SEMINAKS IN NEUROLOGY-VOI.UME
12, NO. 3 SEI'7'F;MHRR I992
Rickettsia1 Infections of the Central Nervous System
T h e Rickettsiaceae are small gram-negative bacteria that, with two exceptions, Rochalimaea and Wolbachia, are capable of growth only inside cells' (Fig. 1-3). T h e taxonomy of these microorganisms is undergoing reevaluation as a result of scqucncing of ribosomal KNA to deterrrrir~ethe evolutio~iaryrela~io~iships arnong bacteria.) T h e ricksettsiae have been divided into three groups: spotted fever, typhus, and others (Table 'l'he purpose of this article is to review the neurologic manifestations of rickettsial infections. Five such infections are of particular importance to Nortli American physicians: Kocky Mountain spotted fever (RMSF), (2 Sever, ehrlichiosis, scrub typhus, and acute febrile cerebrovasculitis (a presun~edrickettsial disease). However, given the speed and extent of international travel, it is necessary to have some awareness of all of the ricksettial infections. Reports of importation of various rickettsial infections by travelers emphasize this point."-7 Furthermore, in recent years a remarkable iricrease in the incidence of infections due to the spotted fever group of rickettsiae has occurred in several countries, iricluding Italy, Spain, Israel, and the United States.' Rickettsiae ~ a rickettsial infection is susare found ~ o r l d w i d e . ' .If pected in a returned traveler a knowledge of the types of rickettsiae in the country to which the patient traveled is necessary. Syrnptorna~icevidence of ir~volverrientof the central nervous system (CNS) occurs in 80% or more of all rickettsial infections." Such involvement is a result of the sysand ~lreirpropensity for temic nature of these i~~fectioris involvement of endothelial cells."' T h e degree of insult to the CNS varies according to the various rickettsial infections; it is most common and most severe with KMSF.;." Indeed CNS corr~plicatior~s are he most common in RMSF, occurring in 20 to 33%~of patientsg Epidemic typhus arrd scrub typhus are coniplicated by neurologic dysfunction in 12% and 2%,,respectively."
EPIDEMIOLOGY 'Ihe epidemiology of rickettsial diseases is that of the ticks, mites, lice, or fleas that trarisrnit these in-
fec~iorisfrom their rodent hosts to man. A brief review of some historical aspects of the more common rickettsial infections corrlbirled with present-day epidemiology serves to place them in perspective. In 1916, da Rocha-Lima, a microbiologist, narned the etiologic agent of epidemic typhus Rickettsia prowazekii, in honor of Drs. Harold Ricketts and Stariislav vorl Prowa~ek,both of whom had died while investigatine "rlckettsial" infections. ' There are five classic rickettsial diseases found in the US." These are shown in Table 2. To this list must be added Ehrlichiae, Rochalimaea henselae, arid possibly the agent of acute febrile cerebrovasculitis, which has yet to be identified. RMSF is the most corrlnlon and most important of the rickettsial infections found in the US. It was first described as a clinical entity in 1899.15It was then found in the Bitterroot Valley of western Montana, where 295 cases and 190 deaths were recorded between 1873 and 1910.Ii There has been a steady decline in cases of RMSF in the wesLern US since 1937, whereas increases have continued to occur in the east, in the South Atlantic, South Central, mid-Atlantic and North Central states and in New England.'"n 1990,649 cases of'RMSF were reported to the Centers for Disease Control (CDC), a 7.6% increase over 1989.17 'l'he incidence rate in 1990 was 0.26 per 100,000 persons. This rate was highest in North Carolina (178 cases; 2.7 per 100,000 persons), Oklahoma (70 cases; 2.2 per 100,000), lennessee (58 cases; 1.2 per 100,000), and South Carolina (43 cases; 1.2 per 100,000). Indeed, there were only nine states that reported no cases." T h e attack rate was highest for children aged 5 to 9 years (0.21 per 100,000) and lowest for persons aged 20 to 29 years (0.07 per 100,000). 'l'he mortality rate for those 20 years of age or older was 6.8%, whereas for those less than 20 years old i t was 2.496." 'l'he ticks responsible for transmission of RMSF to man are shown in Table 1. RMSF is a seasonal disease, with most cases occurririg between May and September, when the tick vector is active.lxTick bites are often painless; so, many patients with RMSF d o not give a history of a tick bite. 0
Departments of Medicine, Dalhousie University and Victoria General Hospital, Halifax, Nova Scotia, Canada and the National Reference Center Tor Rickettsiosis, C.H.U. La Timone, Marseille, Cedex, France Copyright O 1992 by Thieme Medical I'ublishers, Inc., 381 Park Avenue South, New York, N Y 10016. All rights reserved.
Downloaded by: National University of Singapore. Copyrighted material.
7'hornasJ. Marrie, M.D., and Didier Raoult, M.D.
SEMINARS IN NEUROLOGY
VOLUME 12, NUMBER 3
SEPTEMBER 1992
Figure 1. Transmission electron micrograph (TEM) Coxiella burnetii. (Original magnification, 15,000 x .)
ENDEMIC (MURZNE) TYPHUS
Figure 2. Transmission electron micrograph showing Ehrlichia canis within a white blood cell. Note that the rnicroorganisms are within phagocytic vacuoles. (Original magnification, 9000 x .)
Almost all human cases of this illness are associated with large rat popiilations-Rattus norvegicus and Rattus rattus. They serve as a reservoir of Rickettsia typhi. When the rat flea ingests the rickettsiae, they propagate in the epithelial cells of the midgut and are excreted in the feces. Contamination of the skin, conjunctiva, o r respiratory tract of humans by infected flea feces can lead to inf'ection.':'."' Most of' the cases of murine typhus in the US have occurred in eight southern states'"" and Calif~rnia.'~ Unlike other rickettsia1 infections, murine typhus is often acquired in cities, hence one of its names is urban typhus." Murine typhus is found worldwide, especially in port cities (rats) in tropical and subtropical areas. TICK TYPHUS 'I'he many synonyms for tick typhus (Mediterranean spotted fever (MSF), boutonneuse fever, South African tick typhus, Kenya tick typhus, lndia tick typhus, tick bite fever, Marseilles fever, Israeli tick typhus) are clues It is endemic in southern Europe, to its epidemiol~gy.'"~" Africa, the Middle East, and India. Rickettsia conorii is transmitted to man by the bite of the dog tick Rhipicephalus sanguineus. T h e tick must stay attached for 2 hours to transmit the d i ~ e a s e . ' ~ SCRUB TYPHUS
214
Figure 3. Electron micrograph of Rochalimaea henselae sp. nov. (Original magnification, 80,000 x .)
Scrub typhus, which is caused by Rickettsia tsutsugamushi, occurs in Southeast Asia, Japan, Malaysia, Burma, China, eastern Russia, Sri L,anka, Indonesia, the
Downloaded by: National University of Singapore. Copyrighted material.
EPIDEMIC TYPHUS A new form of this disease was recognized in the US in 1975 when Bozeman and c o w o r k e r s l ~ e p o r t e dthat the southern flying squirrel, Glaucomys volans, was a reservoir for R. prowazekii, the etiologic agent of epidemic typhus. In 1981, Duma et al"' reported on seven cases of nonepidemic "epidemic" typhus. In all instances there was a history of frequent contact with flying squirrels, their nests, or their ectoparasites."' A typical scenario was reported by Kusso and coworkers." A fish biologist attempted to rid his home (in western Massachusetts) of the flying squirrels that had invaded his attic. He shot five of them and as he picked them u p he noted insects leaving the carcasses. At this point he felt something bite his neck. Three days later he became ill with headache, fever, arid chills. T h e cerebrospinal fluid (CSF) was normal. He became afebrile following treatment with tetracycline. Serologic studies were consistent with K. prowazekii infection. Flying squirrel-associated epidemic typhus occurs mostly from November through February, giving rise to the suggestion that if you suspect KMSF during the winter, think about epidemic typhus." This is, of course, the time that flying squirrels are most likely to invade houses. T h e flying squirrel inhabits most o f t h e eastern half' of the US; its fleas bite man. Brill-Zinsser disease, a recrudescent form of epidemic typhus, occurs 4 to 50 years after the acute disease."' T h e factors that cause reactivation of the rickettsia that persist in the lymph nodes are unknown. It is now rarely seen in the US, with less than one case per year reported.
RICKETTSIAL INFECTIONS OF CNS-MARRIE, RAOULT Table 1. Summary of Selected Features of Rickettsiae Arthropod Vector
Animal Hosts
R. rickettsii
Tick
R. conorii
Tick
Dogs, rodents, rabbits Rodents, dogs
Queensland tick typhus
R. australis
Tick
Rickettsial pox
R. akari
Mite
R. prowazekii R. prowazekii
Louse Recrudescence of latent R. prowazekii Flea Chigger (trombiculid mite)
Spotted fever Rocky Mountain spotted fever Boutonneuse fever
Typhus Epidemic typhus Brill-Zinser Murine typhus Scrub typhus
Others Q fever Trench fever
Organism
R. typhi R. tsutsugamushi
C. burnetii
None
Rochalimaea quintana
Louse
Philippines, Korea, and India.'S."'Tsutsugamushi is Japarrese for rioxious bug."' T h e true importance of this disease was not recogrliied until w o r l d ~ w a r11 when Inore than 16,000 cases occurred among Allied troop^.^' 'l'he niite usually climbs u p the body from the feet until it finds a warm, moist area for attachment." A skin lesiorr krrowri as an eschar may develop at the site of the bite. These lesions are most likely to be found in the groin, between the buttocks, in the belt area, and in the axilla."" T h e epide~niologicfeatures of Q fever, ehrlichiosis, and Rochalimaea infections are incorporated into discussion of these illnesses.
Table 2. Disease
Recrudescent epidemic typhus (BrillZinser disease) Endemic (murine) typhus Other Q fever Ehrlichiosis Rochalimaea infection
Acute febrile cerebrovasculitis
North/South America Mediterranean, Middle East, Africa, India Australia
Rodents, small marsupials House mice
North America, USSR, South Africa, Korea
Man
Worldwide Worldwide
Rodent Rodent
Worldwide Asia, Australia, Pacific Islands, India, Japan
Cattle, sheep, goats, cats Extensive wildlife cycle
Worldwide
SPOTTED FEVER RICKETTSIOSES PATHOPHYSIOLOGY Rickettsiae that are irltroduced into the skin during the tick meal spread via small vessels to the general circulation, where they enter the vascular endothelial cells causing a vasculitis. On entry into the endothelial cell, they escape from the phagosome into the cytoplasm, where they multiply by biriary fission. Spotted fever group rickettsiae escape from the cell before its destruction. T h e endothelial cell infection results in secretion of procoag~~lant factors, such as tissue factor, the inhibitor
Rickettsial Diseases Found in the United States No. Cases: US
Spotted fever group RMSF
Typhus group Epidemic typhus (squirrel-associated)
Geographic Distribution
Downloaded by: National University of Singapore. Copyrighted material.
Group
Principal Locations
N. Carolina, Oklahoma, Tennessee, S. Carolina. Only 9 states reported no cases in 1990 Rare, 7 cases reported
Eastern half of US (occasional imported case)
50-60 cases per year
Texas, California
About 26 cases per year More than 215 cases from 1987 to present
California, Colorado, Idaho, Oregon Missouri, Virginia, Oklahoma, Georgia, Tennessee, Washington, Arkansas, Illinois, Texas, Louisiana Oklahoma; may be widespread throughout US
12. Recent interest in this microorganism. Blood culture technique has resulted in improved isolation 6 reported to date
Virginia, 5 ; Ohio, 1
',.
F
SEMINARS IN NEUKOLOGY
VOLUME 12. NUMBER 3 SEPTEMBER 1992
CLINICAL MANIFESTATIONS
Figure 4. Photograph of the foot of a patient with Mediterranean spotted fever. A diffuse purpuric rash is evident. A similar rash is evident in Rocky Mountain spotted fever. Note that the rash involves the sole of the foot.
ROCKY MOUNTAIN SPOTTED FEVER
T h e incubation period ranges from 2 to 14 days. 'I'he illness, which is sudden in onset, is characterized initially by fever, headache, and myalgia. Gastrointestinal symptoms, such as nausea, vomiting, diarrhea, and abdominal pain, are frequent. T h e initial symptoms are so nonspecific that the differential diagnosis is broad (Table 3). Furthermore, in its early stages RMSF is indistinguishable from many of the diseases shown in Table 3.'' This has led to recommendation that in areas endemic for RMSF primary care physicians should treat individuals presenting with unexplained fever, with or without other manifestations of RMSF, as if they had the disease.*i.37 T h e rash usually appears 3 to 5 days after the onset of symptoms, but is not seen in 10% of cases, es~eciallvin black ~ a t i e n t s .It is diffuse and involves palms and soles; it is maculopapular and can be purpuric
Table 3. Differential Diagnosis of Rocky Mountain Spotted Fever Viral infections Measles (rubeola) typical and atypical Adenovirus Enterovirus: echoviruses, Coxsackieviruses Pawovirus (erythema infectiosum) Dengue Arboviruses: Eastern and Western equine encephalitis viruses, St. Louis encephalitis Colorado tick fever Human immunodeficiency virus (CDC Group 1 - infectious mononucleosis-like illness) Lymphocytic choriomeningitis virus Hepatitis B Epstein-Barr (infectious mononucleosis)
216
Bacterial infections Mycoplasma pneumoniae Salmonella typhi Neisseria meningitidis (meningococcemia) Neisseria gonorrhoeae (disseminated gonococcal infection) Staphylococcus aureus Borrellia burgdorferi (Lyme disease) Streptococcus pyogenes Treponema pallidurn - secondary syphilis
(Fig. 4). Skin necrosis or gangrene involving the digits or lirnbs may occur in severe cases.:'" Retinal abnormalities seen on funduscopic examination include venous engorgement, retinal edema, hemorrhages, papilledema, and arterial occlusion. Renal failure is frequent in severe KMSF." It may be related to acute tubular necrosis or to hypovolemia. Pulmonary manifestations of RMSF range from cough to the respiratory distress of pulmonary edema. Koutine laboratory data are nonspecific, the white blood cell (WRC) count is generally normal, anemia is uncommon, but thrombocytopenia is observed in one third to one half of cases. Hyponatremia and elevations in serum glutamic-oxalacetic transaminase (SGOT) occur in one third of cases. Analysis of fatal cases of RMSF has shown that older age, hospitalization, lack of treatment, and treatment with chloramphenicol were significantly correlated with death, whereas treatment with tetracycline was protective.:'" Glucose-ti-phosphate dehydrogenase (G6PD) deficiericy is a risk factor for fulminant d i ~ e a s e . ~ " NEUROLOGIC INVOLVEMENT
'l'he frequency and the severity of neurologic abnormalities depend on the severity of the illness (Table 4). Neurologic complications are frequently the cause of death. Headache is often severe and is diffuse or bifrontal,.~1-46 In one study, 23% of patients had serious CNS complications, including stupor, delirium, seizures, ataxia, papilledema, focal neurologic deficits, and coma.:'nComa is more likely to occur in fatal than in nonfatal cases (86 vs 6%)" Cranial and peripheral nerve abnormalities can occur, of which hearing loss is the most frequent. Neck stiffness, which is common, is usually related to neck muscle myalgia. T h e incidence of meningeal signs is about 20% and a diagnosis of bacterial or viral meningitis is often considered in the differential diagnosis of RMSF. Kirk et al" found that 21 of 32 patients (66%) with RMSF who had had a lumbar puncture had abnormalities of the CSF. T h e CSF abnormalities were also studied by Kaplowitz et alJHin 63 patients (Table 5).
Downloaded by: National University of Singapore. Copyrighted material.
of thromboplastin activator, and von Willebrand factor:{:
12, NO. 3 SEI'7'F;MHRR I992
Rickettsia1 Infections of the Central Nervous System
T h e Rickettsiaceae are small gram-negative bacteria that, with two exceptions, Rochalimaea and Wolbachia, are capable of growth only inside cells' (Fig. 1-3). T h e taxonomy of these microorganisms is undergoing reevaluation as a result of scqucncing of ribosomal KNA to deterrrrir~ethe evolutio~iaryrela~io~iships arnong bacteria.) T h e ricksettsiae have been divided into three groups: spotted fever, typhus, and others (Table 'l'he purpose of this article is to review the neurologic manifestations of rickettsial infections. Five such infections are of particular importance to Nortli American physicians: Kocky Mountain spotted fever (RMSF), (2 Sever, ehrlichiosis, scrub typhus, and acute febrile cerebrovasculitis (a presun~edrickettsial disease). However, given the speed and extent of international travel, it is necessary to have some awareness of all of the ricksettial infections. Reports of importation of various rickettsial infections by travelers emphasize this point."-7 Furthermore, in recent years a remarkable iricrease in the incidence of infections due to the spotted fever group of rickettsiae has occurred in several countries, iricluding Italy, Spain, Israel, and the United States.' Rickettsiae ~ a rickettsial infection is susare found ~ o r l d w i d e . ' .If pected in a returned traveler a knowledge of the types of rickettsiae in the country to which the patient traveled is necessary. Syrnptorna~icevidence of ir~volverrientof the central nervous system (CNS) occurs in 80% or more of all rickettsial infections." Such involvement is a result of the sysand ~lreirpropensity for temic nature of these i~~fectioris involvement of endothelial cells."' T h e degree of insult to the CNS varies according to the various rickettsial infections; it is most common and most severe with KMSF.;." Indeed CNS corr~plicatior~s are he most common in RMSF, occurring in 20 to 33%~of patientsg Epidemic typhus arrd scrub typhus are coniplicated by neurologic dysfunction in 12% and 2%,,respectively."
EPIDEMIOLOGY 'Ihe epidemiology of rickettsial diseases is that of the ticks, mites, lice, or fleas that trarisrnit these in-
fec~iorisfrom their rodent hosts to man. A brief review of some historical aspects of the more common rickettsial infections corrlbirled with present-day epidemiology serves to place them in perspective. In 1916, da Rocha-Lima, a microbiologist, narned the etiologic agent of epidemic typhus Rickettsia prowazekii, in honor of Drs. Harold Ricketts and Stariislav vorl Prowa~ek,both of whom had died while investigatine "rlckettsial" infections. ' There are five classic rickettsial diseases found in the US." These are shown in Table 2. To this list must be added Ehrlichiae, Rochalimaea henselae, arid possibly the agent of acute febrile cerebrovasculitis, which has yet to be identified. RMSF is the most corrlnlon and most important of the rickettsial infections found in the US. It was first described as a clinical entity in 1899.15It was then found in the Bitterroot Valley of western Montana, where 295 cases and 190 deaths were recorded between 1873 and 1910.Ii There has been a steady decline in cases of RMSF in the wesLern US since 1937, whereas increases have continued to occur in the east, in the South Atlantic, South Central, mid-Atlantic and North Central states and in New England.'"n 1990,649 cases of'RMSF were reported to the Centers for Disease Control (CDC), a 7.6% increase over 1989.17 'l'he incidence rate in 1990 was 0.26 per 100,000 persons. This rate was highest in North Carolina (178 cases; 2.7 per 100,000 persons), Oklahoma (70 cases; 2.2 per 100,000), lennessee (58 cases; 1.2 per 100,000), and South Carolina (43 cases; 1.2 per 100,000). Indeed, there were only nine states that reported no cases." T h e attack rate was highest for children aged 5 to 9 years (0.21 per 100,000) and lowest for persons aged 20 to 29 years (0.07 per 100,000). 'l'he mortality rate for those 20 years of age or older was 6.8%, whereas for those less than 20 years old i t was 2.496." 'l'he ticks responsible for transmission of RMSF to man are shown in Table 1. RMSF is a seasonal disease, with most cases occurririg between May and September, when the tick vector is active.lxTick bites are often painless; so, many patients with RMSF d o not give a history of a tick bite. 0
Departments of Medicine, Dalhousie University and Victoria General Hospital, Halifax, Nova Scotia, Canada and the National Reference Center Tor Rickettsiosis, C.H.U. La Timone, Marseille, Cedex, France Copyright O 1992 by Thieme Medical I'ublishers, Inc., 381 Park Avenue South, New York, N Y 10016. All rights reserved.
Downloaded by: National University of Singapore. Copyrighted material.
7'hornasJ. Marrie, M.D., and Didier Raoult, M.D.
SEMINARS IN NEUROLOGY
VOLUME 12, NUMBER 3
SEPTEMBER 1992
Figure 1. Transmission electron micrograph (TEM) Coxiella burnetii. (Original magnification, 15,000 x .)
ENDEMIC (MURZNE) TYPHUS
Figure 2. Transmission electron micrograph showing Ehrlichia canis within a white blood cell. Note that the rnicroorganisms are within phagocytic vacuoles. (Original magnification, 9000 x .)
Almost all human cases of this illness are associated with large rat popiilations-Rattus norvegicus and Rattus rattus. They serve as a reservoir of Rickettsia typhi. When the rat flea ingests the rickettsiae, they propagate in the epithelial cells of the midgut and are excreted in the feces. Contamination of the skin, conjunctiva, o r respiratory tract of humans by infected flea feces can lead to inf'ection.':'."' Most of' the cases of murine typhus in the US have occurred in eight southern states'"" and Calif~rnia.'~ Unlike other rickettsia1 infections, murine typhus is often acquired in cities, hence one of its names is urban typhus." Murine typhus is found worldwide, especially in port cities (rats) in tropical and subtropical areas. TICK TYPHUS 'I'he many synonyms for tick typhus (Mediterranean spotted fever (MSF), boutonneuse fever, South African tick typhus, Kenya tick typhus, lndia tick typhus, tick bite fever, Marseilles fever, Israeli tick typhus) are clues It is endemic in southern Europe, to its epidemiol~gy.'"~" Africa, the Middle East, and India. Rickettsia conorii is transmitted to man by the bite of the dog tick Rhipicephalus sanguineus. T h e tick must stay attached for 2 hours to transmit the d i ~ e a s e . ' ~ SCRUB TYPHUS
214
Figure 3. Electron micrograph of Rochalimaea henselae sp. nov. (Original magnification, 80,000 x .)
Scrub typhus, which is caused by Rickettsia tsutsugamushi, occurs in Southeast Asia, Japan, Malaysia, Burma, China, eastern Russia, Sri L,anka, Indonesia, the
Downloaded by: National University of Singapore. Copyrighted material.
EPIDEMIC TYPHUS A new form of this disease was recognized in the US in 1975 when Bozeman and c o w o r k e r s l ~ e p o r t e dthat the southern flying squirrel, Glaucomys volans, was a reservoir for R. prowazekii, the etiologic agent of epidemic typhus. In 1981, Duma et al"' reported on seven cases of nonepidemic "epidemic" typhus. In all instances there was a history of frequent contact with flying squirrels, their nests, or their ectoparasites."' A typical scenario was reported by Kusso and coworkers." A fish biologist attempted to rid his home (in western Massachusetts) of the flying squirrels that had invaded his attic. He shot five of them and as he picked them u p he noted insects leaving the carcasses. At this point he felt something bite his neck. Three days later he became ill with headache, fever, arid chills. T h e cerebrospinal fluid (CSF) was normal. He became afebrile following treatment with tetracycline. Serologic studies were consistent with K. prowazekii infection. Flying squirrel-associated epidemic typhus occurs mostly from November through February, giving rise to the suggestion that if you suspect KMSF during the winter, think about epidemic typhus." This is, of course, the time that flying squirrels are most likely to invade houses. T h e flying squirrel inhabits most o f t h e eastern half' of the US; its fleas bite man. Brill-Zinsser disease, a recrudescent form of epidemic typhus, occurs 4 to 50 years after the acute disease."' T h e factors that cause reactivation of the rickettsia that persist in the lymph nodes are unknown. It is now rarely seen in the US, with less than one case per year reported.
RICKETTSIAL INFECTIONS OF CNS-MARRIE, RAOULT Table 1. Summary of Selected Features of Rickettsiae Arthropod Vector
Animal Hosts
R. rickettsii
Tick
R. conorii
Tick
Dogs, rodents, rabbits Rodents, dogs
Queensland tick typhus
R. australis
Tick
Rickettsial pox
R. akari
Mite
R. prowazekii R. prowazekii
Louse Recrudescence of latent R. prowazekii Flea Chigger (trombiculid mite)
Spotted fever Rocky Mountain spotted fever Boutonneuse fever
Typhus Epidemic typhus Brill-Zinser Murine typhus Scrub typhus
Others Q fever Trench fever
Organism
R. typhi R. tsutsugamushi
C. burnetii
None
Rochalimaea quintana
Louse
Philippines, Korea, and India.'S."'Tsutsugamushi is Japarrese for rioxious bug."' T h e true importance of this disease was not recogrliied until w o r l d ~ w a r11 when Inore than 16,000 cases occurred among Allied troop^.^' 'l'he niite usually climbs u p the body from the feet until it finds a warm, moist area for attachment." A skin lesiorr krrowri as an eschar may develop at the site of the bite. These lesions are most likely to be found in the groin, between the buttocks, in the belt area, and in the axilla."" T h e epide~niologicfeatures of Q fever, ehrlichiosis, and Rochalimaea infections are incorporated into discussion of these illnesses.
Table 2. Disease
Recrudescent epidemic typhus (BrillZinser disease) Endemic (murine) typhus Other Q fever Ehrlichiosis Rochalimaea infection
Acute febrile cerebrovasculitis
North/South America Mediterranean, Middle East, Africa, India Australia
Rodents, small marsupials House mice
North America, USSR, South Africa, Korea
Man
Worldwide Worldwide
Rodent Rodent
Worldwide Asia, Australia, Pacific Islands, India, Japan
Cattle, sheep, goats, cats Extensive wildlife cycle
Worldwide
SPOTTED FEVER RICKETTSIOSES PATHOPHYSIOLOGY Rickettsiae that are irltroduced into the skin during the tick meal spread via small vessels to the general circulation, where they enter the vascular endothelial cells causing a vasculitis. On entry into the endothelial cell, they escape from the phagosome into the cytoplasm, where they multiply by biriary fission. Spotted fever group rickettsiae escape from the cell before its destruction. T h e endothelial cell infection results in secretion of procoag~~lant factors, such as tissue factor, the inhibitor
Rickettsial Diseases Found in the United States No. Cases: US
Spotted fever group RMSF
Typhus group Epidemic typhus (squirrel-associated)
Geographic Distribution
Downloaded by: National University of Singapore. Copyrighted material.
Group
Principal Locations
N. Carolina, Oklahoma, Tennessee, S. Carolina. Only 9 states reported no cases in 1990 Rare, 7 cases reported
Eastern half of US (occasional imported case)
50-60 cases per year
Texas, California
About 26 cases per year More than 215 cases from 1987 to present
California, Colorado, Idaho, Oregon Missouri, Virginia, Oklahoma, Georgia, Tennessee, Washington, Arkansas, Illinois, Texas, Louisiana Oklahoma; may be widespread throughout US
12. Recent interest in this microorganism. Blood culture technique has resulted in improved isolation 6 reported to date
Virginia, 5 ; Ohio, 1
',.
F
SEMINARS IN NEUKOLOGY
VOLUME 12. NUMBER 3 SEPTEMBER 1992
CLINICAL MANIFESTATIONS
Figure 4. Photograph of the foot of a patient with Mediterranean spotted fever. A diffuse purpuric rash is evident. A similar rash is evident in Rocky Mountain spotted fever. Note that the rash involves the sole of the foot.
ROCKY MOUNTAIN SPOTTED FEVER
T h e incubation period ranges from 2 to 14 days. 'I'he illness, which is sudden in onset, is characterized initially by fever, headache, and myalgia. Gastrointestinal symptoms, such as nausea, vomiting, diarrhea, and abdominal pain, are frequent. T h e initial symptoms are so nonspecific that the differential diagnosis is broad (Table 3). Furthermore, in its early stages RMSF is indistinguishable from many of the diseases shown in Table 3.'' This has led to recommendation that in areas endemic for RMSF primary care physicians should treat individuals presenting with unexplained fever, with or without other manifestations of RMSF, as if they had the disease.*i.37 T h e rash usually appears 3 to 5 days after the onset of symptoms, but is not seen in 10% of cases, es~eciallvin black ~ a t i e n t s .It is diffuse and involves palms and soles; it is maculopapular and can be purpuric
Table 3. Differential Diagnosis of Rocky Mountain Spotted Fever Viral infections Measles (rubeola) typical and atypical Adenovirus Enterovirus: echoviruses, Coxsackieviruses Pawovirus (erythema infectiosum) Dengue Arboviruses: Eastern and Western equine encephalitis viruses, St. Louis encephalitis Colorado tick fever Human immunodeficiency virus (CDC Group 1 - infectious mononucleosis-like illness) Lymphocytic choriomeningitis virus Hepatitis B Epstein-Barr (infectious mononucleosis)
216
Bacterial infections Mycoplasma pneumoniae Salmonella typhi Neisseria meningitidis (meningococcemia) Neisseria gonorrhoeae (disseminated gonococcal infection) Staphylococcus aureus Borrellia burgdorferi (Lyme disease) Streptococcus pyogenes Treponema pallidurn - secondary syphilis
(Fig. 4). Skin necrosis or gangrene involving the digits or lirnbs may occur in severe cases.:'" Retinal abnormalities seen on funduscopic examination include venous engorgement, retinal edema, hemorrhages, papilledema, and arterial occlusion. Renal failure is frequent in severe KMSF." It may be related to acute tubular necrosis or to hypovolemia. Pulmonary manifestations of RMSF range from cough to the respiratory distress of pulmonary edema. Koutine laboratory data are nonspecific, the white blood cell (WRC) count is generally normal, anemia is uncommon, but thrombocytopenia is observed in one third to one half of cases. Hyponatremia and elevations in serum glutamic-oxalacetic transaminase (SGOT) occur in one third of cases. Analysis of fatal cases of RMSF has shown that older age, hospitalization, lack of treatment, and treatment with chloramphenicol were significantly correlated with death, whereas treatment with tetracycline was protective.:'" Glucose-ti-phosphate dehydrogenase (G6PD) deficiericy is a risk factor for fulminant d i ~ e a s e . ~ " NEUROLOGIC INVOLVEMENT
'l'he frequency and the severity of neurologic abnormalities depend on the severity of the illness (Table 4). Neurologic complications are frequently the cause of death. Headache is often severe and is diffuse or bifrontal,.~1-46 In one study, 23% of patients had serious CNS complications, including stupor, delirium, seizures, ataxia, papilledema, focal neurologic deficits, and coma.:'nComa is more likely to occur in fatal than in nonfatal cases (86 vs 6%)" Cranial and peripheral nerve abnormalities can occur, of which hearing loss is the most frequent. Neck stiffness, which is common, is usually related to neck muscle myalgia. T h e incidence of meningeal signs is about 20% and a diagnosis of bacterial or viral meningitis is often considered in the differential diagnosis of RMSF. Kirk et al" found that 21 of 32 patients (66%) with RMSF who had had a lumbar puncture had abnormalities of the CSF. T h e CSF abnormalities were also studied by Kaplowitz et alJHin 63 patients (Table 5).
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of thromboplastin activator, and von Willebrand factor:{:
