Neurological Involvement in Acute Q Fever

A Report of 29 Cases and Review of the Literature

Author Information
<http://archinte.ama-assn.org/issues/v162n6/rfull/#aainfo>   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
IOI10073
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 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r1>
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 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r2>  Pets have
also been involved, mainly cats but also dogs. 3
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r3>  Moreover, as C
burnetii can be transported by the wind, a substantial proportion of
patients have reported no direct contact with animals. 4
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r4>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r2>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r5>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r6>  2 of Guillain-Barré
syndrome, 23 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r23> , 24
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r24>  4 of peripheral
neuritis, 25 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r25> , 26
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r26>  and 6 of aseptic
meningitis have been reported. 26-29
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r26>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r30>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r31>
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 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r32>  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.



PATIENTS AND METHODS



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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r33>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r33>
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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r9>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r9>
Blood and CSF samples (when available) were inoculated onto human
fibroblasts grown on a coverslip within a shell vial as previously
described. 34 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r34>  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 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r35>
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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r36>
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.



RESULTS



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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t1.html> ,
Table 2
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t2.html> ,
Table 3
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t3.html> , and
Table 4
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t4.html> ).
Among the 29 patients, 22 were male and 7 were female (male/female sex
ratio, 3.1). The mean age was 46.5 plusmn20.6 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 <http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t1.html> ,
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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t1.html> ,
patients 12, 14, and 17; Table 3
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t3.html> ,
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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t1.html> ,
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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_f1.html> ). The
electroencephalogram carried out in 16 cases revealed abnormalities in 13.
These included diffuse encephalitic involvement with right temporal theta
(theta) waves or postseizure waves.
Two patients had myelitis ( Table 3
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t3.html> ,
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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t3.html> ,
patient 1) with a bulbar involvement. An increased protein level without
pleocytosis was evident in the CSF. One patient ( Table 3
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t3.html> ,
patient 3) had only ocular involvement with a third right cranial nerve
palsy; no lumbar puncture was done.
Eight patients ( Table 4
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t4.html> ,
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.



COMMENT



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 cases 22
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r22> , 25
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r25> , 26
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r26> , 28
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r28> , 29
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r29> , 37
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r37> , 38
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r38>  ( Table 5
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t5.html> ).
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 al 26
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r26>  reported signs of
diffuse meningeal irritation and stupor in 5% of cases ( Table 5
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t5.html> ). The
prevalence of neurological manifestations in acute Q fever varies
considerably. Reviewing 188 cases of Q fever in Australia, Derrick 37
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r37>  describes a single
case of cerebral involvement (paresis and areflexia of the extremities) (
Table 5
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t5.html> ).
Reilly et al, 25 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r25>  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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t5.html> ).
Clark et al 26 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r26>
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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r31>
The neurological symptoms of the 34 patients with meningoencephalitis and/or
encephalitis reported herein and from the literature ( Table 1
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t1.html>  and
Table 2
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t2.html> ) were
nonspecific. Behavioral abnormalities were common (9 patients; 26%), and
Schwartz 19 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r19>
reported a case of manic psychosis. Furthermore, other signs of CNS
involvement have been found as an extrapyramidal neurological syndrome
simulating Parkinson disease (case 32 20
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r20> ), Millard-Gubler
syndrome, 18 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r18>
cerebellar syndrome, 6
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r6> , 20
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r20>  and pyramidal
syndrome. 39 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r39>  A
variety of neuro-ocular findings have been reported in cases of Q fever
encephalitis. Shaked and Samra 13
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r13>  describe bilateral
lateral rectus muscle palsy and optic neuritis with a normal CT of the head.
In addition, Schuil et al 15
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r15>  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 ptosis 11 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r11>
; findings of a CT head scan and lumbar puncture were normal. In the 33
cases where the CSF was examined ( Table 1
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t1.html>  and
Table 2
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t2.html> ),
6-21 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r6>  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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t1.html>  and
Table 2
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t2.html> ). In
1 case, there was a decreased absorption coefficient in the subcortical
white matter of both hemispheres on CT scan. 6
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r6>  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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t1.html>  and
Table 2
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t2.html> ). 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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t3.html> ),
which has been reported only twice before. In 1960, 23
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r23>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r23>  Another case of
Guillain-Barré syndrome was reported in a 42-year-old woman 24
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r24>  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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t3.html> , case
3). Among 103 cases of Q fever reported by Reilly et al, 25
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r25>  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
al 26 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r26>  reported
altered reflexes in 2 of 180 patients. We herein report 2 cases of myelitis
( Table 3
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t3.html> ), but
no cases of isolated myelitis have previously been reported in the
literature ( Table 5
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t5.html> ).
Severe headache associated with a meningeal syndrome is the most common
neurological manifestation in Q fever. 26
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r26>  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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t4.html> ). In
Spelman's study, 28 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r28>
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
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t5.html> ). In
the studies of Reilly et al 25
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r25>  and Derrick, 37
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r37>  there was no
reported case of meningitis ( Table 5
<http://archinte.ama-assn.org/issues/v162n6/fig_tab/ioi10073_t5.html> ). In
the 180-patient series reported by Clark et al, 26
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r26>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r38>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r29>  Leng-Levy et al 27
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r27>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r25>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r40>  Other antibiotics
such as erythromycin, chloramphenicol, co-trimoxazole, and ceftriaxone have
been reported effective in the treatment of acute Q fever. 41-43
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r41>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r44>  and other
mechanisms of injury of Q fever on CNS have been suggested such as that
mediated by circulating immune complexes, 45
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r45>  which are detected
in acute infection. Robbins and Ragan 38
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r38>  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 al 6 <http://archinte.ama-assn.org/issues/v162n6/rfull/#r6>  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 pneumonia 46
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r46>  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
<http://archinte.ama-assn.org/issues/v162n6/rfull/#r31>  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]
<mailto:[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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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.