Unusual presentation of more common disease/injury

Case report

Cerebral haemorrhage as a clinical manifestation of
human ehrlichiosis
Catalina Garc­Ía-Baena, MarÍa Fernanda Cárdenas, Juan Fernando Ramón
Department of Neurosurgery,
Fundacion Santa Fe de Bogota,
Bogota, Colombia
Correspondence to
Dr Juan Fernando Ramón,
​jframonmd@​gmail.​com
Accepted 23 June 2017

Summary
A 16-year-old young man presented to the emergency
room with new-onset generalised tonic-clonic
seizures. Examination showed a Glasgow score of 13
and predominantly crural left hemiparesis. Imaging
demonstrated a right frontoparietal haemorrhage of
non-vascular origin with perilesional oedema. Surgical
drainage was carried out, but rebleeding occurred within
24 hours following surgery, and again 1 week after
discharge. On reinterrogation and examination, Ehrlichia
canis infection was suspected and empirical management
with doxycycline was begun. Improvement was evident
72 hours after antibiotic initiation, and PCR confirmed
the diagnosis; thus, doxycycline was continued for 6
months. After 2 years, seizures recurred and treatment
was reinstated with good clinical response. However,
seizures reappeared whenever treatment discontinuation
was attempted. Lacking alternatives, doxycycline was
maintained up to the third year following the initial
episode. Subsequently, the patient showed complete
resolution without neurological sequelae up to his last
follow-up visit, 12 months following treatment cessation.

Background

To cite: Garc­Ía-Baena C,
Cárdenas MÍF, Ramón JF. BMJ
Case Rep Published Online
First: [please include Day
Month Year]. doi:10.1136/
bcr-2016-219054

Previously unrecognised pathogens have emerged
as humans are increasingly exposed to microbes
that evolve within mammalian-tick enzootic
cycles.1 2 These pathogens include obligate intracellular bacteriae of the family Anaplasmataceae,
which among other characteristics share the ability
to modify surface immunogenic proteins.1 This
latter feature probably contributes to persistent
infectivity of reservoir hosts and facilitates infection
of new alternative niches such as humans.1
Within this family, there is a genus of small
gram-negative bacteriae, measuring 0.5 to 1.5 µm,
known as ehrlichiae. They are obligate intracellular
pleomorphic coccobacilli with special tropism for
macrophages or granulocytes and are found within
the cytosol forming mulberry-like inclusions, which
represent replication within endosomal vacuoles.1 2
Ehrlichiae were recognised as distinct from other
obligate intracellular bacteriae of medical importance in 1945, by the German bacteriologist Paul
Ehrlich.2 They are the causative agents of monocytic ehrlichiosis and granulocytic ehrlichiosis,
prolonged febrile pathologies characteristic of dogs,
which in humans have clinical and geographical
similarities to Rocky Mountain Spotted Fever.1–3
Ehrlichia canis was described in 1963. It is the
primary aetiological agent of canine monocytic

ehrlichiosis, a globally distributed potentially fatal
disease representing the most severe form of ehrlichiae infections,4 5 as well as of tropical canine
pancytopaenia, a haemorrhagic disease.2–4 E. canis
is transmitted by the brown dog tick Rhipicephalus sanguineus and infects monocytes and macrophages.4 5 In humans, the first case of human ehrlichiosis assumed to be due to E. canis was reported
in the USA in 1986, in a 51-year-old man.2 6 It has
since been recognised to be associated with various
non-specific clinical manifestations developing after
a tick bite, such as fever, encephalopathy, mild hepatitis, acute tubular necrosis, anaemia and thrombocytopaenia.2 6 However, the following report
depicts the first case of primary cerebral infection
by E. canis, manifesting as intraparenchymal haemorrhage.

Case presentation
A right-handed 16-year-old young man presented to
the emergency department, 2 hours after having had
two episodes of new-onset generalised tonic–clonic
seizures with partial recovery. Background history
was negative for recent febrile episodes, trauma,
anticoagulation usage, exposure to toxic substances
and use of recreational drugs. The patient did not
have a significant medical history, and family history
was negative. On physical examination, vital signs
were normal and stable, and ophthalmoscopy did
not reveal abnormalities. However, Glasgow score
was 13, given by a decreased palpebral opening and
verbal response. Furthermore, he showed predominantly crural left haemiparesis. There was no nuchal
rigidity or further findings during examination.

Investigations
Simple cerebral CT was performed, given the
acute onset of symptoms and the physical examination findings previously described. It showed a
right frontoparietal haemorrhage, with perilesional
oedema leading to mild ventricular compression,
without ventricular drainage or midline shift (see
figure 1).
Given these findings, tomographic angiography
was performed so as to further investigate the case
and differential diagnoses. It did not demonstrate
vascular malformations or other abnormalities
explicative of the haemorrhage.
Complete blood count was not suggestive of
infection; platelet count was 250 x 109/L, and mean
platelet volume was 12 fL. Furthermore, partial
thromboplastin time was 25.8 (normal control of

Garc­Ía-Baena C, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2016-219054

1

Unusual presentation of more common disease/injury

Figure 1

Simple axial CT showing right frontoparietal cerebral haemorrhage with important perilesional oedema and mild ventricular compression.

27.1), prothrombin time was 10.7 (normal control of 10.7)
with an international normalised ratio of 1. Light transmission
aggregometry showed an 85% maximal aggregation in response
to ADP, epinephrine, collagen, ristocetin and arachidonic acid,
and evaluation by the haematology group ruled out the presence
of blood dyscrasia as a possible cause of the haemorrhage.
Lumbar puncture opening pressure was 18 cm of H2O. Cerebrospinal fluid was crystal clear with glucose of 54 mg/dL and
total protein of 37 mg/dL. Microscopic examination showed no
leucocytes or red blood cells, while Gram and Wright staining
were negative for bacteriae and polymorphonuclear cells,
respectively.
About 2 weeks later, E. canis infection was suspected based
on reinterrogation of the patient’s mother. She revealed that the
patient’s dog had been diagnosed with the infection. On new
physical examination, lesions compatible with tick bites were
identified in-between toes. Thus, we performed PCR tests in
cerebrospinal fluid (CSF) and blood, which effectively confirmed
the diagnosis.

Differential diagnosis

Our initial consideration, given the patient’s age, was that
the haemorrhage was most probably due to a vascular abnormality, but angiographic results showed this was not the case.
Even though differential diagnosis approach to a non-traumatic intracerebral haemorrhage in a young patient must take
into account an infectious aetiology, we were not initially
inclined towards this possibility because the patient did not show
physical signs suggestive of acute infection, complete blood
count was normal, and we had no microbiological evidence of
common pathogens of the central nervous system (CNS). Both
CSF and blood cultures were negative for infection. Furthermore, antibody detection tests for Rickettsia conorii, R. rickettsii, Chlamydia trachomatis and Mycoplasma pneumoniae
were negative, while Mycobacterium tuberculosis DNA was not
detected in CSF.
In addition, in developing countries, a ruptured cyst in neurocysticercosis must be considered as a diagnostic option. However,
this was a less likely diagnosis, as CT did not reveal the typical
cysts or calcifications seen in the disease.
2

Even though a rapidly progressive tumour was also a
possible diagnosis, it was not considered at first, given
that imaging was not suggestive of the presence of a mass.
Furthermore, histopathological evaluation of tissue extracted
during surgery did not confirm the presence of malignancy.
Other possible explanations were hypertensive stroke and
cocaine use, which we were able to rule out with careful clinical
history, physical examination and laboratory studies.
Ehrlichia infection was only suspected on symptom worsening
and a thorough history taking process 1 week after the patient
was discharged.

Treatment

Initially, appropriate anticonvulsive management with oral
phenytoin 600 mg daily as a single dose was begun and continued
after discharge for a total of 6 months. After angiography was
obtained, surgical drainage was carried out. Reoperation was
performed the following day, because Glasgow deteriorated and
haemiparesis worsened. Friable tissue macroscopically suggestive of malignancy was observed during the second intervention.
However, histopathological evaluation did not confirm the presence of tumour tissue.
Once the diagnosis of E. canis infection was suspected on
worsening haemiparesis, empirical management with oral
doxycycline 200 mg per day as a single dose was initiated.
It led to clinical improvement within 72 hours. PCR results
in blood samples confirmed the diagnosis; consequently,
doxycycline 200 mg per day was continued. Because we were
unable to find reports of specific treatment options for intraparenchymal haemorrhage due to this pathogen, long-term
antibiotic was instated until complete recovery was attained,
with periodical assessment of hepatic and renal function.
Doxycycline was discontinued following 6 months of initial
presentation, after paresis was completely reversed and as
seizure recurrence or neurological deterioration was not
evidenced.

Garc­Ía-Baena C, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2016-219054

Unusual presentation of more common disease/injury

Figure 2

Simple axial CT suggestive of right frontoparietal cerebral rebleeding with significant associated oedema.

Outcome and follow-up

Clinical improvement was apparent 24 hours after having
completed the second surgical drainage, and the patient was
discharged within 1 week of observation, during which no additional convulsive episodes were observed. Haemiparesis had
almost completely receded and Glasgow score was 15/15 by the
time he was discharged. Physical examination showed residual
left-sided diminished strength, ++/++++ symmetrical reflexes
and preserved sensation. Appropriate oral anticonvulsive
prophylaxis, as mentioned above, was given on discharge.
One week ensuing, haemiparesis worsened. Tomographic
imaging on this occasion was suggestive of rebleed, associated with extensive oedema (figure 2). On reinterrogation, the
patient’s mother referred that her son used to sleep with his
dog, which had been recently diagnosed with E. canis infection.
Physical examination was positive for petechiae-like lesions in
soles and in-between toes, suggestive of tick bites. Given these
findings and background history, CSF and blood analyses for E.
canis infection were performed extrainstitutionally at a reference laboratory and empirical antibiotic initiated as mentioned
above. By the third month, paresis showed complete resolution and as seizure or neurological deterioration were not seen,
antibiotic therapy together with anticonvulsive treatment was
discontinued following 6 months of initial presentation.
A recurrence of tonic–clonic seizures with the same characteristics was seen 2 years after the first episode. Contrast MRI
showed a circumferential gadolinium-enhancing frontoparietal
lesion with extensive perilesional oedema, located at the same
site previously described. Doxycycline 200 mg/day was reinstated given our previous experience and continued until there
was no clinical or radiological evidence of haemorrhage a few
months after.
On various ensuing occasions in which antibiotic therapy was
suspended, seizures recurred. Thus, in view of the lack of alternatives, antibiotic therapy was continued until the third year
following the initial presentation, with hepatic, renal and blood
analysis controls, which did not show abnormalities. Subsequently, the antibiotic was effectively stopped and the patient
showed complete resolution, with no neurological deficit whatsoever and normal imaging controls (see figure 3) up to his last
Garc­Ía-Baena C, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2016-219054

follow-up visit, which was carried out 1 year after medication
was discontinued.

Discussion
Human infection with E. canis is rare, but it has been reported in
a group of patients identified in Venezuela, who presented with
fever of over 39°C, rash, headache, myalgia and cytopaenia.7
These are recognised as the classical presenting symptoms in
E. canis infection. Nonetheless, they were not present in our
patient; rather, diagnosis was achieved through a thorough clinical interview, during which a clear epizootic association could be
ascertained. The present clinical case highlights the complexity
and variability of newly emerging human infections1 2 by establishing E. canis as a causative agent of intraparenchymal haemorrhage, not associated with systemic findings. Furthermore,
it emphasises the importance of the clinical interview in the
process of establishing an appropriate clinical diagnosis, as the
only clue we had that was suggestive of E. canis infection was the
patient’s interaction with his pet and the detailed physical examination performed. In their natural hosts, ehrlichiae avoid clearance by the immune system, establishing a persistent infection.8
Therefore, chronicity and reactivation with episodes of reduced
immunity are characteristic of ehrlichioses,2 just as observed in
this case report.
In humans, CSF examination in patients diagnosed with ehrlichiosis reveals predominantly lymphocytic pleocytosis found in
73% of patients and an elevated protein concentration in up
to 76%.8 9 There are also reports of perivascular infiltration by
lymphocytes, plasma cells and macrophages (some containing
ehrlichiae inclusions) in the brain and leptomeninges of patients
with E. chaffeensis infection.8 Laboratory data therefore supports
CNS involvement in ehrlichial infection.
A case of frequent complex partial seizures secondary to
dual infection with Anaplasma phagocytophilum and E. chaffeensis was reported in 200610; in contrast to the case presented
here, encephalopathy was diagnosed through medial temporal
lobe and multifocal cortical signal increase in fluid-attenuated
inversion recovery MRI.10 Further cases of CNS involvement
have been described in up to 20% to 70% of patients with
3

Unusual presentation of more common disease/injury

Figure 3

Normal simple T1-weighted axial MRI, performed subsequent to doxycycline discontinuation 3 years after presentation.

human monocytic ehrlichiosis.4 8 9 11 In children, CNS manifestations comprise hyper-reflexia, meningismus, confusion, broadbased gait, cranial neuropathy, ataxia and seizures.11 Long-term
language and motor neurological sequelae have been occasionally observed.11 12 In contrast, meningitis and meningoencephalitis are rare complications in human granulocytic ehrlichiosis.
Few patients develop focal neurological signs and symptoms.13
About 1% shows CNS involvement.8 However, a number of
different peripheral nervous system manifestations have been
described.1 11 13
The association of granulocytic ehrlichiosis with meningitis has
been reported in dogs,14 although some studies utilising broadly
reactive PCR to evaluate brain tissue and CSF suggest that Ehrlichia is unlikely to be related with the development of canine
meningoencephalitis.15 Although neurological signs attributable
to ehrlichiosis are rare, CNS lesions are commonly seen in postmortem examination of infected veterinary specimens.16
On the other hand, canine monocytic ehrlichiosis is recognised
as a haemorrhagic disease in dogs.3 The pathology is characterised by thrombocytopaenia,3 which is the most common haematological finding in dogs with E. canis infection.17 Thrombocytopaenia is hypothesised to be caused by peripheral sequestration
secondary to vasculitis, destruction in the reticuloendothelial
system, inhibition of platelet migration and suppressed production during the chronic phase of the disease.2 8 17 18 It has also
been proposed that an overproduction of antiplatelet antibodies
observed as early as day seven postinfection, could lead to platelet
destruction.19 However, a bleeding tendency seen in dogs with
normal platelet counts suggests that haemorrhage is likely attributable to a qualitative platelet defect, as opposed to thrombocytopaenia.20 Animal studies have demonstrated that compared
with controls, dogs infected with E. canis have reduced platelet
aggregation in response to ADP, epinephrine and collagen.20–25
4

Mechanisms that are thought to contribute to reduced
platelet function include the presence of exhausted platelets that
continue to circulate,26 impairment of platelet factor 3 release
by an unidentified agent27 and coating of the platelet membrane
with light-chain proteins.20 23 Also, it has been suggested that
specific antibodies directed against platelet membrane glycoproteins may interfere with platelet aggregation.28
Another possible explicative mechanism for the occurrence of
haemorrhage is the formation of microorganism clusters within
the vacuole in platelets.8 Thus, it has been suggested that bleeding
in ehrlichiosis is of multifactorial origin.25 In consequence, there
are tangible explanations and support as to why our patient
developed cerebral haemorrhage without thrombocytopaenia.
Since platelet function tests were normal in our patient, we

Learning points
►► Infection by ehrlichial species commonly causing disease

in humans is associated with non-specific central nervous
system manifestations.
►► Although rare, human ehrlichiosis caused by Ehrlichia canis
may manifest exclusively in the brain, in this case as an
intraparenchymal haemorrhage, without associated systemic
findings.
►► Central nervous system haemorrhage in ehrlichiosis
may course without thrombocytopaenia and is possibly
linked to altered platelet function due to the presence of
microorganism clusters within the platelets.
►► The history of a zoonotic link can be a major factor orienting
the diagnosis in an otherwise unexplained a traumatic
central nervous system haemorrhage.
Garc­Ía-Baena C, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2016-219054

Unusual presentation of more common disease/injury
believe that haemorrhage was possibly due to localised vasculitis
within cerebral vessels, secondary to an inflammatory process
caused by the infection.
In summary, evidence provides a sufficient basis to establish a
clinical association between ehrlichiosis and CNS infection and
clinical manifestations. However, to our knowledge, apart from
a case of seizures and anaemia in a dog diagnosed with E. canis
infection,16 there are no further reports of neurological focal
deficits secondary to this specific pathogen, needless to say, of
intraparenchymal haemorrhage secondary to E. canis infection
in a human. The only report of intracranial haemorrhage in a
human is a recently published case of E. chaffeensis infection.
However, apart from it being a different causative agent, the case
differed from ours in that it was a subarachnoid haemorrhage
presenting with thunderclap-type headache.18
Contributors JFR provided initial care for the patient and conceived the idea
of writing the case. JFR, CGB and MFC were part of the clinical team providing
follow-up care, and the three contributed to extract, summarise and interpret the
data from clinical records. CGB and MFC performed the literature review. CGB
drafted the first version of the manuscript and selected the most illustrative images.
MFC obtained informed consent from the patient. JFR, CGB and MFC proof-read and
edited the article and approved the final version of it.
Competing interests None declared.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article)
2017. All rights reserved. No commercial use is permitted unless otherwise expressly
granted.

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Garc­Ía-Baena C, et al. BMJ Case Rep 2017. doi:10.1136/bcr-2016-219054

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