Case of the Month

December 2017

SASTM (Dr Rochelle Lee)

A 43-year-old man presented to the emergency unit, two weeks after returning from Egypt, complaining of tingling of his hands and feet, diarrhoea and vomiting, confusion and hallucinations. A friend who had travelled with him to Egypt was treated for gastro-enteritis on return.

Medical history

Hypertension for which he takes perindopril (a long-acting ACE inhibitor).


No overt signs were elicited. He was afebrile, his blood pressure was normal and tachycardia was noted; oxygen saturation was 97% in room air.


A full blood count, urea and electrolytes, liver function test, cardiac markers, C-reactive protein and HbA1C were all within normal limits.

A CT scan of the brain was normal.

He was discharged on citalopram, etifoxine and esomeprazole with instructions to report back in 24 hours.

He defaulted but was referred back to the same emergency unit three days later, after he had consulted at another hospital where the investigations mentioned above were repeated but were still normal.

He complained of paraesthesia and left chest pain. His interactions with the medical staff and his family were peculiar: he had infantile-like reactions with anxiety and was hallucinating. He complained of left chest discomfort. A neurological examination was normal; in particular, there was no evidence of meningism. He mentioned recent use of cannabis oil which was proven on a urine toxicology screen.

Question 1 - Is the travel history of importance?

Question 1

Is the travel history of importance?

Knowing the epidemiology of infectious diseases in the country to which the patient had travelled is essential to this case. A travel history is important as well as possible exposures during travel – activities and persons/ animals that the traveller might have been in contact with. One must be sure of when the symptoms commenced and determine whether the illness is travel related or developed after the patient’s return home.

The patient was confused at the time of examination so obtaining a detailed history relating to exposure and commencement of symptoms was difficult. The patient was examined for evidence of insect bites but none were found. The patient had not come into close contact with stray or wild animals during his travels. Rickettsial disease should be considered, but other viral illnesses unrelated to travel may result in a similar picture.

What is the differential diagnosis?

The differential diagnosis includes meningitis, encephalitis, a metabolic abnormality and psychosis post-cannabis usage.

What further tests should be requested?

These should be based on the differential diagnosis – to exclude a bacterial or viral meningitis as well as rickettsial infection.

The patient was admitted and further tests were undertaken.

Question 2 - What is Rickettsia conorii and how is it transmitted?

Question 2

What is Rickettsia conorii and how is it transmitted?

Rickettsia conorii is a Gram-negative, obligate intracellular bacterium of the genus Rickettsia that causes human disease called Boutonneuse fève, Mediterranean spotted fever, Israeli tick typhus, Astrakhan spotted fever, Kenya tick typhus, Indian tick typhus, or other names that designate the locality of occurrence while having distinct clinical features.

This disease is a member of the spotted fever group and R. conorii is the most geographically dispersed species in the group, recognized in most of the regions bordering on the Mediterranean and Black Sea, Israel, Kenya, and other parts of North, Central, and South Africa, and India.

The vector is the brown dog tick, Rhipicephalus sanguineus.1

The tick serves as a vector for the bacterium and a host as it feeds on other hosts i.e. small animals including dogs – the main reservoir being dogs, rabbits and small rodents. Following a tick bite, the bacterium enters the bloodstream of the human host and, as it is an obligate intracellular organism, it multiplies in the nucleus of the cells as well as the cytoplasm, causing cellular death. It also multiplies in the nuclei of endothelial cells of the arterioles and venules resulting in vasculitis and increased vascular permeability causing blood leakage into adjacent tissues, a rash, and platelet breakdown resulting in thrombocytopenia.

Question 3 - What is the distribution of R. conorii?
Question 3:

What is the distribution of R. conorii?

It is found mainly in the Mediterranean, Israel and Africa. 3

Question 4 - What are the main clinical features of tick-bite fever with encephalitis (rickettsial encephalitis)?

Question 4

What are the main clinical features of tick-bite fever with encephalitis (rickettsial encephalitis)?

A careful clinical examination will yield clues. A travel history to an endemic area will be the first red flag for possible tick-bite fever. In most patients, the clinical signs may not be clear. The onset of symptoms is usually 7 - 14 days after exposure to a tick and tick bite marks may no longer be visible.

Patients may present with the triad of rash, eschar and fever; however, this may not be present in all cases. Other symptoms may include chills, headache, confusion, abdominal pain, nausea and vomiting, malaise, photophobia and myalgia.4

The rash of tick bite fever classically begins as small (1–5 mm in diameter), blanching, pink macules on the ankles, wrists, or forearms that subsequently spread to the palms, soles, arms, legs, and trunk, usually sparing the face.

The patient may also have a positive Faget sign - this is a sphygmothermic dissociation where the patient has a bradycardia in the presence of a fever.

The patient may not have meningism, including neck stiffness. The Babinski and Kernig reflexes may be absent.

Question 5 - What are the broad differential diagnoses of fever in a returning traveller, with or without confusion?
Question 5

What are the broad differential diagnoses of fever in a returning traveller, with or without confusion?

Bacterial infections
    Secondary syphilis*
    Disseminated gonococcal disease*
    Bacterial endocarditis*
    Scarlet fever
    Rat bite fever*
    Lyme disease
    Relapsing fever
    Murine typhus
    Rickettsial pox
    Sylvatic and epidemic typhus
    Scrub typhus
    Capnocytophaga canimorsus infection
    Mycoplasma pneumoniae infection
    Typhoid and paratyphoid fever

Viral infections
    Hand, foot, and mouth disease*
    Acute (primary) HIV infection
    Cytomegalovirus infection
    Human parvovirus B19 infection
    Colorado tick fever
    West Nile virus disease
    Chikungunya virus disease
    Dengue fever
    Zika virus disease
    Viral hemorrhagic fever
    Japanese encephalitis (travel to Asia and Western Pacific)

Other conditions
    Drug eruptions*
    Kawasaki disease*
    Thrombotic thrombocytopenic purpura Immune thrombocytopenic purpura Immune complex vasculitis
    Toxic shock syndrome*
    Erythema multiforme* Stevens-Johnson syndrome* (4)

might cause rash involving the palms of the hands and the soles of the feet.

Question 6 - What are the laboratory features of tick bite fever and associated encephalitis?
Question 6

What are the laboratory features of tick bite fever and associated encephalitis?
  • Normal white cell count with immature neutrophils
  • Slightly elevated blood sodium level
  • Increased liver transaminases
  • Increased LDH in advanced illness
  • Thrombocytopenia
  • CSF: Raised protein and normal to slightly elevated glucose level.
  • The Weil-Felix test, which detects agglutinating antibodies, is detectable 5 to 10 days following the onset of symptoms, with the antibodies detected being mainly of the immunoglobulin M (IgM) type.5 Note: The Weil Felix test is NOT the serological test of choice to confirm rickettsial infection. This should not be relied upon and requesting this test is to be discouraged.
  • If there is an eschar, a very sensitive test is PCR on a dry swab of the eschar. This test remains positive even if antibiotics have been commenced. As the patient did not have an eschar, this test could not be done.
  • Other tests for the diagnosis of acute cases of rickettsial infection are those which directly detect rickettsiae: PCR of blood specimens (does not remain positive with antibiotic use), immunodetection with tissue biopsy specimens (not offered in South Africa), and a shell vial assay (very slow).
  • Serology tests are most useful after seven days of onset of illness. If requested during the early stages of the disease, the results may be negative but will not exclude the possibility of a rickettsial infection. Because the most important considerations in the choice of a serologic assay in this situation are its sensitivity and the length of delay between the onset and appearance of detectable antibody titers, laboratories so equipped should use indirect immunofluorescent assay (IFA), especially tests specific for IgM.5 IgG titres ≥ 128 and/or IgM titres ≥ 64 (depending on assay) are considered

Question 7 - What is the treatment of suspected tick-bite fever?
Question 7

What is the treatment of suspected tick-bite fever?

Doxycycline remains the first-line treatment in all suspected cases of tick-bite fever and should be started without delay. Ceftriaxone can be started simultaneously if there is a high index of suspicion of a bacterial meningoencephalitis and where the lab results are still unavailable.

For tick-bite fever in children under the age of 8 years, either proven or suspected, doxycycline remains the first-line treatment. Studies have shown that short-term treatment of 5-7 days in the correct dosage does not cause any damage to bone or enamel of teeth.4


The above patient was admitted with a presumptive diagnosis of rickettsial encephalitis based on the travel history and clinical features. Doxycycline was administered, pending results, and the patient showed slight improvement but still had some psychotic features.

The patient had a lumbar puncture and the raised CSF protein was a red flag.

The patient had a negative blood IgM for rickettsiosis, but IgG remained positive with a titre of 128, suggesting resolved tick-bite fever. The lumbar puncture was repeated, and the CSF protein normalised. The patient’s psychotic features remained, and he was treated and transferred for management of a substance-induced psychosis secondary to his use of cannabis and for further psychiatric evaluation.


Tetrahydrocannabinol, the psychoactive agent, can have perceptible effects within minutes, is extremely lipid soluble, can accumulate in fatty tissues reaching peak concentrations within 4 -5 days. It is then slowly released back into the neocortical, limbic, sensory and motor areas of the brain. The tissue elimination half-life is 7 days and absolute elimination is 30 days. Cannabis-induced psychosis can produce short term exacerbation of pre-existing psychotic diseases or lead to acute intoxication. Symptoms experienced during drug-free periods are seldom reported.

The most common symptoms with cannabis use remains auditory and visual hallucinations as well as persecutory delusions, anxiety, grandiosity and irritability. In this case, the patient did not present with any of the symptoms commonly found with cannabis use, but it still cannot be completely excluded.7

Lessons learned

The diagnosis of tick-bite fever-associated encephalitis cannot be excluded completely owing to clinical features of an overlapping psychosis and encephalitis. The only indicator of possible tick-bite fever is the observed decrease in CSF protein and negative blood IgM after treatment with doxycycline.

The other important thing to consider is the travel history. The patient may have had a tick bite in Egypt or South Africa.

If the patient had followed up after his initial consultation, neurological function and abnormalities could have been followed up and signs and symptoms might not have exacerbated, camouflaging other possible clues.

  1. Definition of Rickettsia available at: https://www.ncbi.nlm.nih.gov/books/NBK7624/ 

  2. Companion Vector borne diseases: Rickettsioses available at: http://www.cvbd.org/en/tick-borne-diseases/rickettsioses/rocky-mountain-spotted-fever/pathogenesis-and-transmission/

  3. Warmer weather linked to tick attack and emergence of severe rickettsioses available at: https://openi.nlm.nih.gov/detailedresult.php?img=PMC2581602_pntd.0000338.g006&req=4

  4. Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain Spotted Fever and Other Spotted Fever Group Rickettsioses, Ehrlichioses, and Anaplasmosis — United States. A Practical Guide for Health Care and Public Health Professionals available at: https://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6502.pdf

  5. Laboratory Diagnosis of Rickettsioses: Current Approaches to Diagnosis of Old and New Rickettsial Diseases available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC230049/pdf/352715.pdf

  6. Guidelines for the diagnosis of tick-borne bacterial diseases in Europe available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1469-0691.2004.01019.x/full

  7. Cannabis-induced bipolar disorder with psychotic features can be found at : https://www.ncbi.nlm.nih.gov/pmc/articles/pm2811144/

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