Abstract

Deep brain stimulation (DBS) infection occurs in 3% of adult and 10% of pediatric cases, where the most critical kind is at the intracerebral leads, requiring urgent removal.1-3 Careful confirmation is necessary as explantation elicits symptom reemergence, and reimplantation yields reduced efficacy with an increased reinfection risk.4 Intracerebral DBS infection is underreported, particularly its neuroimaging presentation and occurrences in children. We present the clinical and neuroimaging findings of 4 original pediatric and 24 literature adult cases. Patient 1 (an 11-year-old boy with idiopathic generalized dystonia) received bilateral globus pallidus internus (GPi)-DBS. Six months postoperatively, he developed worsening dystonia and fever, as well as swelling and erythema over the battery, but did not report pain. Incision cultures revealed Staphylococcus aureus. Magnetic resonance imaging (MRI) showed T2/fluid-attenuated inversion recovery (FLAIR) hyperintensity in the lentiform nuclei and amygdala without contrast enhancement (CE) (Fig. 1A–F). The leads were explanted and tested positive. Patient 2 (an 11-year-old girl with dyskinetic cerebral palsy secondary to prematurity) received bilateral GPi-DBS. One month later, purulent discharge occurred at the scalp incision, which was tender, and dystonia did not worsen. Cultures revealed S. aureus. MRI indicated CE at the burr hole and T2/FLAIR hyperintensity around the right lead, which was removed and tested positive (Fig. 1G–L). Patient 3 (a 17-year-old boy with dyskinetic cerebral palsy secondary to prematurity) received bilateral GPi-DBS. One year later, the battery and connecting wires were revised due to worsening dystonia and abnormal device impedances. Eight days postoperatively, incisional discharge occurred at the chest without pain. Cultures revealed Serratia, and white blood cell (WBC) count was elevated (13,000). The DBS system was removed, excluding the leads. During this procedure, the lead protrusions were swabbed and tested positive. MRI demonstrated T2/FLAIR hyperintensity of the left-sided lead, and the leads were explanted (Fig. 1M–R; Fig. S1). Patient 4 (a 4-year-old boy with generalized dystonia of presumed genetic etiology) received bilateral GPi-DBS. Three weeks postoperatively, he presented with fever, erythema, and swelling of the chest incision but no pain or worsening dystonia. The battery and connecting wires were removed, swabs indicated S. aureus, and WBC count was elevated (20,800). MRI demonstrated bilateral T2/FLAIR hyperintensity and CE of the leads, which were removed and tested positive (Fig. 1S–X). Overall, our patients were successfully treated with broad-spectrum antibiotics. Clinically, 4 children experienced skin changes (eg, erythema), 2 had a fever, and 2 demonstrated worsening dystonia, plausibly due to infection severity, location, involvement of active contacts, and pathogen characteristics (Table S1). On MRI, asymmetric T2/FLAIR hyperintensity was observed in 3 cases and CE in 2, but diffusion restriction was absent (Table S2). A literature review (Table S3) of intracerebral DBS infection, including studies reporting (1) neuroimaging and (2) clinical presentation, identified 24 adult cases. Three pediatric cases were found but excluded due to absent neuroimaging.5-7 Clinical signs were often fever (11/24 = 46%), confusion (7/24 = 29%), skin changes (7/24 = 29%), elevated C-reactive protein (CRP, 8/16 = 50%), unremarkable blood work (5/16 = 31%), or elevated WBC count (4/16 = 25%) (Table S1). Neuroimaging included asymmetrical features (computed tomography [CT]: 19/19 = 100% and MRI: 11/11 = 100%), CT hypoattenuation (19/20 = 95%), CT CE (11/14 = 79%), MRI T2/FLAIR hyperintensity (10/11 = 91%), and MRI CE (8/9 = 89%) (Table S2). Notably, no studies mentioned restricted diffusion. Most cases reported CT (20/24 = 83%) versus MRI (11/24 = 46%), presumably due to less accessibility and safety concerns of DBS MRI scanning. Neuroimaging was more consistent than clinical presentation across 4 pediatric and 24 adult cases of lead infection. Consider explantation if T2/FLAIR hyperintensity, T1 CE, or CT hypoattenuation is observed around the leads alongside fever, skin changes, or elevated WBC/CRP. Restricted diffusion, a standard intracerebral infectious indicator, was not found or reported. Most pathogens were skin flora (16/24 = 67%, where 4 of 28 did not specify). Noninfectious peri-lead edema (PLE), occurring in 35.8% of DBS cases, can be difficult to distinguish from lead infection.8 PLE presents postoperatively from 4 to 59 days versus 3 to 200 days (Table S3).8 Whereas PLE also often demonstrates T2/FLAIR hyperintensity around the leads, CE appears less.8 PLE is symptomatic in 8.7% of cases versus 100%. Symptomatic PLE includes confusion, paresis, or aphasia but not the key symptoms of lead infection (ie, fever and skin changes).8 PLE should be considered first as it is more prevalent, treatable, and usually self-resolving (1–70 days).8 Specific conditions may be associated with a greater risk of lead infection, as dystonia was the only etiology of our pediatric cases (Table S4). However, a potential confounder is that dystonia is the most common pediatric DBS indication. Nevertheless, in our experience, the antibiotic regimen, surgery duration, and hardware revisions are similar between etiologies (Tables S4 and S5). Moreover, a recent review of DBS infections identified dystonia (6.5%) and epilepsy (9.5%) with the highest rate (vs. 5% across all indications).9 Pediatric dystonia DBS may have heightened risk as patients' smaller-body habitus hinders healing and bodily contortions strain incision sites and complicate wound care.10 Further research is required to elucidate whether specific DBS indications have increased infection risk and to clarify precise presentations. Overall, these 4 original pediatric and 24 adult literature cases of intracerebral DBS infection may guide future diagnoses. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Manuscript preparation: A. Writing of the first draft, B. Review and critique. A.Z.Y.: 1A, 1B, 1C, 2A, 2B A.B.: 1A, 1B, 1C, 2A, 2B V.P.: 1A, 1B, 1C, 2A, 2B M.J.C.: 1A, 1B, 1C, 2A, 2B A.V.: 1A, 1B, 1C, 2B B.S.: 2B N.S.: 2B J.G.: 2B S.B.: 1A, 1B, 2B L.E.: 1B, 2B B.E.W.: 1A, 2B A.F.: 1A, 2B A.M.L.: 1A, 2B G.I.: 1A, 1B, 1C, 2A, 2B C.G.: 1A, 1B, 1C, 2A, 2B We thank the 4 patients and their families for their willingness to publish their cases. Ethical Compliance Statement: This study protocol was reviewed and approved by SickKids Research Ethics Board (REB) 10068019. This study was conducted in accordance with the World Medical Association Declaration of Helsinki. Subjects provided their written informed consent to publish their case, including the publication of images. Written informed consent was obtained from their parents for publication of the details of their medical case and accompanying images. We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: BEW serves as a central radiological reviewer for the studies for Bayer Healthcare and declares that her spouse is employee of Siemens Healthineers. AL is a consultant to Abbott, Boston Scientific, Insightec, Medtronic and Functional Neuromodulation (Scientific Director). AF recieved consyltancies fees from Abbie, Abbott, Boston Scientific, Dompe Farmaceutici, Ipsen, Iota, Syneos Health. Advisory Boards: Abbvie, Boston Scientific, Ceregate and Ipsen. Honoraria: Abbvie, Abbott, American Academy of Neurology, Boston Scientific, Brainlab, Ipsen, Medtronic, Merz, Movement Disorders Society, Sunovion, Paladin Labs, UCB, Sunovion. Grants: Abbvie, Boston Scientific, Dystonia Medical Research Foundation, University of Toronto, Michael J Fox Foundation, Medtronic, MSA coalition, Praxis, ES. Royalties: Springer. GMI has acted as a paid consultant/advisor to LivaNova Inc, Medtronic Inc and Syneria Inc. He has served on the Advisory Board of Synergia Inc. He has received investigator initiated research funding from LivaNova Inc CG has acted as a paid consultant to Medtronic Inc, Ipsen Inc,. She has served on the Advisory Board of Medtronic Inc. Other authors have no disclosures to report. The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1. Clinical findings of intracerebral DBS infection from our pediatric case series and literature review. The numerator corresponds to the total number of cases that reported a positive finding of a specific feature, whereas the denominator corresponds to the total number of cases that reported a specific feature. See Table S3 for more details. CRP, C-reactive protein; DBS, deep brain stimulation; WBC, white blood cell. Table S2. Neuroimaging findings of intracerebral DBS infection from our pediatric case series and literature review. For the row "Imaging Modalities Used," the numerator corresponds to the number of cases reporting the specific imaging modalities, whereas the denominator corresponds to the total number of cases. For the rows "CT" and "MRI," the numerator corresponds to the total number of cases that reported a positive finding of a specific feature, whereas the denominator corresponds to the total number of cases that reported a specific imaging feature. See Table S3 for more details. CT, computed tomography; DBS, deep brain stimulation; FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging. Table S3. Overview of clinical and neuroimaging findings of intracerebral infection DBS cases from our cohort and a literature review. The literature review was conducted by querying PubMed MEDLINE for "deep brain stimulation" OR "DBS" AND "infection," "abscess," "cerebritis," "complication," and "adverse event," which yielded 1021 results. Inclusion criteria were studies reporting intracerebral DBS infections containing neuroimaging and clinical presentation. After abstracts were screened, 106 studies underwent full-text review, which identified 13 studies of 24 adult cases (1 patient experienced 2 infections). Though 3 reports of pediatric intracerebral DBS infection were found, they were excluded due to lack of neuroimaging. (5–7) ASYM, asymmetrical findings; CE, contrast enhancement; DBS, deep brain stimulation; HYPO, hypoattenuation; IPG, implantable pulse generator; N/A, not applicable; T1/CE, T1 contrast enhancement; T2/F, T2 fluid-attenuated inversion recovery. Table S4. Infection rate of pediatric patients who received deep brain stimulation (DBS) at Sick Kids Hospital. The total number of surgeries is the sum of the initial DBS device insertions, hardware revisions, and battery changes. Table S5. Antibiotic protocol for pediatric patients who receive deep brain stimulation at Sick Kids Hospital. IV, intravenous; q6h, dose every 6 h. Figure S1. Patient 3 preoperative MRI (magnetic resonance imaging). (A) Axial 3D (three-dimensional) T1 reveals marked, symmetric volume loss of the thalami (solid arrows) and the lentiform nuclei. (B) Axial reconstruction of a sagittal 3D FLAIR sequence reveals the corresponding areas of hyperintensity in the deep gray nuclei along with similar symmetric signal abnormality in the perirolandic regions (arrowheads in C). These findings are in keeping with the remote sequelae of profound hypoxic–ischemic encephalopathy. FLAIR, fluid-attenuated inversion recovery. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.