B Transcellular, passing through cells, e. In this scenario, blood-borne bacteria directly invade CNS endothelial cells. Infected leukocytes adhere to endothelial cells, allowing the spread of bacteria or, alternatively, leukocytes can transmigrate and deliver bacteria to the CNS parenchyma.
CNS, central nervous system. They induce the activation of nuclear factor-kappa B- or mitogen-activated protein kinase pathways and subsequently up-regulate leukocyte populations and express numerous proteins involved in inflammation and the immune response [ 16 , 18 ]. However, the precise molecular mechanisms of rickettsial entry into the CNS are not yet described. The most efficient antibiotics to cure rickettsioses are tetracycline derivatives, primarily doxycycline.
The daily dose, mg, is usually administered orally and is sufficient to cure rickettsioses. Treatment duration is 7 days or until 2 days after apyrexia is obtained [ 20 , 21 ]. In severe forms, intravenous doxycycline may be used. Alternatively, chloramphenicol and macrolides azithromycin, clarithromycin, and roxytromycin can be prescribed for treating rickettsial diseases [ 22 , 23 ].
As a consequence, empirical therapy for CNS infections most often does not include antibiotics active on rickettsiae. In spotted fever group SFG rickettsioses, encephalitis is underdiagnosed due to underrecognition and low sensitivity of serologies at the time of early symptoms [ 24 ]. Therefore, it is difficult for clinicians to recognize the clinical, biological, and neuroimaging features of this type of encephalitis [ 25 ]. The onset of symptoms is usually abrupt, with severe headache, fever, chills, myalgias, arthralgias, and prostration.
Neurological symptoms are frequently a prominent feature. Headache, restlessness, insomnia, and back stiffness are common. Delirium or coma alternating with restlessness is present during the peak of fever [ 26 , 27 , 29 — 31 ]. Encephalitis, which may be fatal, is a frequent manifestation in case of delayed diagnosis and treatment [ 32 ]. In addition, several authors have described severe sequelae in patients who survived R.
Histological studies have highlighted that the pathologic changes in RMSF are most severe in the skin, but the heart, lungs, and CNS also are involved. The brain is edematous, and minute petechial hemorrhages are present. The characteristic microscopic lesions are small round nodules composed of elongated microglia, lymphocytes, and endothelial cells [ 29 , 38 , 39 ]. These are scattered diffusely through the brain in close relation to small vessels.
Vessels in the center of the lesions show severe degeneration. Endothelial cells are swollen, and the lumen may be occluded. Areas of focal necrosis are common as the result of thrombosis of small arteries. Some degree of perivascular infiltration without the presence of nodules may be seen in both the meninges and brain parenchyma [ 29 ]. To the best of our knowledge, there is just one report of experimental in vitro rickettsial infection of neuronal cells.
Joshi and Kovacs [ 40 ] demonstrated that neurons are efficiently infected by R. A double-immunofluorescent staining technique was employed to identify infected neurons, using anti- R. The extent of apoptotic cell death of immunocytochemically identified neurons was determined by terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labelling TUNEL assay. To verify that the observed neuronal degeneration was R. The authors also included R.
The CNS is also a crucial target in other rickettsial diseases [ 41 , 42 ]. It has been demonstrated by a specific immunohistochemistry technique, during the development of mouse-model studies, that rickettsiae reach brain tissues when injected intravenously [ 43 ]. Such studies demonstrate that rickettsiae are able to cross the blood—brain barrier to reach brain tissues.
The other rickettsial infections that may affect the nervous system exhibit pathological and clinical changes similar to those of RMSF [ 29 ]. In rickettsial meningitis, the cerebrospinal fluid shows pleocytosis with lymphocyte predominance, hypoglycorrhachia, and hyperproteinorrhachia.
In large MSF case series from France and Spain, patients with severe and fatal forms of the disease developed complications, including acute renal failure, thrombocytopenia, myocarditis, pneumonitis, gastric hemorrhage, shock, and multiple organ failure [ 44 — 47 , 49 ]. Furthermore, a few reports in the literature have described CNS involvement in the course of MSF, presenting as meningitis [ 50 , 51 ], encephalitis [ 45 , 47 , 49 , 50 , 52 , 53 ], meningoencephalitis [ 47 , 54 — 56 ], or myelitis [ 50 ].
Among the patients who survived these severe forms, only 2 did not suffer sequelae. Sequelae were severe, despite an appropriate doxycycline treatment of mg every 12 hours [ 54 , 57 ].
Japanese spotted fever JSF , caused by R. This rickettsial disease is characterized by high fever, rash, and inoculation eschar at the tick bite site [ 58 ]. JSF is clinically similar to scrub typhus, caused by O.
CNS involvement is rare, but cases complicated by pneumonia or meningoencephalitis have been reported [ 59 — 61 ]. The first fatal case was reported by Kodama and colleagues in [ 65 ]. All patients exhibited fever and mental disturbance, including 3 patients with nuchal rigidity and 3 patients with seizures.
All patients had aseptic meningitis [ 66 ]. The first R. However, in , R. This syndrome is defined by the association of a tick bite and an inoculation eschar to the scalp, surrounded by a circular erythema, and painful regional lymphadenopathies [ 78 ]. Although rare, the most frequent general symptoms are fever, nuchal lymphadenopathy, fatigue, dizziness, headache, sweat, myalgia, arthralgia, and loss of appetite [ 68 , 79 ]. Symptoms suggestive of acute encephalitis with febrile relapses and a persistence of neurasthenic disorders have also been reported [ 68 , 80 ].
Although R. In , R. In , Parola and colleagues reported 6 more cases of R. To date, R. The disease is most commonly mild and self-limiting without any sequellae. However, in , Jensenius and colleagues reported 6 patients with evidence of long-lasting subacute neuropathy following ATBF contracted during a safari to southern Africa [ 88 ]. Initially, the organism was considered as nonpathogenic.
However, several patients with a mild and self-limiting disease associating fever, headache, and myalgia had serological evidence of R. Human cases have been reported in several European countries, e. However, a more severe clinical disease has been reported and may be associated with severe symptoms such as CNS disorders [ 95 , 96 ] verified by PCR in the cerebrospinal fluid, together with serologic evidence.
These include an agitated delirium that, when untreated, may progress to death. A severe headache is almost always present.
Neurological complications include seizures, confusion, and coma. In severe cases, patients develop meningoencephalitis, with meningism, tinnitus, and hyperacusis, followed by deafness, dysphoria, and agitation. In Brill—Zinsser disease, the recurrent form of epidemic typhus that may occur months to years after the initial infection, symptoms are similar to the primary infection, although generally milder [ 29 , 98 ].
It is most often a mild illness, but severe forms have been reported in refugee camps, and a fatal case in the United Kingdom was infected in Spain [ 99 ]. Headache is common, but meningitis and encephalitis are occasionally reported [ ]. Mental confusion, seizures, stupor, and ataxia may occur infrequently [ , — ].
In some cases, systematic signs and symptoms may be minimal, and neurological manifestations may be the primary clinical manifestations of R. No neurologic sequellae have been reported in the past [ 29 , 42 ]. However, recently, an abducens nerve palsy and meningitis induced by R. The etiological agent is R. Rickettsialpox is still occurring in the state of New York [ , ], and European cases of R.
Clinical signs of R. At the mite inoculation site, a vesicle appears, which dries up, leaving a scar. A generalized papular rash develops, which can also be vesicular, resembling chickenpox. Other signs of the disease include regional lymphadenopathy, nausea, and neurological symptoms such as meningitis, photophobia, dizziness, eye movement, and neck stiffness.
The disease is self-limiting, usually without complications, but myalgias and headache may persist for 2 more weeks after the rash [ ]. Originally described as a mild, self-limiting illness, recent case reports demonstrated the occurrence of more severe forms with complications.
Acute infections often begin with high-grade fever, headache, myalgias, and a maculopapular rash after a short incubation period averaging 5 days [ , ]. Infection has the potential to progress to severe sepsis with multiorgan failure, requiring prolonged hospitalization and admission to intensive care [ ].
Since R. Less common manifestations of QTT include splenomegaly, abdominal pain, renal failure, dry cough, and conjunctivitis [ ].
Some reports documented confusion, seizures, and hallucinations as features of the disease [ ]. Flea-borne spotted fever is caused by R. It is transmitted to humans by fleas, in particular Ctenocephalides felis fleas. Patients often present with elevated fever, headache, and myalgia. A cutaneous rash is inconstant.
Other manifestations may include abdominal pain, nausea, vomiting, cough, eschar, and photophobia. Rare cases of neurological involvement have been reported, notably, hearing loss and subacute meningitis [ , ]. The genus Orientia contains two known species, O.
Scrub typhus is a common cause of febrile illness in Asia. Fever and headache are the most common features of scrub typhus [ ]. During World War 2, scrub typhus was a well-recognized cause of lethal meningitis in the Asia—Pacific region. Nowadays, only scarce data exist on the clinical burden of these pathogens in patients with CNS disease, e.
Isolated cases of acute encephalitis, abducens nerve palsy, and acute transverse myelitis due to O. Even though we have focused our review on members of the genus Rickettsia , we have searched the literature for CNS infection caused by the related organisms Ehrlichia and Anaplasma species. Neurological involvement in human monocytic ehrlichiosis, caused by E.
Most cases present as aseptic meningitis, but complications such as ataxia, cranial nerve paresis, meningoencephalitis, multiorgan failure, optic neuritis, seizures, and demyelinating polyneuropathy have been reported [ , , — ]. In addition, E. In addition, A.
Through a literature review, we identified 13 rickettsioses, including scrub typhus, causing CNS infections ranging from simple headache to lethal meningoencephalitis. In addition, surviving patients may suffer incapacitating sequellae. To date, the precise mechanisms of rickettsial pathogenesis for the CNS are only partially known, but animal models have demonstrated their pro-apototic effect for neurons. However, these bacteria are constantly susceptible to tetracyclines that may efficiently be used to cure patients.
The remaining challenge is to integrate rickettsioses more systematically in the differential diagnosis of CNS infections. Without this effort, the diagnosis and treatment may be delayed, increasing the risk of severe forms.
Abstract As a result of migrations and globalization, people may face a possible increase in the incidence of central nervous system rickettsial infections CNS R. Introduction Recent reports have warned about the impact of global warming in facilitating the transmission of certain vector-borne infectious diseases.
Epidemiology of rickettsial diseases Rickettsiae are strictly intracellular bacteria that are vectored by various arthropods. Download: PPT. Fig 1. Phylogenetic tree of Rickettsia species inferred from the comparison of concatenated sequences from the gltA and sca 4 genes.
Fig 2. Developmental cycle and host range of Rickettsia -infected ticks. Table 1. Geographical distribution and arthropod vectors of Rickettsia and Orientia species causing CNS infections. Clinical manifestations of rickettsial infections Spotted fever rickettsioses typically present with a triad made of fever, inoculation eschar s , and generalized cutaneous rash. Fig 4. Mechanisms of bacterial penetration through the blood—brain barrier. Treatment of rickettsioses The most efficient antibiotics to cure rickettsioses are tetracycline derivatives, primarily doxycycline.
Neuropathology in the framework of rickettsial diseases Spotted fever group rickettsiae In spotted fever group SFG rickettsioses, encephalitis is underdiagnosed due to underrecognition and low sensitivity of serologies at the time of early symptoms [ 24 ].
Tick-borne lymphadenopathy R. Typhus group rickettsiae Epidemic typhus. Murine typhus. Transitional group rickettsiae Rickettsialpox. Queensland tick typhus. Flea-borne spotted fever. Scrub typhus The genus Orientia contains two known species, O. Rickettsia-related organisms Even though we have focused our review on members of the genus Rickettsia , we have searched the literature for CNS infection caused by the related organisms Ehrlichia and Anaplasma species.
Conclusion Through a literature review, we identified 13 rickettsioses, including scrub typhus, causing CNS infections ranging from simple headache to lethal meningoencephalitis. Clin Microbiol Rev, 26, — Pathogenesis: Joshi SG and Kovacs AD Rickettsia rickettsii infection causes apoptotic death of cultured cerebellar granule neurons. J Med Microbiol, 56, — Rickettsial infections and the central nervous system.
Clin Infect Dis,26, — Neurol Clin, 17, — J Clin Microbiol, 40, — Key learning points Rickettsioses are arthropod-transmitted and zoonotic diseases with a worldwide distribution. As the infection progresses, people typically experience confusion and severe weakness—often with cough, difficulty breathing, and sometimes vomiting.
When the infection is advanced, gangrene may develop, the liver or spleen may enlarge, the kidneys may malfunction, and blood pressure may fall dangerously low causing shock Shock Shock is a life-threatening condition in which blood flow to the organs is low, decreasing delivery of oxygen and thus causing organ damage and sometimes death.
Blood pressure is usually low Death can result. Because rickettsiae and rickettsia-like bacteria are transmitted by ticks, mites, fleas, and lice, doctors ask people. Being bitten is a helpful clue—particularly in geographic areas where rickettsial or a related infection is common.
However, many people do not recall such a bite. If doctors suspect Q fever, they may also ask whether people were at or near a farm because cattle, sheep, and goats are the host for the bacteria that cause this infection. A physical examination is done to determine which parts of the body are affected and what the rash looks like. Doctors also look for an eschar that people may not have noticed and for swollen lymph nodes.
Testing is usually needed to confirm the diagnosis. Often, doctors cannot confirm an infection with rickettsiae or rickettsia-like bacteria quickly because these bacteria cannot be identified using commonly available laboratory tests. Special blood tests for these bacteria are not routinely available and take so long to process that people usually need to be treated before test results are available.
Doctors base their decision to treat on the person's symptoms and the likelihood of possible exposure. In immunofluorescence assays, foreign substances produced by the bacteria antigens are labeled with a fluorescent dye. The polymerase chain reaction PCR technique is used to increase the amount of the bacteria's DNA, so that the bacteria can be detected more rapidly.
Antibiotics are usually started without waiting to get the results of tests. Early treatment of rickettsial infections can prevent complications from developing, reduce the risk of dying, and shorten the recovery time. Rickettsial infections respond promptly to early treatment with the antibiotics doxycycline preferred or chloramphenicol.
These antibiotics are given by mouth unless people are very sick. In such cases, antibiotics are given intravenously. After treatment, most people with a mild infection noticeably improve in 1 or 2 days, and fever usually disappears in 2 to 3 days. People take the antibiotic for a minimum of 1 week—longer if the fever persists. When treatment begins late, improvement is slower and the fever lasts longer. If the infection is untreated or if treatment is begun too late, people may die, especially if they have epidemic typhus Epidemic Typhus Epidemic typhus is a rickettsial disease that is caused by Rickettsia prowazekii and spread by body lice.
It is spread by chiggers mite larvae. People with scrub typhus have a fever, chills, and a headache Ciprofloxacin Fluoroquinolones Fluoroquinolones are a class of broad-spectrum antibiotics that are used to treat a variety of infections. Fluoroquinolones include the following: Ciprofloxacin Delafloxacin Gemifloxacin read more and other similar antibiotics may be used to treat Mediterranean spotted fever but are usually not used to treat other rickettsial or related infections.
Understanding how this bacterium interacts with the cells of its host could lead to new therapeutic strategies for diseases caused by related pathogens, including Rocky Mountain spotted fever and typhus. Their findings will be reported in the December 16, , issue of the journal Cell.
This receptor is a subunit of a protein complex present mainly in the nucleus, but also in the cell cytoplasm and at the cell membrane. Rickettsial bacteria are transmitted by fleas, ticks, and lice to humans and other mammals, where they can cause dangerous and sometimes fatal infections. There are two types of Rickettsial pathogens—the spotted fever group, which includes the Rickettsia conorii bacteria studied by Cossart and her colleagues, and the typhus group.
Both must live inside cells to survive. Mediterranean spotted fever is transmitted by a dog tick. The symptoms are generally mild and respond to antibiotics that shorten the course of the disease.
But serious complications occur as much as 10 percent of the time, usually in patients who are elderly or who have some other underlying disease. Left untreated, Mediterranean spotted fever can be deadly. Cossart and her team demonstrated that the Ku70 protein on the surface of host cells is critical for R.
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