meningoencephalitis;
encephalitis; meningitis, Guillain-Barré syndrome; neuritis; and myelitis.
Between January 1985 and January 2000, the
diagnosis of acute Q fever was confirmed in 1269 patients. Forty-five patients
(3.5%) with acute Q fever had a headache, meningeal syndrome, and/or abnormal
encephalitic or myelitis signs. Among these, 14 patients with normal CSF were
excluded from the study and were considered to have meningeal irritation. We
were not able to obtain epidemiological or clinical information for 2 patients,
and these 2 were therefore also excluded.
All patients had significant titers of
antibodies against C burnetii
phase II antigens, and none had serological evidence of chronic Q fever. Among
the 10 patients tested for the presence of specific CSF antibodies, 6 tested
positive (with significant levels of CSF IgG >1:200 by immunofluorescence),
and 1 of these also had IgM antibodies. The albumin quotient showed a damaged
blood-CSF barrier in 5 cases. The IgG index was above 0.8 for 3 patients, but 2
had a damaged blood-CSF barrier. Thus, the IgG index was suggestive of
intrathecal synthesis of C burnetii
antibodies in only 1 case. Attempts to isolate C
burnetii from blood in 2 cases and from CSF in 5 cases where CSF was
abnormal were unsuccessful. Molecular detection in CSF produced negative
results in the 3 cases where it was carried out. Bacterial cultures of blood
and CSF (including for Mycobacteria)
were negative, and attempts to isolate herpesvirus and enterovirus failed. The
serological assay findings for Brucella,
Leptospira, Salmonella, Borrelia burgdorferi, human immunodeficiency virus,
herpesvirus, and enterovirus were negative.
Epidemiological, clinical, and biological data
for the reported cases are summarized in Table 1,
Table 2,
Table 3,
and Table 4).
Among the 29 patients, 22 were male and 7 were female (male/female sex ratio,
3.1). The mean age was 46.5 20.6 years
(range, 7-83 years). No immunocompromised situation was noted. Fourteen
patients had a strong epidemiological risk of Q fever because they were in
close contact with goats or goat products. Several exposure factors were
identified: living in rural areas in 13 of 25 cases; profession (farmer,
veterinarian, or shepherd) in 6 of 26 cases; contact with farm animals,
specifically goats, or parturient cats in 13 of 23 cases; and ingestion of raw
milk or farm goat cheese in 4 of 13 cases.
Clinically, 26 patients were febrile and 12 had
myalgia or arthralgia. Nine of the 27 patients had a flulike syndrome, and 3
had pneumonia. Platelet counts were low in 6 cases, and the erythrocyte
sedimentation rate was abnormal in 17. There were abnormalities of liver
function tests in 8 cases. As for prognosis of the 29 patients, 2 with meningoencephalitis
died (Table 1,
patients 10 and 11): an 83-year-old woman and a 70-year-old man. Both had
severe and diffuse encephalitic signs, and in patient II the findings of a
computed tomography (CT) brain scan were normal. Patient 10 was treated with
clavunalic acid–amoxicillin and patient 11 with rifampin. Neurological sequelae
were noted in 4 of 29 patients (Table 1,
patients 12, 14, and 17; Table 3,
patient 1). These consisted of a palsy of nerve VI in 1 case, a central
vestibular vertigo in 1, a pyramidal syndrome in 1, and a bilateral facial
palsy in 1. Two of these patients were treated with doxycycline, 1 with
rifampin, and 1 with ciprofloxacin. Twenty-three patients recovered within days
or weeks (maximum of 3 months). The course of clinical symptoms showed that, as
in patients 1 and 2, neurological aggravation periods lasted from a few hours
to a few days, alternating with complete or partial recovery periods. Recovery
seemed to occur regardless of treatment. Treatments included erythromycin (2
cases), ampicillin (3 cases), doxycycline (10 cases), pefloxacin (3 cases), and
rifampin (5 cases).
Three major syndromes were observed:
meningoencephalitis or encephalitis in 17 patients, meningitis in 8, and
myelitis and polyradiculoneuritis or peripheral neuritis in 4. Among those
patients with meningoencephalitis (Table 1,
patients 1-17), encephalitic symptoms varied. Symptoms included abnormalities
of behavior or psychiatric problems (6/17; 35%), confusion and/or somnolence
(12/17; 71%), seizures (5/17; 29%), and focal neurological deficit (11/17;
765%). Cerebrospinal fluid was abnormal in 12 cases, with pleocytosis
characterized by a predominance of lymphocytes in the CSF in 11 cases and an
increased protein level in 1. The glucose level was normal in all cases.
Computed tomography brain scans were abnormal in
3 (21%) of 14 cases, with nonspecific diffuse brain edemas in 2 cases and
pseudonecrotic edemas in the right temporal area in the third case. Magnetic
resonance imaging (MRI) confirmed on these 2 patients diffuse cerebral edemas.
In another case, a CT brain scan was normal, but a brain MRI demonstrated
bilateral periventricular edemas (Figure 1).
The electroencephalogram carried out in 16 cases revealed abnormalities in 13.
These included diffuse encephalitic involvement with right temporal theta () waves or
postseizure waves.
Two patients had myelitis (Table 3,
patients 2 and 4) with a motor weakness and sensory loss in the limbs, although
CSF was normal. In one case, medullar MRI was performed but was normal. One
patient had Guillain-Barré syndrome (Table 3,
patient 1) with a bulbar involvement. An increased protein level without
pleocytosis was evident in the CSF. One patient (Table 3,
patient 3) had only ocular involvement with a third right cranial nerve palsy;
no lumbar puncture was done.
Eight patients (Table 4,
patients 1-8) had only meningitis with pleocytosis, which was characterized by
a predominance of lymphocytes in 6 cases and an increased protein level in the
other 2. The glucose level was normal in all cases.
In this study, we report neurological
manifestations that include a headache severe enough to prompt a lumbar
puncture to rule out meningitis in 3.5% of hospitalized acute Q fever cases22, 25, 26, 28, 29, 37, 38 (Table 5).
When we excluded patients who had only a headache and normal CSF, the
prevalence of neurological symptoms in acute Q fever was 2.2%. In a review of
acute Q fever in California, Clark et al26 reported signs of
diffuse meningeal irritation and stupor in 5% of cases (Table 5).
The prevalence of neurological manifestations in acute Q fever varies
considerably. Reviewing 188 cases of Q fever in Australia, Derrick37 describes a single
case of cerebral involvement (paresis and areflexia of the extremities) (Table 5).
Reilly et al,25 in a series of 103
patients with Q fever in Plymouth, England (46 acute infections, 5 chronic
infections, and 52 past infections), reported an astounding 22% incidence of
neurological complications in acute infections (Table 5).
Clark et al26 found
disorientation and confusion (and occasionally encephalitic apathy) in 7% of
patients. Exposure factors were rarely available in previously reported cases,
but the prevalence of clinical and epidemiological conditions associated with
neurological involvement and reported by our team in the retrospective analysis
on acute Q fever suggests that neurological involvement in acute Q fever is not
linked with predisposing conditions but with strong environmental exposure.31
The neurological symptoms of the 34 patients
with meningoencephalitis and/or encephalitis reported herein and from the
literature (Table 1
and Table 2)
were nonspecific. Behavioral abnormalities were common (9 patients; 26%), and
Schwartz19 reported a
case of manic psychosis. Furthermore, other signs of CNS involvement have been
found as an extrapyramidal neurological syndrome simulating Parkinson disease
(case 3220),
Millard-Gubler syndrome,18 cerebellar syndrome,6, 20 and pyramidal
syndrome.39 A variety of
neuro-ocular findings have been reported in cases of Q fever encephalitis.
Shaked and Samra13 describe bilateral
lateral rectus muscle palsy and optic neuritis with a normal CT of the head. In
addition, Schuil et al15 describe bilateral
optic neuritis in a farmer who presented with loss of vision in his right eye
and painful eye movements; a CT scan showed bilateral optic nerve thickening.
In another case, Miller Fisher syndrome was reported with bilateral paralysis
of the sixth cranial nerves and with upgaze and mild bilateral ptosis11; findings of a CT
head scan and lumbar puncture were normal. In the 33 cases where the CSF was
examined (Table 1
and Table 2),6-21 cells were present
in 23 cases (70%); cell counts ranged from 19/µL to 1600/µL. In all but 1 case,
these were predominantly mononuclear cells. The glucose level was low in only 1
patient. The protein level was increased in 11. Findings of neuroradiological
examinations were rarely abnormal and were not specific. Six (18%) of the 34
meningoencephalitis cases had neuroradiological abnormalities evidenced on
brain imaging (Table 1
and Table 2).
In 1 case, there was a decreased absorption coefficient in the subcortical
white matter of both hemispheres on CT scan.6 Magnetic resonance
imaging carried out in this case showed increased signal intensity on
T2-weighted images in the right cerebellar hemisphere. The electroencephalogram
was often abnormal (85% of cases; n = 23) when this investigation was carried
out (Table 1
and Table 2).
It showed a nonspecific involvement of the CNS.
With respect to myelitis, polyradiculoneuritis,
and peripheral neuropathy, we herein report 3 cases of Guillain-Barré syndrome
(Table 3),
which has been reported only twice before. In 1960,23 a 61-year-old woman
had bilateral optic neuritis and sensory and motor peripheral neuropathy with
paraesthesia of her legs and arms; she was treated with chloramphenicol and had
no sequelae.23 Another case
of Guillain-Barré syndrome was reported in a 42-year-old woman24 with facial diplegia
and loss of proximal motor coordination of the lower limbs. In our study, there
was 1 case of peripheral neuropathy with palsy of the third right nerve (Table 3,
case 3). Among 103 cases of Q fever reported by Reilly et al,25 there was 1 case of
lower-limb peripheral neuropathy (wasted and flaccid) with paraesthesia in a
32-year-old man with jaundice and hepatosplenomegaly. The CSF findings were
normal. There was minimal leg weakness after 1 year of follow-up. Clark et al26 reported altered
reflexes in 2 of 180 patients. We herein report 2 cases of myelitis (Table 3),
but no cases of isolated myelitis have previously been reported in the
literature (Table 5).
Severe headache associated with a meningeal
syndrome is the most common neurological manifestation in Q fever.26 Findings on CSF
examination are usually described as normal in Q fever infection. In the
present study, CSF was normal in 14 (34%) of 41 cases. We have herein reported
8 cases of aseptic meningitis (Table 4).
In Spelman's study,28 examination of the
CSF revealed mild pleocytosis in 2 of 26 cases of lumbar puncture and an
elevated protein level in 14 of the 26 cases (Table 5).
In the studies of Reilly et al25 and Derrick,37 there was no reported
case of meningitis (Table 5).
In the 180-patient series reported by Clark et al,26 stiffness of the back
or neck severe enough to suggest meningeal irritation was observed in 9
patients (5%). Of 5 lumbar punctures performed, 1 resulted in an abnormal CSF
finding. During an outbreak of Q fever among American and British troops in
Italy during World War II, lumbar punctures were performed in 3 cases because
of neck stiffness, but the CSF was normal in all 3 cases.38 In a report of C burnetii occurrences in the northwest of
England and North Wales between 1965 and 1967, among 10 patients with headache,
neck stiffness, and pyrexia, only 1 had meningitis.29 Leng-Levy et al27 reported 2 cases of
acute Q fever with meningitis. In total, to the best of our knowledge, 6 cases
of acute Q fever with meningitis have been reported.
As for prognosis, in most instances the
neurological involvement is mild. However, in the Plymouth series,25 6 of the 45 patients
with acute Q fever had residual neurological impairment, including motor weakness,
recurrent meningismus, blurred vision, residual paresthesia, and sensory loss
involving the left leg. In our 34 encephalitis cases, recovery was complete for
22 patients within days or weeks (3 months at the most); there were no
long-term relapses, and neurological sequelae were found in 7 cases (21%).
There were 2 cases of peripheral neuritis with neurological impairment. No
deaths have been reported prior to this work. Recovery seems to take place
regardless of treatment. Although many cases of Q fever infection will resolve
without antimicrobial therapy, doxycycline (200 mg daily) is the recommended
treatment. It has also been suggested, because of the possible CSF passage of C burnetii, that fluoroquinolones be used
in cases associated with meningeal involvement because of the good CSF
concentration of these compounds.40 Other antibiotics
such as erythromycin, chloramphenicol, co-trimoxazole, and ceftriaxone have
been reported effective in the treatment of acute Q fever.41-43 The type of
treatment in our series does not seem to be correlated with the presence of
neurological sequelae.
With respect to physiopathology, the mechanism
by which infection with C burnetii
may cause symptoms attributable to the CNS is not known. Coxiella burnetii has been identified by
immunofluorescence in brain capillary endothelial cells,44 and other mechanisms
of injury of Q fever on CNS have been suggested such as that mediated by
circulating immune complexes,45 which are detected in
acute infection. Robbins and Ragan38 succeeded in
isolating C burnetii from the CSF
of 1 patient and in guinea pigs after serial passages. Our attempts to isolate C burnetii from CSF in 5 cases in which
the CSF was abnormal were always unsuccessful. The case reported by Sawaishi et
al6 is the first in
which C burnetii has been
isolated and detected by polymerase chain reaction in CSF. Pathological
findings of the brain in a patient who died of Q fever pneumonia46 showed small
perivascular hemorrhages with capillary endothelial swelling and a few
capillary thrombi. No perivascular infiltrate was noted, but Giemsa staining
demonstrated coccoid and bacillary rickettsial forms inside neuroglial cells as
well as extracellularly.
Our data show that individuals with specific
occupational exposure are at a significantly higher risk of neurological
involvement than are other patients with acute Q fever.31 This could mean that
individuals in specific occupations are exposed to strains of C burnetii that have a greater
pathological potential for the neurological system. Or it could mean that these
individuals are exposed more frequently, and the neurological involvement
results from multiple exposure and reinfection. Indeed, the clinical
manifestations in these occupationally exposed individuals were different from
those of others: these occupationally exposed patients had hepatitis and
pneumonia less frequently and a worse prognosis even though they were not older
or more frequently immunocompromised. Therefore, we consider that neurological
manifestations characterize a distinct clinical entity.
In conclusion, neurological signs are prevalent
in acute Q fever. Patients with CNS involvement do not demonstrate differences
in predisposing conditions, but more frequently have occupational exposure to
goats than patients with acute Q fever but no neurological involvement. There
are 3 major neurological entities associated with Q fever: (1)
meningoencephalitis or encephalitis; (2) lymphocytic meningitis (both of these
entities have already been described) and (3) peripheral neuropathy (myelitis,
polyradiculoneuritis, or peripheral neuritis, which have been less frequently
identified). The outcome of all 3 of these entities may be severe. Two deaths
occurred in our series, and residual neurological impairment may be permanent
in 4 other cases. Q fever should be included in the differential diagnosis of
acute neurological disease, and serological testing should be performed in all
cases of meningoencephalitis, meningitis, and peripheral neuropathy because Q
fever requires specific antibiotic treatment. Moreover, systematic screening
for Q fever may explain some previously undiagnosed cases of acute neurological
disease.
Author/Article Information
From Unité des Rickettsies, Centre National de la Recherche Scientifique (Drs
Bernit, Brouqui, and Raoult) and Service de Neurologie, Hôpital de La Timone
(Dr Pouget), Marseille, France; Service de Maladies Infectieuses, Hôpital Gui
de Chauliac, Montpellier, France (Dr Janbon); Service de Maladies Infectieuses,
Hôpital Pellegrin-Tripode, Bordeaux, France (Dr Dutronc); and Service de
Neurologie, Hôpital de Rangueil, Toulouse, France (Dr Martinez).
Corresponding author: Didier Raoult, MD, PhD, Unité des Rickettsies, Centre
National de la Recherche Scientifique, UPRESA 6020 IFR 48, Faculté de Médecine,
Université de la Méditerranée, 27 Boulevard Jean Moulin, 13385 Marseille CEDEX
05, France (e-mail: [log in to unmask]).
Accepted for publication July 30, 2001.
We wish to thank J. R. Birtle, PhD, for his
revision of the English manuscript.
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Diplomat American
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