Central nervous system involvement of anaplasmosis

Abstract

A 64-year-old woman presented with 24 hours of lethargy, confusion, headache, nausea and vomiting. Examination revealed expressive aphasia, conjunctival suffusion and a tick embedded in her popliteal fossa. Labs revealed hyponatraemia, transaminitis, leucopenia, thrombocytopenia and an elevated C reactive protein. Peripheral blood smear was unremarkable. MRI/magnetic resonance angiogram revealed bilateral frontoparietal subarachnoid haemorrhage which was further confirmed by lumbar puncture which revealed six nucleated cells, 92% lymphocytes, 1460 red blood cells, normal glucose and protein and negative cryptococcal antigen, herpes simplex PCR and Lyme PCR. Serum Lyme IgG/IgM antibodies and PCR, Erlichia chaffeensis serum IgG/IgM antibodies and PCR and anaplasma serum IgG/IgM antibodies were negative. Anaplasmosis serum PCR was positive. The tick was identified as Ixodes scapularis. The patient was diagnosed with anaplasmosis and treated with 21 days of doxycycline resulting in improvement of symptoms, but lingering headaches and word finding difficulties.

Background

This is an unusual presentation of tick-borne human granulocytic anaplasmosis (HGA), with a previously unpublished neurological manifestation of expressive aphasia and bilateral frontal lobe subarachnoid haemorrhage (SAH). We believe this is a valuable contribution to the literature as early recognition and treatment of HGA typically results in excellent outcomes.

Case presentation

In autumn, in a mid-Atlantic state of the USA, a 64-year-old woman presented to the emergency department with a 24-hour history of confusion and lethargy. She stated that on the day prior to presentation, she was suddenly stricken with lethargy. The following morning, she had worsened lethargy, subjective fever, mild headache, nausea, vomiting and increased confusion. Prior to this event, she was a very active person, with only a history of hypertension. She worked on her horse farm with daily exposures to horses, donkeys, cats, dogs, chickens and mice.

On presentation, her vitals, including temperature, were within normal limits and she did not appear to be in acute distress. On examination, she had mild conjunctival suffusion, and her neck was supple without lymphadenopathy. Cardiac, pulmonary and abdominal examinations were benign. Neurologically, she did not have any focal motor/sensory deficits but was displaying expressive aphasia and memory lapse of the past 24 hours. Though no skin rashes were found on physical examination, an engorged tick was found embedded in her popliteal fossa.

Investigations

Laboratory values revealed a mild hyponatraemia and hypokalaemia and moderate transaminitis: aspartate aminotransferase of 89 U/L (reference 0–32) and alanine aminotransferase of 108 U/L (reference 0–33). The complete blood count (CBC) showed a white blood cell count of 3.49×10⁹/L(reference 4–10.4×10⁹/L) (absolute lymphocyte count 0.41 (reference 1–3.4)) and platelets of 92 ×10⁹/L (reference 150–350). C reactive protein was elevated at 12.4 mg/dL (reference <0.50).

MRI, on admission, noted focal increased signal intensity over the left frontal lobe with leptomeningeal enhancement, interpreted by radiology as possible focal SAH in the setting of reversible cerebrovascular vasoconstriction syndrome (figure 1). At this time, neuroradiology suggested a follow-up magnetic resonance angiogram (MRA), which was conducted on hospital day 2. In the study, susceptibility weighted imaging (SWI) was done, which confirmed bilateral frontotemporal SAH (figure 2). Additionally, MRA images noted a paucity and irregularity of the left middle cerebral artery (MCA). Per neurology consult, a non-contrast head CT was performed on day 3 that did not reveal radiographic evidence of intracranial blood.

Figure 1.

Initial MRI which showed Fluid attenuated inversion recovery (FLAIR) focal increased signal intensity over the left frontal lobe with leptomeningeal enhancement suggestive of subarachnoid haemorrhage versus leptomeningitis.

Figure 2.

Follow-up SWI depicting findings of bilateral subarachnoid haemorrhages over the frontoparietal region. SWI, susceptibility weighted imaging.

Lumbar puncture performed on hospital day 2, produced 13 cc of cerebral spinal fluid (CSF) collected into four test tubes all showing clear, colourless fluid with an opening pressure of 18 mm Hg. CSF results revealed six nucleated cells, 1460 red blood cells (RBCs) in tube 4, glucose of 60, protein of 38 and culture negative. Additional labs included negative results for: respiratory viral panel, COVID-19, HIV antigen and antibody screening, Cytomegalovirus and Epstein -Barr Virus by PCR, hepatitis serologies, Lyme CSF PCR, Leptospira serum IgM antibody and PCR, anaplasma serum IgG and IgM, Ehrlichia chaffensis (E. chaffeensis) serum IgG and IgM, cryptococcal CSF Ag, herpes simplex virus CSF PCR and Ehrlichia serum PCR. Anaplasma serum PCR was positive.

Differential diagnosis

Given the laboratory abnormalities, the patient’s risk factors, the setting of autumn in the Mid-Atlantic area of the USA, a zoonotic pathogen was suspected including: Leptospira, Brucella, Francisella and Bartonella. Finding the tick in her popliteal fossa led to a workup for tick-borne illnesses. This included peripheral blood smear for intra-erthrocytic or extra-erthrocytic parasites including Babesia or evidence of white blood cell incluisons consistent with Anaplasma or Ehrlichia. The presenting symptoms of waxing and waning expressive aphasia, headache and memory loss prompted a neurological workup. The MRI finding of an SAH was corroborated with an MRA with SWI and a lumbar puncture that revealed persistence of RBCs in tube 4. However, follow-up non-contrast head CT did not reveal intracranial blood. With no evidence of an aneurysm on MRA/SWI, lack of xanthochromia in the CSF fluid, and with the clinical history, finding of an engorged, embedded tick and rapid improvement on antibiotic therapy, the SAH was not suspected to be from an aneurysmal bleed. Thus confirmatory testing with digital subtraction angiography (DSA) was considered unwarranted.¹ The MRI, MRA and Lumbar Puncture findings were consistent with a non-aneurysmal SAH with cerebral vasospasm due to neurological sequelae of a tick-borne infection. Due to the acuteness of the infection, the anaplasma antibodies were still negative, but the anaplasma serum PCR confirmed the infection.

Treatment

Anaplasmosis is treated with 100 mg of two times per day doxycycline either orally or intravenously for 10 days. Alternative treatments include rifampin 300 mg orally two times per day for 10 days. Patients typically respond rapidly to treatment, showing improvement within 48 hours.²

Outcome and follow-up

Following the patient’s initial treatment with doxycycline, the electrolytes, liver function tests, CBC and inflammatory markers rapidly normalised. However, the patient was again hospitalised 6 weeks later due to persistent headache, word finding difficulties, memory loss and generalised fatigue. Repeat MRI and MRA of the brain showed significant increase in the FLAIR hyperintensity and hypointensity involving bilateral frontal, parietal occipital lobes, consistent with SAH with persistent left MCA anterior division vasospasm (figure 3). Repeat CSF studies at that time found RBC 1000×10¹²/L and 750×10¹²/L serial testing, and no acute infectious markers, thus no additional antibiotics were given. Electroencephalogram conducted throughout admission was not concerning of seizure activity.

Figure 3.

Interval significant increase in the T1-weighted hyperintensity and hypointensity on SWI convexity sulci involving bilateral frontal, parietal occipital lobes, suggesting subarachnoid haemorrhage. SWI, susceptibility weighted imaging.

The patient was discharged from the hospital with speech therapy follow-up. The patient has had marked improvement and returned to her cognitive baseline 3 months later.

Discussion

Finding the tick plus our patient’s leucopenia, thrombocytopenia and transaminitis suggested infection with Lyme, Anaplasmosis or Ehrlichiosis. The Ixodes scapularis is the tick vector for Borrelia burgdorferi (Lyme disease, B. Burgdorferi), Anaplasma phagocytophilum (human granuloctytotropic anaplasmosis, HGA, A. phagocytophilum) and Babesia microti (babesiosis). A host can be co-infected from one tick with more than one of these bacterium. Since there was no evidence of haemolytic anaemia and the blood smear did not reveal intra-erythrocyte Maltese cross forms consistent with B. microti, treatment with atovaquone and azithromycin was not initiated.

Anaplasmosis (HGA) is caused by the bacterium A. phagocytophilum and transmitted by an infected Ixodes tick. Ehrlichiosis is most commonly caused by the bacterium E. chaffeensis (HME), though Ehrlichia ewingii (HEE) is an emerging species causing human disease, with both being transmitted by an infected Amblyomma americanum (lone star) tick. They all present similarly, with non-specific fevers, myalgias, lethargy, headache and gastrointestinal symptoms. As mentioned, the triad of leucopenia, thrombocytopenia and mildly elevated liver function enzymes is common and should trigger consideration of these infectious aetiologies.^3–5 Of note, evidence suggests that time from transmission to symptom onset in anaplasmosis can be within 24 hours.⁶ Rash is uncommon, occurring in <10% of patients with HGA.⁵ For rapid diagnosis, the morulae, which are basophilic intracytoplasmic inclusion bodies on Wright stain of the buffy coat smear, can be seen 25%–75% of the time in granulocytes in HGA but only around 3% of the time in monocytes in HME.⁴

The findings of confusion, expressive aphasia and leptomeningeal enhancement and SAH were puzzling. Neurological involvement with tick-borne organisms usually demonstrate a lymphocytosis and increased protein in the CSF. The symptoms of Lyme neuroborreliosis (LNB) range from mild confusion to severe encephalitis, cranial neuropathies and motor or sensory radiculoneuropathies. LNB may have MRI findings of encephalitis, meningeal, leptomeningeal or neural enhancement. About 50% of patients with LNB have nonspecific abnormal imaging findings predominantly within the frontal cortex white matter arcuate fibres. There is speculation that a secondary autoimmune mechanism mimicking demyelinating disease is the cause of these MRI findings. In rare instances, LNB presents with stroke, SAH or intracerebral haemorrhage.⁷

Of Anaplasma and Ehrlichia, the latter is more commonly associated with Central nervous system manifestations, including meningitis and meningoencephalitis in approximately 20% of cases.⁴ Leptomeningeal enhancement has been reported on imaging in HME.⁸ Rarely, Ehrlichia can lead to coma and seizures.⁴ By contrast, confusion is a recognised, but rare presentation of HGA. In a case series of 33 patients at a suburban hospital in Boston, only one (3%) had confusion as a presenting symptom.⁹ The initial finding of inflammatory leptomeningeal enhancement on MRI, then confirmed to be SAH on MRA/SWI, over the left frontal lobe help explain the manifestation of expressive aphasia in our patient. Serum testing for E. chaffeensis, B. borgdorferi and A. phagoctyophilum was negative; however, antibodies can take several weeks to develop. A diagnosis of anaplasmosis was made from the positive serum PCR. To our knowledge, no prior report has described either expressive aphasia or SAH with vasospasm in a patient with anaplasmosis.

It should be noted the limitations of the case report. First, CSF red cells were measured only in tube 4, and not compared with tube 1. The lumbar puncture was conducted on hospital day 2, which correlated with the initiation of antibiotics and from that point the patient began to show clinical and laboratory improvement. Due to the patient’s initial rapid clinical improvement and her fear of lumbar punctures, we did not repeat a second lumbar puncture on initial presentation. However, repeat lumbar punctures weeks later still revealed present, but declining RBCs in the CSF. Second, due to the clinical improvement on antibiotics and an MRA/SWI that did not reveal an aneurysm, an aneurysmal bleed as the cause of the SAH was not considered to have a high pretest probability and thus a DSA was not requested. DSA studies are mostly used to evaluate SAH due to aneurysmal bleeds. The SWI images are capable of differentiating leptomeningeal enhancement versus SAH. Finally, we did not test the CSF fluid for anaplasma PCR. However, with the positive anaplasma serum PCR, the swollen tick still embedded in the patient’s popliteal fossa and the clinical improvement on antibiotic therapy, we conclude that the patient’s symptoms were secondary to infection from A. phagocytophilum.

Patient’s perspective.

I appreciate the effort and compassion of the medical team who worked on my care.

I hope that that future medical proffesionals can learn and grow from the my case.

Learning points.

• Consider tick-borne illnesses for any patient presenting with the triad of transaminitis, leucopenia and thrombocytopenia.

• Human granulocytic anaplasmosis (HGA) is caused by the bacterium Anaplasma phagocytophilum and transmitted by an infected Ixodes tick. It most commonly presents with non-specific fevers, myalgias, lethargy, headache and gastrointestinal symptoms.

• Rarely, HGA can present with neurological manifestations including confusion. Our case reports add expressive aphasia and subarachnoid haemorrhage with vasospasm as novel presenting signs and symptoms for anaplasmosis.

• The diagnosis of HGA can be made with serum antibodies or PCR for the causative bacteria. Granulocytic morulae can suggest a diagnosis but are only observed in 25%–75% of cases.

• Severe presentation warrants empiric treatment with doxycycline while awaiting lab confirmation of the diagnosis. Patients should respond rapidly to treatment, and lack of improvement after 48 hours warrants consideration of an alternative diagnosis.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).