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

Disclosures No financial disclosures No off-label drug use

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. http://www.cdc.gov/rmsf/symptoms/

“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;42:499-502. ADC FLAIR Crapp S, Harrar D, Strother M, Wushensky C, Pruthi S. Pediatric radiology 2012;42:499-502.

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

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;7:724-732.

http://www.cdc.gov/rmsf/stats/index.html

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;57:1114-1128 Baganz MD, et al. AJNR American journal of neuroradiology 1995;16:919-922.

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

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 http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5504a1.htm http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5504a1.htm

Study Design Retrospective record search adult and children Positive RMSF IgM or IgG between 2007-13 Retrospective record search adult and children Chart review: Case definition for RMSF Chart review neurological involvement beyond headache Detailed history, laboratory, imaging analysis

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

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

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%

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

Rash

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

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

9 month old 12 days from onset encephalitis and seizures DWI

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

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;150:480-488.

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

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

Key References Crapp S, Harrar D, Strother M, Wushensky C, Pruthi S. Pediatric radiology 2012;42:499-502. Dantas-Torres F. Lancet Infectious diseases 2007;7:724-732 Venkatesan A et al. Clinical infectious diseases. 2013;57:1114-1128 Baganz MD, et al. AJNR American journal of neuroradiology 1995;16:919-922. Helmick CG, et al. The Journal of infectious diseases 1984;150:480-488.

Questions? Michael.j.bradshaw@vanderbilt.edu Karen.bloch@vanderbilt.edu

http://www.cdc.gov/rmsf/stats/index.html

http://www.cdc.gov/rmsf/stats/index.html