1. Rocky Mountain Spotted Fever Encephalitis
Michael J. Bradshaw MD, Kelsey Ivey MD, Francesca Bagnato MD, NgocHanh Vu MD, Sumit Pruthi MBBS, Karen C. Bloch MD, MPH

2. Disclosures
No financial disclosures
No off-label drug use

3. Case
7 year old girl
1 week fever, headache, confusion, centripetal rash
Disoriented, nuchal rigidity
WBC 14, Plt 76, Na 131, TBil: 1.7, AST: 95, ALT: 56
LP: Nuc: 190 (Neut 83% Lymph: 4, Mono: 13) CRBC: 110, Gluc: 56/68 blood, Prot:72   
This is a 7 year old girl with one week of fever, headaches, confusion and a centripetal rash who was encephalopathic with nuchal rigidity on examination. Her labs demonstrated leukocytosis, thrombopenia and elevated bilirubin and liver enzymes. She had a lumbar puncture with 190 nucleated cells with a neutrophilic predominance and elevated protein.

4. “Starry Sky sign” DWI ADC FLAIR
Crapp S, Harrar D, Strother M, Wushensky C, Pruthi S. Rocky Mountain spotted fever: 'starry sky' appearance with diffusion-weighted imaging in a child. Pediatric radiology 2012;42:
ADC
FLAIR
Crapp S, Harrar D, Strother M, Wushensky C, Pruthi S. Pediatric radiology 2012;42:

5. Case 1
Empirical antibimicrobials including vanc/ceftr, acyclovir, doxycycline
Acute Rickettsia rickettsii IgG: 1:2048 IgM: 1:256
DIAGNOSIS: RMSF meningoencephalitis
Gradually improved to baseline, now healthy 12 year old

6. Rocky Mountain Spotted Fever
Rickettsia rickettsii - gram negative coccobacillus
Tick-borne – esp American dog tick
Infects endothelial and vascular smooth muscle cells
Brain, skin, liver, lungs, kidneys, GI tract
Classic triad: fever, headache, rash (3-70% from 3-14 days)
Treatment: doxycycline
Dermacentor variabilis
Dantas-Torres F. Lancet Infectious diseases 2007;7:

8. RMSF Encephalitis
Inflammation of brain parenchyma with neurologic dysfunction
Altered mental status, seizures, focal neurological deficits, inflamed CSF, lesions on MRI, etc
Incidence is poorly defined
Increased risk of death (88% in comatose pts)
Venkatesan A et al. Clinical infectious diseases. 2013;57:
Baganz MD, et al. AJNR American journal of neuroradiology 1995;16:

9. Objectives
Evaluate clinical, biological and radiological features of RMSF with and without encephalitis in adults and children
Determine the frequency of the Starry Sky sign in RMSF encephalitis

10. RMSF Case Definition Clinical: Fever and
Rash, headache, myalgia, anemia, thrombocytopenia or transaminase elevation
Laboratory:
Supportive: elevated IgG or IgM
Confirmed: 4 fold change in Ig titer, positive PCR, IHC or culture
Neurologic involvement: neurologic signs or symptoms beyond headache

11. Study Design Retrospective record search adult and children
Positive RMSF IgM or IgG between
Retrospective record search adult and children
Chart review: Case definition for RMSF
Chart review neurological involvement beyond headache
Detailed history, laboratory, imaging analysis

12. Results 666 positive serologies from 479 individuals
300 with sufficient data for review
666 positive serologies from 479 individuals
80 with RMSF
27 with RMSF with neurologic involvement
15 with MRI; 16 with LP

13. Total
Age < 18
Age >/= 18
(n = 27)
(n = 13)
(n = 14)
Median age, years (range)
26 (0.5-83)
7 (0.5-16)
55 (26-83)
Sex: Female
10 (37%)
9 (69%)
4 (29%)
Prior presentation w/in 14 days
19 (70%)
11 (85%)
8 (57%)
Reported tick exposure w/in 30 days
9 (45%)
8 (62%)
11 (79%)
Neurology consultation
5 (38%)
5 (36%)
Infectious disease consultation
20 (74%)
13 (100%)
7 (50%)
Rash
9 (64%)
Altered mental status
26 (96%)
13 (93%)
Seizure
6 (22%)
1 (7%)
Meningisumus
3 (23%)
3 (21%)
UMN signs
5 (19%)
2 (14%)
Cranial nerve palsy
3 (11%)
Ataxia
1 (8%)
Sensory changes
2 (7%)
Brain MRI
17 (63%)
10 (77%)
Lumbar puncture
EEG
4 (31%)
Symptom onset to doxycycline, average; median (range)
6 days;
4 days (0-30)
5.8 days;
5 days (1-15)
6.4 days;
2 days (0-30)*
* 2 untreated

14. Laboratory Findings Lab Total Age < 18 Age >/= 18
CSF RBC, median (range)
4 (0-489)
6 (0-110)
12.5 (0-489)
CSF WBC, median (range)
98 (1-964)
176 (19-964)
3 (1-399)
CSF PMN %, median (range)
26.5% (0-90)
35.5% (15-83)
14.5% (0-90)
CSF glucose, median (range)
61.5 (31-84)
52.5 (31-67)
66 (54-84)
CSF protein, median (range)
64 (23-850)
116 (44-273)
51 (23-850)
Platelets </= 135
56%
54%
57%
AST or ALT > 40
67%
69%
64%
Hyponatremia Na <135
68%
78%
60%

15. Outcomes at Discharge GOS = Glasgow Outcome Scale Total Age < 18
Duration hospitalization
6 days (0-117)
8 days (1-18)
3.5 days (0-117)*
ICU
9 (45%)
5 (38%)
4 (29%)
Days in ICU, median (range)
5 (2-16)
5 days (2-16)
4.5 (3-16)
GOS 5 (Good Recovery; resumption of normal activities with no or minor deficits)
70%
69%
72%
GOS 4 (Moderate Disability; Disabled, but independent)
13%
23%
GOS 3 (Severe Disability; Conscious, but disabled, dependent for daily support)
17% 7%
27%
*2 unknown
GOS = Glasgow Outcome Scale

16. Rash

17. Neuroimaging Findings
Age
Sex
Neurologic signs and symptoms
Time from illness onset to MRI
MRI findings
CT findings
6 months F
encephalitis, seizure, CN6 palsy
9 days
starry sky DWI and T2, leptomeningeal enhancement
normal
9 months
encephalitis, seizures
12 days
extensive DWI changes, T2 in WM
13 months M
13 days
starry sky DWI and T2
32 months
encephalitis, hyperreflexia 6
encephalitis, seizures, hyperreflexia, babinski
7 days 7
meningoencephalitis
15 days 9
encephalitis, hyperreflexia, babinski, ataxia
5 days
ADEM pattern 16
encephalitis, horizontal diplopia, dizziness
10 days
meningoencephalitis, seizures
3 days
abnormal T2 signal in the right cerebral hemisphere 12
Multiple punctate DWI lesions 36
paresthesias, joint pain
35 days 54
meningoencephalitis, gait difficulty
30 days 57
encephalitis
23 days
N/A 67
24 days
T2 hyperintensities subcortical and periventricular WM and punctate focus in cerebellar hemisphere 72
22 days
multiple T2 hyperintensities bilateral deep white matter
hypodense subcortical right
DWI = Diffusion weighted imaging

18. 6 month old, 9 days from onset meningoencephalitis, seizure, CN6 palsy
DWI
ADC
FLAIR
FFE
T1 +C

19. 9 month old 12 days from onset encephalitis and seizures
DWI

20. 13 month old, 13 days from onset encephalitis, seizures
12 year old, 9 days from onset meningoencephalitis
DWI
DWI
9 year old, 5 days from onset encephalitis,
UMN signs, ataxia
FLAIR

21. Starry Sky Sign
When imaged within 15 days of onset 60% had starry sky sign
All were children
Unknown specificity for RMSF
May represent vasculitis, perivascular inflammation/edema,
Infiltration of Virchow-Robin spaces by lymphocytes, macrophages and PMLs at autopsy
Helmick CG, et al. The Journal of infectious diseases 1984;150:

22. Further investigation/Limitations
Compare RMSF with neurologic involvement to those without neurologic involvement
Review charts for starry sky sign in order to evaluate specificity/other causes
Limitations: retrospective, relatively small numbers

23. Summary Neurologic involvement is common in RMSF
Children were more likely to have seizures, CN deficits
Starry sky sign on MRI is common (60%) within 2 weeks
Outcomes are overall favorable but better in children and there were significant exceptions

24. Key References
Crapp S, Harrar D, Strother M, Wushensky C, Pruthi S. Pediatric radiology 2012;42:
Dantas-Torres F. Lancet Infectious diseases 2007;7:
Venkatesan A et al. Clinical infectious diseases ;57:
Baganz MD, et al. AJNR American journal of neuroradiology 1995;16:
Helmick CG, et al. The Journal of infectious diseases 1984;150:

25. Questions? Michael.j.bradshaw@vanderbilt.edu