Imaging Spectrum of CNS Coccidioidomycosis: Prevalence and Significance of Concurrent Brain and Spinal Disease

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1 Neuroradiology/Head and Neck Imaging Original Research Lammering et al. Concurrent Brain and Spinal Disease With CNS Coccidioidomycosis Neuroradiology/Head and Neck Imaging Original Research Jeanne C. Lammering 1 Michael Iv Nidhi Gupta Rajul Pandit Mahesh R. Patel Lammering JC, Iv M, Gupta N, Pandit R, Patel MR Keywords: brain, coccidioidal meningitis, coccidioidomycosis, spine DOI: /AJR Received May 19, 2012; accepted after revision October 9, All authors: Department of Radiology, Santa Clara Valley Medical Center, 751 S Bascom Ave, San Jose, CA Address correspondence to J. C. Lammering (jchunglammering@gmail.com). AJR 2013; 200: X/13/ American Roentgen Ray Society Imaging Spectrum of CNS Coccidioidomycosis: Prevalence and Significance of Concurrent Brain and Spinal Disease OBJECTIVE. The purpose of this study was to evaluate the prevalence and significance of concurrent coccidioidal brain and intraspinal disease. MATERIALS AND METHODS. We conducted a retrospective imaging review of 23 patients with proven coccidioidal CNS meningitis. RESULTS. All patients had intracranial abnormalities, and 86% (19/22) who underwent spinal imaging had signs of intraspinal disease, including leptomeningeal enhancement (84%), arachnoiditis (63%), and cord signal abnormalities (37%); seven of 15 patients (47%) who underwent myelography had complete spinal blocks. CONCLUSION. The high prevalence of concurrent brain and intraspinal coccidioidomycosis supports a low threshold for spinal imaging. C occidioides immitis is a dimorphic fungus endemic to the soil of the southwestern United States and areas of Mexico, Central America, and South America and accounts for more than 100,000 infections annually [1 4]. Primary infection occurs in the lungs after inhalation of airborne arthrospores. Of infected patients, 1 5% develop disseminated disease, which occurs more frequently in pregnant women, immunocompromised patients, and individuals of African, Hispanic, and Filipino descent [1]. CNS involvement is the most severe and frequent manifestation of disseminated disease, comprising one third to one half of these cases and accounting for the majority of deaths in disseminated infection [4, 5]. The mean survival time after the onset of symptoms in patients with untreated CNS coccidioidomycosis is 4 months, whereas the mean survival time for those treated with amphotericin B is 21 months [6]. Intracranial imaging features in coccidioidal meningitis have previously been described in many studies [2, 7 14]. However, we have found few case reports in the literature describing imaging features of coccidioidomycosis with concomitant disease in the spinal canal, excluding direct extension from osseous infection [4, 15 19]. Spinal disease is of clinical significance because its presence may alter management, including the level of reservoir placement for effective treatment in the presence of a more cephalad block. The purpose of our study was to evaluate the prevalence and imaging manifestations of both brain and nonosseous spinal disease in patients with coccidioidal meningitis. Materials and Methods Patients Twenty-three patients who underwent CNS imaging and had proven coccidioidal meningitis from January 26, 1998, to August 24, 2011, were identified using a keyword search for coccidioidomycosis, cocci, and coccidioidal meningitis in the PACS of our institution. All patients were diagnosed with coccidioidal meningitis by positive complement-fixing antibody titers in the CSF and blood. Patient demographics were as follows: 18 male and five female patients; age range, 5 74 years, with a mean age of 36 years; and 13 of Hispanic descent, four blacks, four whites, and two of Asian descent. Three patients were HIV positive. This retrospective study was approved by the Santa Clara Valley Medical Center institutional review board and was conducted in accordance with HIPAA guidelines. MRI Acquisitions Imaging was performed on a 3-T HDXT platform MR scanner (GE Healthcare) after and including 2009 and a 1.5-T Signa LX Echospeed platform MR scanner (GE Healthcare) before Different neuroimaging modalities were reviewed: MRI of the brain (n = 23), MR angiog AJR:200, June 2013

2 Concurrent Brain and Spinal Disease With CNS Coccidioidomycosis raphy (MRA) of the circle of Willis (n = 10), MRI of the cervical spine (n = 19), MRI of the thoracic spine (n = 15), MRI of the lumbar spine (n = 17), and CT and fluoroscopic myelograms (n = 15). One of the 23 patients (case 17) was sent to our institution for consultation but had an MRI and a CT myelogram performed at an outside facility. Because patients were scanned for routine clinical purposes over a 13-year period, there was some variation in the pulse sequences obtained. Before 2003, MRI studies of the brain contained the following sequences: sagittal T1-weighted, axial T1-weighted, axial T2-weighted, axial FLAIR, and gadolinium-enhanced axial, coronal, and sagittal T1-weighted imaging. After and including 2003, MRI studies of the brain included axial diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) maps, and axial gradient-recalled echo (GRE) images in addition to the aforementioned sequences. One patient had a limited number of sequences performed including axial FLAIR and gadolinium-enhanced axial and coronal T1-weighted imaging for unclear reasons. On brain MRI examinations performed after and including 2009 on the 3-T MR scanner, the following parameters were used: DWI (TR/TE, 8700/89; matrix, ; slice thickness/intersection gaps, 5/0); ADC (TR/TE, 8700/89; matrix, ; slice thickness/intersection gaps, 5/0); FLAIR axial (TR/TE, 9500/124; inversion time [TI], 2250 ms; matrix, ; slice thickness/intersection gaps, 5/1.5); FLAIR sagittal (TR/TE, 2500/24; TI, 2250 ms; echo-train length [ETL], 7; matrix, ; slice thickness/intersection gaps, 5/2); unenhanced and gadolinium-enhanced T1-weighted axial (TR/TE, 925/20; ETL, 3; matrix, ; slice thickness/intersection gaps, 5/1.5); gadolinium-enhanced T1-weighted sagittal (TR/TE, 767/20; ETL, 3; matrix, ; slice thickness/ intersection gaps, 5/1.5); T1-weighted coronal (TR/ TE, 767/20; ETL, 3; matrix, ; slice thickness/intersection gaps, 5/1.5); T2-weighted axial (TR/TE, 6000/100; ETL, 24; matrix, ; slice thickness/intersection gaps, 5/1.5); and GRE (TR/TE, 575/15; flip angle, 20 ; matrix, ; slice thickness/intersection gaps, 5/1.5). On brain MRI examinations performed before 2009 on the 1.5-T MR scanner, the following parameters were used: DWI (TR/TE, 13,000/97; matrix, ; slice thickness/intersection gaps, 5/0); FLAIR axial (TR/TE, 10,000/130; TI, 2200 ms; matrix, ; slice thickness/intersection gaps, 5/2.5); T1- weighted axial (TR/TE, 600/14; matrix, ; slice thickness/intersection gaps, 5/2.5); T1- weighted sagittal (TR/TE, 550/14; matrix, ; slice thickness/intersection gaps, 5/2.5); gadolinium-enhanced T1-weighted axial (TR/TE, 600/20; matrix, ; slice thickness/intersection gaps, 5/2.5); gadolinium-enhanced T1- weighted sagittal (TR/TE, 475/20; matrix, ; slice thickness/intersection gaps, 5/2.5); T1- weighted coronal (TR/TE, 550/14; matrix, ; slice thickness/intersection gaps, 5/2.5); T2- weighted axial (TR/TE, 3500/102; ETL, 16; matrix, ; slice thickness/intersection gaps, 5/2.5); and GRE (TR/TE, 650/55; flip angle, 30 ; matrix, ; slice thickness/intersection gaps, 5/2.5). MRI studies of the cervical, thoracic, and lumbar spine consisted of sagittal STIR, axial and sagittal T1-weighted, axial and sagittal T2- weighted, and gadolinium-enhanced axial and sagittal T1-weighted sequences. Sagittal STIR images were not obtained before Most MRI studies of the cervical spine also included axial multiplanar gradient-recalled images. In addition to routine sequences, seven patients had either or both sagittal or coronal heavily T2-weighted MR myelograms of the spine. On spinal MRI examinations performed after and including 2009 on the 3-T MR scanner, the following parameters were used for cervical spine: T1-weighted axial (TR/TE, 825/12; ETL, 2; matrix, ; slice thickness/intersection gaps, 3/1); T1-weighted sagittal (TR/ TE, 2000/34; TI, 160 ms; ETL, 8; matrix, ; slice thickness/intersection gaps, 3/1); T2- weighted axial (TR/TE, 3275/120; ETL, 16; matrix, ; slice thickness/intersection gaps, 3/1); T2-weighted sagittal (TR/TE, 3475/110; ETL, 23; matrix, ; slice thickness/intersection gaps, 3/1); STIR sagittal (TR/TE, 4575/7 8; TI, 160 ms; matrix, ; slice thickness/intersection gaps, 3/1); GRE axial (TR/TE, /10 13; matrix, ; slice thickness/intersection gaps, 4/0.3); gadolinium-enhanced T1-weighted axial with fat saturation (TR/TE, 750/12; ETL, 3; matrix, ; slice thickness/intersection gaps, 3/1); and gadolinium-enhanced T1-weighted sagittal with fat saturation (TR/TE, /19 20; ETL, 2; matrix, ; slice thickness/intersection gaps, 3/1). For thoracic spine after and including 2009, parameters were as follows: T1-weighted axial (TR/TE, 1017/20; ETL, 3; matrix, ; slice thickness/intersection gaps, 6/2); T1- weighted sagittal FLAIR (TR/TE, 2800/34; TI, 1171 ms; ETL, 4; matrix, ; slice thickness/intersection gaps, 3/1); T2-weighted axial (TR/TE, 4000/85; ETL, 20; matrix, ; slice thickness/intersection gaps, 6/2); T2- weighted sagittal (TR/TE, 3200/85; ETL, 16; matrix, ; slice thickness/intersection gaps, 3/1); STIR sagittal (TR/TE, 4000/34; TI, 160 ms; ETL, 9; matrix, ; slice thickness/intersection gaps, 3/1); gadolinium-enhanced T1-weighted axial with fat saturation (TR/TE, 1017/20; ETL, 3; matrix, ; slice thickness/intersection gaps, 6/2); and gadolinium-enhanced T1-weighted sagittal with fat saturation (TR/TE, 867/20; ETL, 2; matrix, ; slice thickness/intersection gaps, 3/1). For lumbar spine after and including 2009, parameters were as follows: T1-weighted axial (TR/TE, 767/13; ETL, 2; matrix, ; slice thickness/intersection gaps, 5/1); T1-weighted sagittal FLAIR (TR/TE, 2800/34; TI, 160 ms; ETL, 7; matrix, ; slice thickness/intersection gaps, 4/1); T2-weighted axial (TR/ TE, 2400/110; ETL, 23; matrix, ; slice thickness/intersection gaps, 4/1); T2-weighted sagittal (TR/TE, 4600/125; ETL, 23; matrix, ; slice thickness/intersection gaps, 4/1); STIR sagittal (TR/TE, 4000/34; TI, 160 ms; ETL, 12; matrix, ; slice thickness/ intersection gaps, 4/1); gadolinium-enhanced T1-weighted axial with fat saturation (TR/TE, 867/12; ETL, 2; matrix, ; slice thickness/intersection gaps, 5/1); and gadolinium-enhanced T1-weighted sagittal with fat saturation (TR/TE, 867/20; ETL, 2; matrix, ; slice thickness/intersection gaps, 4/1). On spinal MR examinations performed before 2009 on the 1.5-T MR scanner, the following parameters were used for cervical spine: T1-weighted axial (TR/TE, 600/10; ETL, 2; matrix, ; slice thickness/intersection gaps, 4/1); T1- weighted sagittal (TR/TE, 575/10; ETL, 2/3; matrix, ; slice thickness/intersection gaps, 3/1); T2-weighted axial (TR/TE, 600/10; ETL, 2; matrix, ; slice thickness/intersection gaps, 4/1); T2-weighted sagittal (TR/TE, 3000/85; ETL, 17; matrix, ; slice thickness/intersection gaps, 3/1); STIR sagittal (TR/TE, 4000/50; TI, 140 ms; matrix, ; slice thickness/intersection gaps, 3/1); GRE axial (TR/TE, 750/15; matrix, ; slice thickness/intersection gaps, 4/5); gadolinium-enhanced T1-weighted axial with fat saturation (TR/TE, 400/10; ETL, 2; matrix, ; slice thickness/intersection gaps, 4/1); and gadolinium-enhanced T1-weighted sagittal with fat saturation (TR/TE, 650/10; ETL, 2; matrix, ; slice thickness/intersection gaps, 3/1). For thoracic spine before 2009, parameters were as follows: T1-weighted axial (TR/TE, 575/12; ETL, 14; matrix, ; slice thickness/intersection gaps, 6/1); T1-weighted sagittal (TR/TE, 425/12; ETL, 3; matrix, ; slice thickness/intersection gaps, 4/1); T2-weighted axial (TR/TE, 4150/102; ETL, 14; matrix, ; slice thickness/intersection gaps, 6/1); T2-weighted sagittal (TR/TE, 3400/102; ETL, 16; matrix, ; slice thickness/intersection gaps, 4/1); STIR sagittal (TR/TE, 3075/42; TI, 155 ms; ETL, AJR:200, June

3 Lammering et al. TABLE 1: Intracranial Findings of Coccidioidomycosis Case Sex Age (y) Ethnicity Leptomeningeal Enhancement Overall MCA Cistern Hydrocephalus Infarct(s) White Matter Disease Parenchymal Lesions Head MR Angiography Findings 1 M 68 Black Present Right unilateral Absent Old right pons and left thalamus 2 F 48 Asian descent Absent Present Absent Absent Moderate, TEF Present Absent 3 M 48 Hispanic Present Bilateral Severe, shunt Acute right thalamus Present Absent 4 a M 37 Black Present Bilateral Moderate, TEF, shunt Present Absent 5 a M 20 Hispanic Present Bilateral Moderate, TEF Acute left basal ganglia, Present Absent Negative bifrontal subcortical white matter 6 M 46 White Present Bilateral Moderate, TEF, shunt Absent Absent Present 7 M 29 Hispanic Present Bilateral Moderate, TEF, shunt Absent Present Absent 8 M 31 Hispanic Present Bilateral Severe, TEF, shunt Absent Absent Absent 9 F 23 Hispanic Present Absent Mild, TEF, shunt Absent Absent Absent 10 F 14 White Present Bilateral Severe, TEF, shunt Absent Absent Absent Negative 11 M 45 White Present Bilateral Absent Absent Absent Absent 12 M 33 Hispanic Present Absent Absent Absent Absent Absent 13 a M 44 Black Present Bilateral Moderate Old right MCA distribution Present Absent 14 F 8 Hispanic Present Bilateral Severe, TEF, shunt Acute bilateral MCA and right ACA distribution, right basal ganglia Absent Absent Diffuse narrowing of bilateral supraclinoid ICA, MCA, ACA, and PCA 15 M 66 Hispanic Present Bilateral Mild Acute left MCA distribution Present Absent Left ICA terminus and MCA occlusion 16 M 18 Hispanic Present Bilateral Moderate, TEF, shunt Absent Absent Absent 17 b M 50 Black Absent Absent Absent Absent Absent Absent Negative 18 F 32 Asian Present Bilateral Absent Absent Present Absent Negative descent 19 M 28 Hispanic Present Bilateral Mild, shunt Absent Absent Absent Negative 20 M 5 White Present Bilateral Severe, TEF Acute PLIC and corona radiata Absent Absent Diffuse narrowing of bilateral MCA, ACA, and PCA 21 M 33 Hispanic Present Bilateral Mild, shunt Absent Absent Absent 22 M 74 Hispanic Present Bilateral Mild Acute left cerebellum, Present Present Negative thalamus, scattered foci bilateral temporal lobes; old left pons 23 M 33 Hispanic Present Bilateral Moderate, shunt Absent Absent Absent Note MCA = middle cerebral artery, TEF = transependymal flow, ACA = anterior cerebral artery, PLIC = posterior limb of internal capsule, ICA = internal carotid artery, PCA = posterior cerebral artery. a HIV positive. b Outside study AJR:200, June 2013

4 Concurrent Brain and Spinal Disease With CNS Coccidioidomycosis Fig. 1 5-year-old boy (case 20). A, Coronal T1-weighted gadolinium-enhanced MR image shows nodular basilar leptomeningeal enhancement most pronounced in perisylvian cisterns (arrows). B, Axial T2-weighted MR image shows acute hydrocephalus with transependymal flow of CSF. 8; matrix, ; slice thickness/intersection gaps, 4/1); gadolinium-enhanced T1-weighted axial with fat saturation (TR/TE, 425/14; ETL, 3; matrix, ; slice thickness/intersection gaps, 6/1); and gadolinium-enhanced T1-weighted sagittal with fat saturation (TR/TE, 600/10; ETL, 2; matrix, ; slice thickness/intersection gaps, 4/1). For lumbar spine before 2009, parameters were as follows: T1-weighted axial (TR/TE, 600/10; ETL, 3; matrix, ; slice thickness/ intersection gaps, 4/1); T1-weighted sagittal (TR/ TE, 500/10; ETL, 3; matrix, ; slice thickness/intersection gaps, 4/1); T2-weighted axial (TR/TE, 4000/102; ETL, 16; matrix, ; slice thickness/intersection gaps, 4/1); T2-weighted sagittal (TR/TE, 3150/85; ETL, 16; matrix, ; slice thickness/intersection gaps, 4/1); STIR sagittal (TR/TE, 3800/20; TI, 155 ms; ETL, 12; matrix, ; slice thickness/intersection gaps, 4/1); gadolinium-enhanced T1-weighted axial with fat saturation (TR/TE, 600/10.2; ETL, 3; matrix, ; slice thickness/intersection gaps, 5/1); and gadolinium-enhanced T1-weighted sagittal with fat saturation (TR/TE, 600/10.0; ETL, 3; matrix, ; slice thickness/intersection gaps, 4/1). For sagittal and coronal MR myelograms, the following parameters were used: T2-weighted sagittal (TR/TE range, 6000/ ; matrix, ; slice thickness/intersection gaps, 2/1); and T2-weighted coronal (TR/TE range, 6000/ ; matrix, ; slice thickness/ intersection gaps, 2/0). MRA of the intracranial circulation was performed using 3D time-of-flight (TOF) acquisition with postprocessed maximum intensity projections. Parameters for MRA after and including 2009 on the 3-T MR scanner were as follows: 3D circle of Willis A TOF (TR/TE, 23/3; matrix, ; slice thickness 1.4 mm). Parameters for MRA before 2009 on the 1.5-T MR scanner were as follows: 3D circle of Willis TOF (TR/TE, 34/4; matrix, ; slice thickness 1.4 mm). All brain and spinal MRI examinations were performed using FOVs of mm and mm, respectively. For the majority of myelograms, conventional fluoroscopy was used to obtain intrathecal access for administration of nonionic iodinated contrast material in the lumbar spine, the cervical spine, or both. Alternatively, contrast material was administered through a preexisting ventriculostomy catheter if available. The flow of CSF was evaluated using only fluoroscopy in two cases, whereas delayed CT images were obtained in the remainder of cases. Image Analysis A retrospective consensus review of each initial and follow-up examination was performed by two fellowship-trained neuroradiologists, each with greater than 10 years of experience. MR images of the brain were evaluated for leptomeningeal enhancement, hydrocephalus, transependymal flow of CSF, infarction, white matter disease, and focal parenchymal lesions. MRA images were reviewed for signal abnormalities and patency and caliber of the intracranial vasculature in the circle of Willis. MR images of the spine were evaluated for leptomeningeal enhancement, nerve root clumping and thickening, intramedullary cord signal abnormality, and focal extramedullary intradural lesions. Myelograms were reviewed for subarachnoid filling defects and CSF blocks. Each patient s clinical history was also investigated for associated symptoms at time of imaging. Postmortem results from one patient were available for review. B Results All 23 patients had intracranial MRI abnormalities. Brain imaging findings for each patient are summarized in Table 1. Leptomeningeal enhancement occurred in 21 of 23 patients (91%), predominantly localized to the basilar cisterns. In addition, 19 of these 21 patients (90%) had enhancement in the middle cerebral artery (MCA) cisterns (Fig. 1A [case 20]), in whom 18 had bilateral and one had unilateral right-sided enhancement. Hydrocephalus occurred in 18 of 23 patients (78%) and was graded as moderate to severe in 13 of these 18 patients (72%). Of these 18 patients, 11 (61%) had transependymal flow of CSF, and 12 (67%) had CSF shunting (Fig. 1B [case 20]). Infarcts were seen in eight of 23 patients (35%); six were acute (26% [6/23]) (Fig. 2A [case 15]), and three were old (13% [3/23]). One patient (case 22) had acute infarcts in the left cerebellum, thalamus, and bilateral temporal lobes and an old infarct in the pons. In another patient (case 1), old pontine and left thalamic infarcts were present in addition to acute edema in the left ventral aspect of the pons, adjacent to a focal area of interpeduncular cistern leptomeningeal enhancement. Focal parenchymal lesions were identified in three of 23 patients (13%) (Fig. 3 [case 6]). Nine of 23 patients (39%) had scattered periventricular white matter T2-hyperintense signal abnormalities. Of the 10 patients who underwent intracranial MRA, three (30%) had abnormal findings. One patient (case 14) had diffuse irregularity of the bilateral anterior cerebral arteries, MCAs, posterior cerebral arteries, and supraclinoid internal carotid arteries. The AJR:200, June

5 Lammering et al. A Fig year-old man (case 15). A, Axial diffusion-weighted MR image shows area of acute infarction in left middle cerebral artery territory. B, Maximum intensity projection from MR angiogram of intracranial circulation shows occlusion of left supraclinoid internal carotid and middle cerebral arteries (arrows). Fig year-old man (case 6). Sagittal T1- weighted gadolinium-enhanced MR image shows irregular peripherally enhancing lesion (arrow) in cerebellum. second patient (case 15) had occlusion of the left supraclinoid internal carotid and MCAs (Fig. 2B [case 15]). The third patient (case 20) had diffuse irregularity of all intracranial vessels. All of these patients had infarcts in the territory of the abnormal vessels. Of the 23 patients with abnormal brain MRI findings, 22 underwent spinal imaging in the form of MRI or postmyelography CT (or both); of these 22 patients, 19 (86%) had concomitant spinal abnormalities. Of these 22 patients, 19 underwent cervical, thoracic, or lumbar spine MRI (or a combination of these regions), and 12 had sequential follow-up imaging. The three patients without spinal MRI were among the 15 patients evaluated by using myelography. Findings on initial and follow-up MR images and myelograms are summarized in Table 2. On initial spinal MRI, 14 of 19 patients (74%) had spinal leptomeningeal enhancement (Fig. 4 [case 4]), seven of 19 patients (37%) had nerve root clumping and thickening (Fig. 5 [case 6]), three of 19 patients (16%) had intramedullary spinal cord T2-hyperintense signal abnormality (Fig. 6C [case 6]), and three of 19 patients (16%) had focal extramedullary intradural lesions (Figs. 7C and 7D [case 2]). When the serial follow-up imaging in 12 patients was included, the total numbers and percentages of findings were as follows: 16 of 19 patients (84%) had spinal leptomeningeal enhancement, 12 of 19 patients (63%) had nerve root clumping and thickening, seven of 19 patients (37%) had intramedullary T2-hyperintense signal abnormality, and eight of 19 patients (42%) had focal extramedullary intradural lesions. Of the 12 patients with follow-up MRI of the spine, 11 (92%) had spinal leptomeningeal enhancement, which finding was present on initial examination in nine of these 12 patients (75%). Three patients (cases 1, 21, and 23) developed leptomeningeal enhancement on follow-up, and three patients (cases 3, 6, and 21) had resolution of leptomeningeal enhancement on subsequent imaging. Six of 12 patients (50%) had stable leptomeningeal enhancement compared with initial examinations. Seven of 12 patients (58%) had nerve root clumping and thickening. Two of these patients had similar findings on initial examination, whereas five patients subsequently developed these findings on later imaging. Six of 12 patients (50%) had intramedullary T2- hyperintense signal abnormality. This finding was new on follow-up imaging in four patients and was stable on follow-up in two patients. Two of the patients with intramedullary T2- hyperintense signal abnormality had hydrocephalus, downward displacement of the cerebellar tonsils, and dilatation of the spinal cord with an identifiable communication between the syrinx and the 4th ventricle (Figs. 8A and 8B [case 21] and 9 [case 10]). Five of 12 patients (42%) had focal extramedullary intradural lesions, all of which were not present at the time of initial examination; two of these patients had extramedullary intradural spinal abscesses (Fig. 6B [case 6]). Fluoroscopic and CT myelograms were performed in 15 patients. Of these 15 patients, 10 (67%) had focal extramedullary intradural lesions and nerve clumping (Fig. 5 [case 6]). Of these 10 patients, three (30%) had nonobstructive filling defects (Fig. 10 [case 5]), and seven (70%) had complete subarachnoid CSF blocks (Figs 7A and 7B [case 2]). Of the eight B 1338 AJR:200, June 2013

6 Concurrent Brain and Spinal Disease With CNS Coccidioidomycosis TABLE 2: Intraspinal Findings of Coccidioidomycosis Case and Examination 1 Regions Scanned a Leptomeningeal Enhancement Arachnoiditis Intramedullary Cord Abnormality Focal Intradural Lesion(s) Initial L Absent Present Absent Absent 20 mo L Absent Present Absent Absent 30 mo C,L Present Present Absent L4 through S1 (abscess) 2 C,L Present Present Absent T12 through L2 (abscess) 3 Postmyelography CT Finding(s) a C,T,L; L4 complete block; upper thoracic and lumbar filling defects T,L; T11-12 complete block; cervical and thoracic filling defects Initial C,T,L Present Absent Absent Absent C; No block; cervical filling defects 2 mo b L NA Present Absent Lumbar spine 14 mo C,T,L Present Present Absent Absent 33 mo C Absent Absent Absent Absent 4 C Present Absent Absent Absent Initial C,T,L Present Absent Absent Absent T,L; No block; T8 through T12 filling defects 13 mo b C,T,L NA Absent Absent Absent Initial C Present Absent Absent Absent 6 mo C,T,L Present Present C2 through T1 with cord expansion C2 and lumbar spine 9 mo C,T,L Present Present No change Also involving thoracic spine 23 mo C,T Present Absent Increased with atrophy of cervical cord Worsening, with loculated CSF C,L; C2-3 partial block with filling defects C,T; C2-3 complete block with filling defects Initial C,T,L Present Absent Cervical, thoracic, and Absent lumbar cord with expansion 3 mo C,T,L Present Absent Unchanged Absent 8 C,T,L Present Present Absent Absent 9 Initial C,T,L Present Absent Absent Absent C,T,L; No block; thoracic filling defects 18 mo C,T,L Present Present C2 through T2 Lower thoracic through S1 10 Initial C,T,L Present Absent Absent Absent 1 mo C,T,L Present Absent Medulla through T10 with Absent expansion and tonsillar herniation 2 mo C Present Absent Unchanged Absent 11 C,T,L Absent Present Absent C5-6 (enhancement) C,T,L; C7 and L5-S1 block; upper thoracic filling defects 12 C,T,L Absent Absent Absent Absent C,T,L; No block; lumbar spine filling defects (Table 2 continues on next page) AJR:200, June

7 Lammering et al. TABLE 2: Intraspinal Findings of Coccidioidomycosis (continued) Case and Examination Regions Scanned a Leptomeningeal Enhancement patients who underwent serial myelograms, six (75%) had subarachnoid filling defects and nerve clumping. Of these six patients, four (67%) had complete CSF blocks. Three of these complete CSF blocks were not seen on initial imaging: two were de novo, and one progressed from a partial block to a complete block on follow-up. Because our hospital is a referral center for coccidioidomycosis treatment, many patients in our study were imaged before starting treatment to obtain a baseline examination. For patients with symptoms at the time of imaging, the most commonly Arachnoiditis Intramedullary Cord Abnormality documented complaints included headache, nausea, vomiting, and confusion. In the eight patients without back pain or radiculopathy documented in the medical record, only one patient had normal findings on spinal MR images. The remaining seven patients had spinal abnormalities including four with CSF blocks and two with filling defects on myelography. Only one patient in our study had new onset of back pain corresponding to spinal disease, which was an extramedullary intradural abscess displacing the cord and causing L1-2 complete CSF block (Fig. 7 [case 2]). Focal Intradural Lesion(s) Postmyelography CT Finding(s) a Initial C,T,L Present Present Absent Absent 25 mo C,L Present Present Absent Absent 28 mo T,L Present Present Absent Absent 15 C,T,L; No block or filling defects 16 C; No block or filling defects 17 c C,T,L Present Present Absent L5-S1 L; L5 block with filling defects 18 Initial C Absent Absent Absent C,T,L; No block or filling defects 4 mo C Absent Absent Absent L; No block or filling defects 19 C,T,L Present Present C1-2 and C6 through T1 C,T,L; T10 block with filling defects with cord expansion Initial C Present Absent C5 through upper thoracic spine 94 mo C,T,L Present Present Posterior medulla through inferior T2 104 mo C Present Absent Unchanged 22 Initial L Present Absent Absent Absent 6 mo C,T,L Absent Absent Absent Absent 23 Initial C Absent Absent Absent 13 mo C,T,L; T5 through T7 filling defects 75 mo C C mo T,L Present Present Improved in cervical region; new lesion from T9 through conus Lumbar, abnormal enhancement C,T,L; L3 block with cervical, thoracic, and lumbar filling defects Note For cases in which follow-up was done, examinations are classified either as Initial for original study or by follow-up interval duration relative to original study. NA = not applicable. a C = cervical spine, T = thoracic spine, L = lumbar spine. Dash denotes spinal MRI was not performed. b No contrast material administered. c Outside study. An autopsy was performed in one patient (case 6). On gross examination of the brain, thickened and fibrotic leptomeninges were present over the cerebral convexities, cerebellar hemispheres, and brainstem with granulomas containing Coccidioides spherules, most of which were present within multinucleated giant cells. The basilar, vertebral, and smaller penetrating arteries had subintimal and adventitial fibrosis with associated intraluminal narrowing. There was an abscess in the obliterated subarachnoid space adjacent to the left dorsolateral aspect of the medulla with additional parenchymal 1340 AJR:200, June 2013

8 Concurrent Brain and Spinal Disease With CNS Coccidioidomycosis Fig year-old HIV-positive man (case 4). Sagittal T1-weighted gadolinium-enhanced MR image shows diffuse leptomeningeal enhancement along brainstem, cerebellum, and cervical cord (arrows). granulomas in the cerebellum. Loss of myelin and axons was seen at the medullary spinal cord junction beneath this abscess. Mycelia were identified in two granulomas in the midbrain, a rare finding in the CNS. Gross examination of the spinal cord showed thickened and adherent leptomeninges containing granulomas centered around spherules, particularly severe around the cervical and upper thoracic levels. The spinal nerve roots were embedded in the fibrotic tissues. The anterior medial spinal artery and small leptomeningeal vessels had thickened and fibrotic walls and narrowed or occluded vascular lumina. Extensive myelin loss and reduction of axons in the dorsal and lateral column white matter adjacent to the central gray matter was observed. In addition, parenchymal rarefaction and neuropil gliosis without cavitation was present in the central gray matter. A parenchymal granuloma was also present in the dorsal horn of C4. Discussion To our knowledge, this study represents the first case series to characterize spinal imaging features of nonosseous coccidioidal infection and the frequency of concurrent intraspinal disease in patients with intracranial involvement. Previous reports in the literature of spinal imaging manifestations of coccidioidomycosis predominantly describe involvement of bony structures with direct extension of infection into the adjacent spinal canal [15 19]. Spinal findings other than spondylitis have been reported in case studies and histopathologic studies [4 6, 15] but, except for leptomeningeal enhancement in the cervical region [7, 18], have not been illustrated in a case series. Although osseous spinal coccidioidal infection has been associated with clinical symptoms of back pain and radiculopathy [19], nonosseous spinal disease does not always present with clinically detectable symptoms. Intraspinal coccidioidomycosis was seen even in the absence of back pain or radiculopathy in seven of eight alert patients in our study for whom complete medical records were available. Four of these patients had unsuspected complete CSF blocks, which may have changed therapeutic management. Two of these patients had dural filling lesions on myelography. Only one of the 19 patients who underwent spinal imaging had new onset of back pain corresponding to his spinal disease, which was an extramedullary intradural abscess displacing the cord and causing complete L1-2 CSF block (Figs. 7A 7D [case 2]). Seven of the remaining 18 patients who underwent spinal imaging were not included in this assessment owing to incomplete medical records without definite evidence of absence of back pain or radiculopathy. Of the 11 patients without history of back pain or radiculopathy, an additional three were excluded from this assessment owing to altered mental status, which may have prevented an accurate history from being obtained. Therefore, the reported number of seven patients in our study with coccidioidal spinal disease even in the absence of back pain or radiculopathy is most likely an underestimation. However, it supports the principle that coccidioidal spinal involvement may be present even without symptoms. This is of clinical significance because the presence of spinal disease and CSF block may alter management, including the level of reservoir placement for treatment in the presence of a more cephalad block. Nonobstructive focal extramedullary intradural lesions and CSF block were seen in a significant number of our patients. Of the 15 patients with myelograms (eight of whom underwent serial imaging), 10 (67%) had filling defects: 30% (3/10) of these were nonobstructive, and 70% (7/10) were complete CSF blocks. The cause of filling defects and subarachnoid block is presumably related to adhesive inflammatory exudate and fibrosis involving the spinal meninges and spinal nerve roots, mirroring the process occurring in the basal leptomeninges of the brain [4, 6]. This pathogenesis is confirmed in the autopsy results from case 6, in which there was marked thickening and fibrosis of the leptomeninges and arachnoiditis in the upper cervical spine, corresponding to the complete C2-3 CSF block seen in this patient on myelography. Intramedullary signal abnormalities were also present in 37% (7/19) of the patients in our study who underwent spinal MRI. To our knowledge, the presence of intramedullary hyperintensity on T2-weighted images has not been reported in a case series in patients with coccidioidal meningitis, although this finding has been described in association with other infectious causes of spinal disease, such as tuberculosis and syphilis [20 22]. Two of the patients Fig year-old man (case 6). Axial T2-weighted MR image shows clumping and thickening of nerve roots (arrow). AJR:200, June

9 Lammering et al. with intramedullary signal abnormality in our study had hydrocephalus, downward displacement of the cerebellar tonsils, and dilatation of the spinal cord with an identifiable communication between the syrinx and the 4th ventricle. Several authors have proposed causes for the development of syringomyelia, particularly in patients with Chiari I malformations [23 26]. Among the classic hypotheses, Gardner s [23] hydrodynamic theory proposes that pulsatile ventricular CSF pressure is transmitted from the 4th ventricle to the central canal through an open connection, eventually resulting in a progressive dilatation of the central canal ( waterhammer effect ). Kawaguchi et al. s [27] case report of a patient with hydrocephalus and syringomyelia connected to the 4th ventricle, with improvement after endoscopic 3rd ventriculostomy, supports this proposed mechanism. Similar connections between the 4th ventricle and syringomyelia were identified in four patients with underlying tuberculous meningitis in the A Fig year-old man (case 6). A, Sagittal T2-weighted MR image shows cerebellar tonsillar herniation and expansion of cervical cord (arrow) with intramedullary T2 hyperintensity extending from C2 through C7. B, Sagittal T2-weighted MR image 9 months later than A shows progressive expansion of intramedullary T2 hyperintensity extending from cervicomedullary junction to visualized thoracic cord. Additionally, there is loculated CSF within ventral CSF space in upper cervical spine (arrow). C, Axial T2-weighted MR image shows expansion and intramedullary T2 hyperintensity within cervical spine (arrow). literature [20]. Although this hydrodynamic theory may help explain syrinx formation in two patients in our study who had similar findings of tonsillar herniation secondary to hydrocephalus and a patent connection between the 4th ventricle and the central canal, it does not fully explain the pathophysiology of syringomyelia in the five other patients with no such identifiable connection on MRI. In patients in the present study, syringomyelia without connection to the 4th ventricle or hydrocephalus may be explained by the intramedullary pulse pressure theory proposed by Greitz [26]. His theory suggests that syringohydromyelia results from increased intramedullary pulse pressure caused by CSF pressure fluctuations in the subarachnoid space and venous circulation disturbances leading to extracellular fluid accumulation in the spinal cord. These pressure fluctuations may be related to either a fixed subarachnoid obstruction or a dynamic obstruction, as with mobile B cerebellar tonsils. In one study [28], abnormal CSF flow patterns and elevated systolic velocities in the foramen magnum were found in some patients with idiopathic syringomyelia, supporting the role of CSF hydrodynamics in the pathogenesis of syringomyelia. In our study, all seven patients with abnormal intramedullary T2-hyperintense signal abnormalities had leptomeningeal enhancement, and four of these patients also had subarachnoid blocks from adhesions evident on CT myelography. Of note, one of these patients (who later had an autopsy performed after death from presumed pneumonia [case 6]) first developed marked hydrocephalus and cerebellar tonsillar herniation requiring drainage by ventriculostomy, before development of his cord abnormality. From the available autopsy results, this patient s spinal cord abnormality was located in the watershed area supplied by sulcal branches of the anterior spinal artery, penetrating branches of the posterior spinal arter- C 1342 AJR:200, June 2013

10 Concurrent Brain and Spinal Disease With CNS Coccidioidomycosis ies, and branches of the circumferential pial network. Vascular narrowing of the spinal and leptomeningeal arteries in the presence of severe fibrotic arachnoiditis may have resulted in inadequate arterial perfusion and insufficient venous drainage causing chronic edema, hypoxia, and acidosis in the substance of the cord [29]. This correlates with the white and gray matter destruction seen during autopsy. In light of the intramedullary pulse pressure theory, one might postulate that, had this patient lived longer, the spinal cord noncavitary edema observed on both radiologic and pathologic examinations could have eventually progressed to syrinx formation via CSF hydrodynamic factors influenced by fixed and extensive spinal arachnoiditis and vasculitis [26, 30]. This is consistent with the findings in the study by Koyanagi et al. [21] in which intramedullary T2-weighted signal abnormalities or syringomyelia were frequently found at the same level as spinal arachnoiditis. In addition to highlighting the frequency of concurrent spinal disease in patients with intracranial coccidioidal meningitis, our case series of 23 patients provides further insight into the spectrum of intracranial A B imaging findings seen with coccidioidomycosis. Although the most common CNS complication of coccidioidal infection is basilar meningitis [15], our results show that MCA cistern involvement is also a characteristic finding. MCA cistern leptomeningeal enhancement was present in 19 of 21 patients (90%) with leptomeningeal enhancement in our study. The basic histopathologic process for meningitis seen with coccidioidal infection, whether basilar or involving the MCA cisterns, involves a pyogranulomatous and fibroblastic reaction affecting the meninges, small to medium-sized vessels, and adjacent perivascular zones [5, 6, 13]. This process results in production of inflammatory exudate in the affected regions. Progression of disease eventually leads to endarteritis obliterans and extension of infection and inflammation into the brain and spinal cord parenchyma, causing edema, ischemia, and necrosis [5, 6]. This was seen in case 1, in which left ventral pontine edema was noted adjacent to interpeduncular leptomeningeal disease. As seen in our study, leptomeningeal inflammation may lead to obstructive and communicating hydrocephalus in the brain, C D Fig year-old man (case 2). A, Coronal image from CT myelography shows complete subarachnoid block at T11. B, Sagittal image from MR myelography shows complete subarachnoid block at L1-2. C, Axial T2-weighted MR image shows cystic mass (arrow) in left posterior subarachnoid space corresponding to level of block. D, Axial T1-weighted gadoliniumenhanced MR image shows hypointensity with adjacent abnormal enhancement (arrow) corresponding to level of block. as well as arachnoiditis and spinal subarachnoid block in the spinal canal [4 6, 13]. Previously described intracranial imaging features of coccidioidal infection also seen in the patients in the present study include infarcts, periventricular white matter abnormality, and parenchymal masses and abscesses [2, 3, 7 11]. Infarction, presumably related to vasculitis and endarteritis obliterans [6, 13], was present in 35% (8/23) of patients in the present study. It occurred predominantly in the basal ganglia, brainstem, thalamus, and cerebral white matter, occasionally also involving the cerebral cortex and deep gray matter. In the three patients with irregular MRA findings, areas of infarct corresponded to the vascular territory of diseased vessels. Two of these MRAs (interestingly, both performed in children) were positive for vessel irregularity and diffuse narrowing of the circle of Willis. The third MRA with abnormal findings, which was performed in an elderly gentleman, showed near-complete occlusion of the left carotid terminus and proximal MCA. Autopsy results in a different patient also support marked meningeal inflammation and vas- AJR:200, June

11 Lammering et al. A B Fig year-old man (case 21). A, Sagittal T2-weighted MR image shows intramedullary T2 hyperintensity extending from C5 through thoracic spine. B, Sagittal T2-weighted MR image 9 years later than A shows progression of signal abnormality consistent with syringomyelia and syringobulbia (arrow). culitis involving the basilar, vertebral, and smaller penetrating arteries as the presumed cause for ischemic disease. Interestingly, the patient in whom the autopsy was performed did not yet have imaging findings of infarct, most likely reflecting the compensatory mechanism of the intracranial circulation. White matter signal abnormality, another finding previously reported with coccidioidal infection, was present in 39% (9/23) of the patients in this study. Parenchymal masses and abscesses occurred with less frequency (13% [3/23]), similar to published rates, which range from < 1% to 33% [15]. Previously reported rare but significant complications of CNS coccidioidomycosis that were not seen in our study include subarachnoid hemorrhage from necrotizing vasculitis or ruptured mycotic aneurysm, intrasellar granuloma formation, and dural infiltration mimicking meningioma en plaque [14, 31, 32]. Because our institution is a county hospital, a limitation of the present study is possible selection bias for patients with advanced Fig year-old HIV-positive man (case 5). Axial image from CT myelography shows nonobstructive filling defect (arrow) in posterior subarachnoid space. Fig year-old girl (case 10). Sagittal T2- weighted MR image shows marked hydrocephalus, cerebellar tonsillar herniation, diffuse cervical and thoracic cord syrinx (arrow), and connection between 4th ventricle and syrinx (arrowhead). disease at presentation. That many patients in this study were referred to our hospital for coccidioidomycosis treatment also contributes to this selection bias. Moreover, although coccidioidomycosis was confirmed by serologies in each patient, we cannot entirely exclude an alternative cause for the imaging findings. Histopathologic information for correlation with imaging findings was not available in the majority of the patients in the present study. However, this may be a universal limitation because surgical intervention is not always indicated for diagnosis or treatment in patients with known disseminated coccidioidal infection. For example, in many of the patients in our study who had spinal subarachnoid blocks, modifications were made in the treatment plan ranging from intrathecal amphotericin B administration to reservoir or ventriculoperitoneal shunt placement or revision. These changes were monitored over time while observing interim differences in clinical status. In evaluation of CNS coccidioidal infection, additional MR sequences may assist in distinguishing it from other infections, including pyogenic or tuberculous infection AJR:200, June 2013

12 Concurrent Brain and Spinal Disease With CNS Coccidioidomycosis DWI and ADC sequences characteristically show restricted diffusion with low ADC in the wall and cavity of pyogenic and tubercular abscesses. Although restricted diffusion in fungal abscesses may be variable, one study has shown low ADC in the wall with high ADC in the fungal cavity itself [33, 34]. In addition, DWI and ADC sequences may distinguish between abscess and granuloma. In a study of tuberculous infection, restricted diffusion was characteristic of abscess and variable for granuloma depending on solid versus liquefying necrotic characteristics [35]. MR spectroscopy can also be useful to distinguish fungal from pyogenic or tuberculous infection. Pyogenic infection characteristically shows elevated peaks of amino acids (leucine, isoleucine, and valine) at 0.9 parts per million (ppm), of succinate at 2.41 ppm, and of acetate at 1.92 ppm. Tuberculous infection shows elevated lipid and lactate peaks at 1.3 ppm. In addition to elevated lipid, lactate, and amino acid peaks, fungal abscesses show multiple peaks between ppm assigned to trehalose [33 39]. Identifying even a dormant coccidioidal granuloma is of clinical significance owing to the potential risk of reactivated, fulminant CNS coccidioidal infection in immunosuppressed patients [15]. Because patients with dormant coccidioidal granulomas may have normal CSF titers, imaging plays a pivotal role in directing diagnosis and clinical management, as well as possibly determining prognosis [9]. In summary, coccidioidomycosis involving the CNS is associated with devastating complications. For radiologists, knowledge of the full spectrum of CNS findings is important to facilitate early diagnosis and optimize treatment. Intracranial coccidioidal findings frequently include MCA cistern leptomeningeal enhancement as well as the characteristically described basilar distribution. 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