The utility of brain biopsy in pediatric cryptogenic neurological disease

Hugo Layard Horsfall MBBS, BSc (Hons)1,2, Sebastian M. Toescu MBChB (Hons), BSc (Hons), MRCS1,3, Patrick J. Grover MSc, FRCS1, Jane Hassell MBBS, MRCPCH4, Charlotte Sayer MBBS, MRCPCH4, Cheryl Hemingway MBChB, FRCPCH, PhD4, Brian Harding MA, BM, BCh, DPhil, FRCPath6,5, Thomas S. Jacques MA, MB, BChir, PhD, MRCP, FRCPath6,7, and Kristian Aquilina MD, FRCS(SN)1
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  • 1 Departments of Neurosurgery,
  • | 4 Neurology, and
  • | 6 Histopathology, Great Ormond Street Hospital for Children, London;
  • | 2 Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke’s Hospital and University of Cambridge;
  • | 3 Developmental Imaging and Biophysics Section and
  • | 7 Developmental Biology and Cancer Department, UCL GOS Institute of Child Health, London, United Kingdom; and
  • | 5 Department of Pathology, Children’s Hospital of Philadelphia, Pennsylvania
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OBJECTIVE

The authors’ aim was to characterize a single-center experience of brain biopsy in pediatric cryptogenic neurological disease.

METHODS

The authors performed a retrospective review of consecutive brain biopsies at a tertiary pediatric neurosciences unit between 1997 and 2017. Children < 18 years undergoing biopsy for neurological pathology were included. Those with presumed neoplasms and biopsy performed in the context of epilepsy surgery were excluded.

RESULTS

Forty-nine biopsies in 47 patients (25 females, mean age ± SD 9.0 ± 5.3 years) were performed during the study period. The most common presenting symptoms were focal neurological deficit (28.6%) and focal seizure (26.5%). Histopathological, microbiological, and genetic analyses of biopsy material were contributory to the diagnosis in 34 cases (69.4%). Children presenting with focal seizures or with diffuse (> 3 lesions) brain involvement on MRI were more likely to yield a diagnosis at biopsy (OR 3.07 and 2.4, respectively). Twelve patients were immunocompromised and were more likely to yield a diagnosis at biopsy (OR 6.7). Surgery was accompanied by severe complications in 1 patient. The most common final diagnoses were infective (16/49, 32.7%), followed by chronic inflammatory processes (10/49, 20.4%) and occult neoplastic disease (9/49, 18.4%). In 38 cases (77.6%), biopsy was considered to have altered clinical management.

CONCLUSIONS

Brain biopsy for cryptogenic neurological disease in children was contributory to the diagnosis in 69.4% of cases and changed clinical management in 77.6%. Biopsy most commonly revealed underlying infective processes, chronic inflammatory changes, or occult neoplastic disease. Although generally safe, the risk of severe complications may be higher in immunocompromised and myelosuppressed children.

ABBREVIATIONS

EBV = Epstein-Barr virus; PCR = polymerase chain reaction.

OBJECTIVE

The authors’ aim was to characterize a single-center experience of brain biopsy in pediatric cryptogenic neurological disease.

METHODS

The authors performed a retrospective review of consecutive brain biopsies at a tertiary pediatric neurosciences unit between 1997 and 2017. Children < 18 years undergoing biopsy for neurological pathology were included. Those with presumed neoplasms and biopsy performed in the context of epilepsy surgery were excluded.

RESULTS

Forty-nine biopsies in 47 patients (25 females, mean age ± SD 9.0 ± 5.3 years) were performed during the study period. The most common presenting symptoms were focal neurological deficit (28.6%) and focal seizure (26.5%). Histopathological, microbiological, and genetic analyses of biopsy material were contributory to the diagnosis in 34 cases (69.4%). Children presenting with focal seizures or with diffuse (> 3 lesions) brain involvement on MRI were more likely to yield a diagnosis at biopsy (OR 3.07 and 2.4, respectively). Twelve patients were immunocompromised and were more likely to yield a diagnosis at biopsy (OR 6.7). Surgery was accompanied by severe complications in 1 patient. The most common final diagnoses were infective (16/49, 32.7%), followed by chronic inflammatory processes (10/49, 20.4%) and occult neoplastic disease (9/49, 18.4%). In 38 cases (77.6%), biopsy was considered to have altered clinical management.

CONCLUSIONS

Brain biopsy for cryptogenic neurological disease in children was contributory to the diagnosis in 69.4% of cases and changed clinical management in 77.6%. Biopsy most commonly revealed underlying infective processes, chronic inflammatory changes, or occult neoplastic disease. Although generally safe, the risk of severe complications may be higher in immunocompromised and myelosuppressed children.

ABBREVIATIONS

EBV = Epstein-Barr virus; PCR = polymerase chain reaction.

In Brief

The authors report a series of 49 pediatric brain biopsies for cryptogenic neurological disease. The paper adds value to the current evidence base by demonstrating the utility and safety of brain biopsy. Histopathological analysis enabled the authors to inform and modify clinical management, improving patient outcomes. Furthermore, it provides insight into the spectrum of diagnoses encountered in a busy 21st century urban neurosurgical center.

The utility of brain biopsy for suspected brain tumors is well established and has a high diagnostic yield.1–3 Less well understood is the role of brain biopsy in cryptogenic neurological disease, which is defined by presentation with a severe neurological syndrome, in an acute or chronic fashion, whose etiology remains unclear despite extensive investigation. The literature detailing the indications, diagnostic yield, and morbidity of biopsy in children is sparse.4–8 Consequently, centers differ in opinion regarding the risk and value of the procedure. In addition, the increasing use of immunosuppression in children, mostly related to transplantation and inflammatory disease, has altered the spectrum of cryptogenic brain lesions. In the modern diagnostic era, with improved sensitivity of radiological, serological, and genetic investigations, a limited number of pediatric series have been published.8–10 Prior publications relate to experience before 1980, when diagnostic pathways and imaging protocols, before the availability of MRI, were very different.5,7,11 Other publications relate to adult practice, where a substantial proportion of biopsies are undertaken in the setting of neurodegenerative disease.12–14

In the pediatric population, many common diagnoses such as vasculitis, infection, and inflammatory disease can be very effectively treated with modern pharmaceutical agents. Thus, diagnostic brain biopsy has the potential for high clinical impact in children.

The objective of this retrospective series of consecutive cases, derived from a quaternary institution with a high volume of pediatric transplant activity, was to describe our experience of brain biopsy for pediatric cryptogenic neurological disease with a focus on surgical technique, diagnostic yield, and effect on patient management.

Methods

Patients were identified from a prospectively maintained neurosurgical operative database, which was retrospectively queried with the keyword “biopsy” and subsequently filtered to exclude nonbrain biopsies. All brain biopsies performed between 1997 and 2017 were identified. All patients were younger than 18 years. Those undergoing targeted biopsy for suspected tumor or biopsy performed in the context of resective epilepsy surgery were excluded. Those included were patients undergoing diagnostic biopsy for neurological presentations of uncertain etiology. Our institution does not require additional patient consent or ethics approval for retrospective case note reviews of this nature.

Two pediatric neurologists (J.H. and C.H.) reviewed the case notes to assess the diagnostic workup and to confirm the cryptogenic nature of the neurological presentation. Preoperative MRI and surgical techniques were reviewed by 3 neurosurgeons (S.M.T., P.J.G., and K.A.). MRI changes were characterized as diffuse (i.e., > 3 lesions visible), multifocal (2 or 3 lesions visible), or focal (single lesion visible). MRI changes were categorized as concordant with final diagnosis when the radiologist’s report stated a single specific diagnosis that matched that from laboratory analysis of biopsy material. Adverse events were recorded prospectively in an operative database and reviewed contemporaneously at departmental surgical morbidity and mortality meetings. Although there was no predetermined panel of tests for each biopsy sample, the diagnostic considerations and requirements for each case were always discussed in advance with the pathologists and microbiologists. All biopsy samples were sent fresh from the operating room and divided to allow processing for microbiology, including Gram stain, cultures, and polymerase chain reaction (PCR) for the detection of nucleic acids, virology, electron microscopy, and conventional pathology, including immunostaining. Histopathology was contemporaneously reviewed by 2 histopathologists (T.S.J. and B.H.). Biopsy samples were retrospectively categorized as diagnostic or not on the basis of the histopathological report and microbiological and virological studies. Biopsies with clear diagnostic descriptions on these grounds, and those with highly suggestive changes such as chronic or granulomatous inflammation or when an infectious agent was newly identified, were classified as being contributory to diagnosis.

Descriptive statistics were performed in R (R Core Team 2017). Fisher’s exact test was used to compare proportions. Nonnormally distributed continuous data were analyzed with the Mann-Whitney U-test. A prespecified α of 0.05 was chosen. Odds ratios were used to depict the relative likelihood that patients with specified features would go on to have a biopsy result that contributed to the diagnosis compared with the remainder of the cohort.

Results

Demographics and Presentation

A total of 15,620 neurosurgical procedures were performed during the study period. Keyword search and filtering revealed that 168 brain biopsies were performed in total during the study period (biopsies undertaken as part of resective oncology or epilepsy surgery were coded as the latter and therefore likely excluded from this figure). Of these, 49 biopsies were performed in 47 patients (25 females) with cryptogenic neurological disease, at a mean age of 9.0 ± 5.3 years (± SD). The 2 repeat biopsies were performed almost 1 year apart in both cases. The most common presenting symptoms were focal neurological deficit (28.6%); focal seizure (26.5%); and fever, obtundation, or new movement disorder (all 20.4%) (Fig. 1A). The biopsy procedure was performed at a median of 90 days following symptom onset, with the shortest interval being 4 days and the longest being after more than 5 years of indolent symptom course followed by a 2-year deterioration with increasing seizures and evolving focal neurological deficits. There was no statistically significant difference between time to biopsy from symptom onset and whether a diagnosis was reached at biopsy (Fig. 1B). While there was a shorter median time to biopsy in the second chronological half of the cohort compared with the first half (90 vs 365 days), this difference was not statistically significant (p = 0.411).

FIG. 1.
FIG. 1.

A: Bar plot of presenting symptoms and signs and their frequencies. B: Density plot of duration of symptoms prior to biopsy in patients who had a diagnosis reached on biopsy and those who did not. Dashed vertical lines show the mean symptom duration for the 2 groups, values indicated. The p value is shown for the Mann-Whitney U-test (data markedly positively skewed). Figure is available in color online only.

Prior to biopsy, children underwent a thorough investigative workup. The variation in presentation precluded a specific prescribed approach, but investigations were wide ranging, including, but not limited to, serology for autoimmune encephalopathies and atypical infections, metabolic screening, bone marrow studies, white cell enzymes, and biopsy of other organs, including skin, muscle, and peripheral nerve. Children with suspected vasculitis underwent angiography; children with suspected inflammatory disorders underwent appropriate immunological (serum and CSF), thrombophilia, and targeted genetic investigations, as determined by specialist pediatric neurologists. Children with suspected infections, in particular, immunocompromised patients, underwent extensive microbiological and virological testing on systemic and CSF samples as determined by pediatric infectious disease specialists, microbiologists, and virologists. Brain MRI was available in 42 of the 47 patients; CSF sampling results were available in 40 patients, and EEG was performed in 27 patients. Cases in which MRI and CSF results were not available occurred before the introduction of electronic patient records at our hospital. Examples of representative images from the cohort are shown in Fig. 2. All children were discussed in multidisciplinary clinical meetings to ensure that wide expertise from multiple relevant specialties was available at every stage of investigation.

FIG. 2.
FIG. 2.

A: Preoperative CT scan obtained in a 12-year-old girl who presented with a 4-week history of headaches, vomiting, and constitutional symptoms. Imaging was consistent with a diagnosis of tuberculous meningitis. Brain biopsy ruled out malignancy—and was thus contributory to clinical management—but did not show typical tuberculous lesions. The causative Mycobacterium sp. was not identified on tissue culture, stains, or PCR. The patient was started on empirical antituberculous therapy, and her condition improved clinically. B: Axial T2-weighted MR image obtained in a 16-year-old boy with a bone marrow transplant who presented with fevers and generalized seizures. Biopsy of the left parietal focal abnormality revealed toxoplasmosis. C–F: Coronal FLAIR MR images obtained in a 14-year-old boy with a complex history of neonatal meningitis, epilepsy, and bone marrow transplantation 7 years earlier. He presented with headaches and arm weakness. Initially, the imaging differential was of multifocal demyelination (C). Serial imaging showed progression of changes in the right diencephalon with an evolving differential toward neoplastic disease (D). The biopsy revealed gliomatosis cerebri, which can be appreciated on a images obtained 9 months postbiopsy (E and F). Coronal FLAIR MR image showing infiltration in the temporal and deep frontal lobes and right superior cerebellar peduncle (E). Sagittal T1-weighted postcontrast MR image showing enhancing lesions in the cerebellum, temporal lobe, and thalamus (F).

The odds ratios depicted in Table 1 represent the relative likelihood that a patient in a given subgroup will yield a diagnosis on biopsy compared with the remainder of the cohort. Children presenting with focal seizures (OR 3.07, 95% CI 0.63–15.0) were most likely to yield a diagnosis on biopsy. Diffuse MRI changes (OR 2.4, 95% CI 0.44–13.23) were most likely to lead to a diagnosis on biopsy.

TABLE 1.

Odds ratios for diagnostic biopsy given presenting symptoms and signs and MRI findings

Diagnostic Biopsy*OR95% CI
Presenting symptoms & signs
 Headache3/50.710.11–4.51
 Fever6/100.690.18–2.68
 Focal seizures11/133.070.63–15.0
 Generalized seizures4/80.440.1–1.92
 Encephalopathy5/71.220.22–6.78
 Coma7/101.140.27–4.83
 Focal neurological deficit10/141.250.35–4.44
 Hydrocephalus1/30.230.02–2.62
 Movement disorder7/101.140.27–4.83
Immunosuppressed patients
 All diagnoses11/126.70.78–57.6
 Infective diagnoses8/125.781.4–23.89
MRI findings
 Normal1/20.480.03–8.32
 Diffuse (>3 lesions)8/102.40.44–13.23
 Multifocal (2 or 3 lesions)10/170.560.15–2.04
 Focal (single lesion)9/131.180.29–4.83

Presented as the number of patients with a diagnostic biopsy and the listed symptom or sign/total number of patients with the listed symptom or sign.

Denominators do not add up to 49, as many patients presented with more than one symptom/sign.

Denominators total 42, as MRI reports and images were unavailable in 5 patients.

The majority of referrals to neurosurgery were from neurology (35/49, 71.4%), with fewer referrals from infectious diseases (4/49, 8.2%), bone marrow transplant (4/49, 8.2%), immunology (1/49, 2.1%), and endocrinology (1/49, 2.0%) specialists. Four of 49 biopsies (8.2%) were managed primarily by the neurosurgical team with input from other specialists. Twelve patients were immunocompromised; 7 had previously undergone organ transplantation (6 bone marrow and 1 kidney). Immunosuppressed patients had a higher OR (6.7, 95% CI 0.78–57.6) of yielding a diagnosis on biopsy and a significantly higher OR (5.8, 95% CI 1.4–23.9) of having an infective diagnosis determined on biopsy (Table 1).

Surgical Procedure and Morbidity

The majority of cases (27/49, 55.1%) were performed through a small craniotomy; 19 cases (38.8%) were performed stereotactically through a burr hole, 2 (4.1%) were performed endoscopically, and 1 (2.0%) was performed with robotic assistance. Nineteen of the 27 open biopsies (70.4%) and 15 of the 19 stereotactic biopsies (78.9%) yielded material that was contributory to diagnosis, but there was no statistically significant difference in these proportions (difference 8.5%, 95% CI −27.9% to 13.5%; p = 0.735). Stereotactic biopsies were undertaken using a frameless technique. Biopsies from brains with normal findings on MRI were taken from the right prefrontal region, anterior to the motor cortex; no gross neurological deficits related to surgery were noted postoperatively. None of the biopsies performed endoscopically or robotically yielded material that was contributory to diagnosis. Thirty-nine of the 49 biopsies (79.6%) were lobar/hemispheric, 6 were midline, and 4 were of posterior fossa structures. In 2 patients (both in the most recent year [2017] of the current series), brain biopsy was performed as part of a stereotactic bilateral thalamic centromedian nucleus electrode implantation for refractory status epilepticus.

Three patients experienced moderate postoperative complications. One developed new postoperative focal seizures that were controlled with antiepileptic medication; 1 developed postoperative left-handed weakness, which resolved within 30 days; and 1 developed a superficial surgical site infection treated with oral antibiotics in the community.

One patient, a 15-year-old boy with thrombocytopenia, microangiopathy, and immunosuppression due to a recent bone marrow transplant, suffered a fatal postoperative intracerebral hematoma. He was being treated for severe systemic candidiasis and showed limited response to the antimicrobial therapies given. A biopsy was performed via a right frontal craniotomy to confirm that the radiological lesions were indeed Candida spp. and to exclude any other pathology. On the 1st postoperative day, a CT scan, obtained in response to anisocoria, showed an ipsilateral intracerebral hematoma. Despite prompt evacuation of the hematoma, there was no improvement in the patient’s neurological status.

Diagnosis and Treatment

Pathological analysis of biopsy material was contributory to diagnosis in 34 cases (69.4%). There was no statistically significant difference in the proportion of diagnoses clinched from brain biopsies in the first versus the second half of the cohort (p = 0.495). Preoperative MRI diagnosis was concordant with final diagnosis in 45.7% of cases. Table 2 shows all final diagnoses and their frequency, and Fig. 3 shows examples of the pathology seen at biopsy. Two patients underwent repeat biopsy 1 year apart. In one, chronic inflammatory changes were found on both occasions. In the other, an immunocompromised boy with previous bone marrow transplant, the first biopsy was inconclusive, and he was clinically diagnosed with posterior reversible encephalopathy syndrome; the second biopsy identified aspergillosis.

TABLE 2.

Final diagnoses and frequency

DiagnosisNo. of CasesBiopsy Contributory to Diagnosis, no. (%)
Infective
M. tuberculosis43 (75)
T. gondii22 (100)
Aspergillus spp.22 (100)
 EBV33 (100)
 No organism identified21 (50)
Streptococcus pneumoniae11 (100)
Staphylococcus aureus10 (0)
Astrovirus encephalitis11 (100)
Neoplastic
 Gliomatosis cerebri33 (100)
 Astrocytoma22 (100)
 Medulloblastoma11 (100)
 DNET11 (100)
 Germinoma11 (100)
 Poorly differentiated malignant leptomeningeal tumor11 (100)
Other
 ADEM22 (100)
 Rasmussen’s encephalitis43 (75)
 Vasculitis10 (0)
 Chronic inflammatory lesions106 (60)
 Mitochondrial disease20 (0)
 Cortical dysplasia11 (100)
 CLIPPERS10 (0)
 FIRES20 (0)
 PRES10 (0)
Total4934 (69.4)

ADEM = acute disseminated encephalomyelitis; CLIPPERS = chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids; DNET = dysembryoplastic neuroepithelial tumor; FIRES = febrile infection-related epilepsy syndrome; PRES = posterior reversible encephalopathy syndrome.

FIG. 3.
FIG. 3.

Examples of the pathology found at biopsy. A: A biopsy that revealed a CNS embryonal tumor composed of diffuse sheets of hyperchromatic cells. B: A dural biopsy showing granulomatous inflammation characterized by necrosis (black arrowhead), epithelioid histiocytes (white arrowhead), and giant cells (arrow). C and D: Brain biopsy showing Toxoplasma gondii cysts (C, arrow) confirmed on immunohistochemical analysis (D). E and F: Brain biopsy obtained a patient with a fungal infection characterized by granulomatous inflammation, shown by the frequent giant cells (E, arrow) and fungal hyphae on Grocott staining (F). Bar = 50 μm.

Overall, infection (16/49, 32.7%) was the most common cause of cryptogenic neurological deterioration in this series. The most frequent organisms identified were Mycobacterium tuberculosis (4 cases), Epstein-Barr virus (EBV; 3 cases), Toxoplasma gondii, and Aspergillus spp. (2 cases each), with 8/16 (50.0%) infective cases occurring in immunocompromised patients. Microbiological testing of biopsy material was contributory to diagnosis in several cases. In one patient, Aspergillus fumigatus was isolated on extended incubation of biopsy material, later confirmed on 18S PCR. The other case of aspergillosis (Aspergillus delacroxii) and 2 cases of toxoplasmosis were diagnosed on PCR of biopsy material, where CSF PCR studies prior to this had not yielded diagnoses. EBV was confirmed on tissue PCR in the context of histological changes consistent with EBV-driven inflammation (abnormal white matter and perivascular lymphocytic infiltrates) in 3 cases, in patients in whom EBV had already been identified on CSF studies but with uncertain significance, resulting in targeted treatment for this infection. Viral deep sequencing on lesional tissue identified astrovirus as the causative organism in a case of fulminant encephalitis in an immunocompromised patient. Histopathological analysis of brain biopsy material in this case had shown neuronal apoptosis with microglial activation, as detailed in our original case report.15

No organisms were identified in 2 patients with infective syndromes. One had meningoencephalitis in the setting of X-linked severe combined immunodeficiency and bone marrow transplantation and was managed supportively. The other patient presented with focal seizures and had multifocal calcified lesions on CT scanning; biopsy revealed active chronic inflammation with granulomata formation. The child was initially given antituberculous therapy but later switched to chronic granulomatous disease treatment and eventually underwent a bone marrow transplant.

In 38 of the 49 cases (77.6%), biopsy results were felt to have altered clinical management of the patient, including cases in which targeted antimicrobial therapy was instituted (8 patients), radiotherapy or chemotherapy was instituted (5 patients), higher-risk antiinflammatory treatments were commenced (12 patients, and 1 case in which these treatments were avoided), further surgery was carried out (3 hemispherotomies for Rasmussen’s encephalitis), or referral to palliative care services was made (4 patients). One patient died, and the remaining 4 patients were managed conservatively with the avoidance of higher-risk treatment modalities. There was no difference in the likelihood of biopsy altering clinical management between early (pre-2008) and late (post-2008) epochs of the cohort (Fisher’s exact test, p = 0.703).

Discussion

Diagnostic Yield and Utility of Brain Biopsy

Our data indicate that brain biopsy in children has a high diagnostic yield of 69.4% in children with neurological presentations that have defied diagnosis despite detailed clinical investigation. We found no statistically significant difference in the proportion of diagnostic biopsies in the early, compared with the late, epoch of the current series. Results from retrospective series8 and a meta-analysis4 reported diagnostic yields of 48.5% and 53.8%, respectively, in pediatric cryptogenic neurological disease. The diagnostic yields seen in older studies5,7,11 offer somewhat limited insight due to the fact that modern-day diagnostic techniques would have likely permitted earlier diagnosis through noninvasive means, such as extensive serological testing and better imaging modalities. However, we show in this contemporary series that even with the advent of high-field MRI and genetic sequencing, a proportion of patients will continue to evade diagnosis, even with invasive methods such as brain biopsy.

The concordance of preoperative MRI with final diagnosis was 45.7%; a similar finding was described in a recent cohort in the United Kingdom.9 MR images described as concordant were those that were specific to a single diagnosis and ultimately correct; many of the other images provided a differential diagnosis among which was the final diagnosis. However, in an extremely heterogeneous patient group, final diagnosis was often a composite of imaging, serological, and biopsy information. MRI does remain an important staging post of investigation in this cohort, yet even within experienced clinical groups, it rarely carries the certainty to allow consideration of new treatment options that may confer a higher risk. We have shown that biopsy often provides a definitive answer in these difficult cases.

The added value of a putatively diagnostic procedure lies in being able to prescribe treatment that otherwise would not have been offered. Thus, in our study, 77.6% of biopsies (38/49) were considered to have altered clinical management. This is slightly higher than that in other reports, in which biopsies altered management in 64.7%,10 67.1%,4 and 71.9%8 of patients. These data suggest that a brain biopsy offers real-world clinical utility in the pediatric population. An added benefit of a biopsy-defined diagnosis in rare cryptogenic disease is that prognosis may be better defined, while offering to parents an explanation for their child’s neurological deterioration.

Presentation and Diagnoses

The most common presenting symptoms and signs in this series were focal neurological deficit and focal seizure (Fig. 1). Venkateswaran et al. found that the most common presenting feature in their cohort was seizure activity (37/66, 56.1%)8 and that presentation with focal neurological deficits resulted in an increased likelihood of diagnostic biopsy. Our results replicate this, showing a higher odds ratio for diagnostic biopsy after presentation with focal seizures or focal neurological deficit, although the numbers in each group are small and the 95% confidence interval crosses unity. We also found that diffuse MRI findings were more likely to lead to a diagnostic biopsy (OR 2.4, 95% CI 0.44–13.23). This may be due to more severe, fulminant cases with diffuse imaging changes possessing more florid pathology that is more easily appreciable on examination of biopsy material, as well as a greater lesion burden amenable to biopsy.

We note that the population biopsied in the present study included several immunocompromised (12/47) and bone marrow transplant (7/12) patients. Two-thirds of these patients were found to have infections based on microbiological and virological testing of brain tissue samples where CSF and systemic samples had not yielded a diagnosis. These patients had significantly higher odds of yielding an infective diagnosis from brain biopsy than their immunocompetent counterparts (OR 5.78, with 95% CI > 1). Clinicians caring for immunocompromised patients with cryptogenic neurological disease may wish to consider biopsy early to confirm the presence of treatable organisms, narrow the number of antimicrobial drugs being given to a patient, and determine total duration of treatment.

The most frequent diagnoses (Table 2) in the present study were infective (16/49, 32.7%), and the most frequent organism identified was M. tuberculosis (4 cases). In 3 of the 4 tuberculosis cases, biopsy material was contributory to diagnosis in revealing necrotizing granulomatous inflammation. In the fourth tuberculosis case (Fig. 2A), biopsy ruled out malignancy—and was thus felt to have been contributory to clinical management—but the sample did not show typical tuberculous lesions. The causative Mycobacterium sp. was not identified on tissue culture, stains, or PCR in any case; thus, patients were started on empirical antituberculous therapy after exclusion of other granuloma-forming conditions, and all improved clinically. In all cases of toxoplasmosis and aspergillosis, diagnosis was made on microbiological studies of biopsy material where organisms had not previously been identified on CSF. Indeed, novel sequencing techniques mean that we are now more likely to obtain positive results of infection on brain biopsy samples when this has not been possible on CSF.

Chronic inflammatory processes (20.4%)16 and occult neoplastic disease (18.4%) were also common. The latter were always diffusely infiltrative lesions without a defined mass; thus, they had defied accurate prior radiological diagnosis. Many of the diagnoses seen in this series, such as CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids),17 FIRES (febrile infection-related epilepsy syndrome),18 astrovirus encephalitis,15,19 and chronic or fulminant viral encephalitis20,21 have been reported in isolation. This report is able to set these rare diagnoses in the context of their clinical presentation in a wider pediatric cohort. Venkateswaran et al. diagnosed a high proportion of vasculitis in their cohort (18.2%),8 while in our series there was just 1 case, an antineutrophilic cytoplasmic antibody–positive vasculitis in a 12-year-old girl presenting with hypertensive encephalopathy and acute visual loss.

Surgical Technique, Safety, and Timing of Biopsy

The optimal timing of brain biopsy remains a challenging issue. While the majority of biopsies in this series led to a definitive diagnosis and a change in clinical management, the risks associated with the surgical procedure—particularly in immunocompromised, myelosuppressed, or coagulopathic patients—mandates that biopsy remains a last resort, to be considered after less invasive investigations are completed. Our practice has evolved throughout this series: in the latter half, biopsy was performed at a shorter interval following symptom onset (a median of 90 days compared with 365 days in the first half), with the shortest time to brain biopsy from symptom onset being 4 days (in a 1-year-old boy with obstructive hydrocephalus due to a posterior fossa mass lesion). There are limited comparative data on time to biopsy in the literature. The recent pediatric series8–10 do not state length of time from patient presentation to biopsy. Our results showed no statistically significant difference between the median time to biopsy stratifying by biopsy yield (contributory vs noncontributory). However, the data are heavily positively skewed, more so in the group without diagnostic yield, indicating that patients with the longest symptom courses eventually yielded negative biopsies in this clinical setting.

Brain biopsy is not a risk-free procedure, and these risks are increased in the immunocompromised population. In this study, there were 3 moderate complications, and 1 death following a postoperative intracranial hematoma in an immunosuppressed and thrombocytopenic bone marrow transplant patient. In subjecting such complex patients to brain biopsy, it should be acknowledged that there is a greater risk of serious complications. However, in such cases in which the risk of death or disability is high due to the underlying organic condition, biopsy offers a last chance of diagnosis of a potentially treatable condition. The risk of postoperative neurological morbidity can be mitigated by performing a biopsy of lesions in noneloquent sites. On the basis of our experience, performing a biopsy in a nonlesional area of the brain is safe and has utility; 1 of 2 samples from the right prefrontal cortex in patients with normal findings on MRI resulted in a diagnosis and neither caused any postoperative focal neurological deficit.

In this series, there was no significant difference in diagnostic yield for the 2 most numerous operative techniques deployed, open or stereotactic (70.4% vs 78.9%, p = 0.735). The fact that none of the endoscopic or robotic biopsies yielded diagnostic material is likely due to a small sample size (n = 3, combined). Different surgical techniques have specific procedural risks. For example, open biopsy may be safer than stereotactic biopsy, as hemorrhage can be surgically controlled. However, it is important to appreciate that the reported risk of hemorrhage after brain biopsy in cryptogenic neurological disease is less than that in malignant disease.22,23

Diagnostic Nomenclature

The literature offers different levels of diagnostic yield based on subjective rationale. Due to the rare nature of cryptogenic neurological disease and a lack of standardized reporting mechanisms, the definition of a “useful” biopsy is varied. For example, Rice et al. used “definitive,” “suggestive,” or “nondiagnostic” from histopathological results based on the certainty of the likely diagnosis indicated in the neuropathologist’s report.24 In this report, we took a pragmatic approach, classifying pathology reports as contributory to diagnosis if definitive or highly suggestive changes were noted. Venkateswaran et al. differentiated between “diagnostic” and “diagnostic and useful” based on its impact on management.8 Furthermore, another study demonstrated a low diagnostic yield of 29% due to their strict definition of diagnostic material.25

In pediatric cryptogenic neurological disease, establishing a diagnosis to institute disease-specific therapy is the primary scenario in which brain biopsy is useful. A second situation is to rule out malignancy or inflammatory conditions to permit further treatment, especially immune suppression. Finally, a nondiagnostic brain biopsy can, in some situations, provide clinical utility by excluding conditions that might require harmful treatment.26

Limitations

Our study was retrospective in nature and therefore is subject to caveats of missing and incomplete data. For example, in many cases, it was not possible to discern the true extent of the biopsy. An optimal brain biopsy sample—particularly in cases in which there was no focal radiological or macroscopic lesion—is a cubic centimeter of noneloquent brain, including cortex and white matter as well as leptomeninges, and a small sample of dura (larger dural excisions can lead to complications in the form of CSF leak). It was difficult to deduce the total volume of our biopsy samples. During the 20 years this study period encompasses, there have been significant advancements in diagnostic modalities, such as serological tests, PCR for infective agents, and improvements in the quality of MRI. Tracking these changes to understand whether they had led to a reduction in the need for biopsy was not possible in this study. On the other hand, brain biopsy may be considered a more useful tool now that samples can be subjected to more detailed testing, such as deep genetic sequencing for infective agents.

Conclusions

The present study evaluates the utility of brain biopsy in cryptogenic neurological disease in children. By definition, cryptogenic neurological disease remains a diagnostic conundrum. We have shown in this retrospective single-center series that there is utility in performing brain biopsy in this patient cohort. It is generally safe, has a high diagnostic yield, and often directly influences management decisions. The timing of the biopsy remains a difficult and patient-specific issue, with the need to balance rapid neurological decline, thorough noninvasive investigation, surgical risk, and local expertise. Logical infrastructure and clear communication in a multidisciplinary team is essential for decision-making to ensure optimized treatment plans.

Acknowledgments

S.M.T. is supported by a Great Ormond Street Hospital Children’s Charity (Award #174385) and is an Honorary Research Fellow at the Royal College of Surgeons. T.S.J. is grateful to funding from the Brain Tumour Charity, Children with Cancer UK, Great Ormond Street Hospital Children’s Charity (INSTINCT), Olivia Hodson Cancer Fund, Cancer Research UK, and the National Institutes of Health Research. All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Toescu, Grover, Hassell, Sayer, Hemingway, Jacques, Aquilina. Acquisition of data: Toescu, Grover, Hassell, Sayer, Hemingway, Harding, Jacques, Aquilina. Analysis and interpretation of data: Toescu, Layard Horsfall, Grover, Hassell, Sayer, Hemingway, Harding, Jacques. Drafting the article: Toescu, Grover, Layard Horsfall. Critically revising the article: Toescu, Layard Horsfall, Hassell, Sayer, Hemingway, Harding, Jacques, Aquilina. Reviewed submitted version of manuscript: Toescu, Layard Horsfall, Grover, Hassell, Sayer, Hemingway, Harding, Jacques, Aquilina. Administrative/technical/material support: Layard Horsfall, Harding, Jacques.

References

  • 1

    Hall WA. The safety and efficacy of stereotactic biopsy for intracranial lesions. Cancer. 1998;82(9):17491755.

  • 2

    Kim JE, Kim DG, Paek SH, Jung H-W. Stereotactic biopsy for intracranial lesions: reliability and its impact on the planning of treatment. Acta Neurochir (Wien). 2003;145(7):547555.

    • Search Google Scholar
    • Export Citation
  • 3

    Tilgner J, Herr M, Ostertag C, Volk B. Validation of intraoperative diagnoses using smear preparations from stereotactic brain biopsies: intraoperative versus final diagnosis—influence of clinical factors. Neurosurgery. 2005;56(2):257265.

    • Search Google Scholar
    • Export Citation
  • 4

    Bai HX, Zou Y, Lee AM, et al. Diagnostic value and safety of brain biopsy in patients with cryptogenic neurological disease: a systematic review and meta-analysis of 831 cases. Neurosurgery. 2015;77(2):283295.

    • Search Google Scholar
    • Export Citation
  • 5

    Boltshauser E, Wilson J. Value of brain biopsy in neurodegenerative disease in childhood. Arch Dis Child. 1976;51(4):264268.

  • 6

    Kaufman HH, Catalano LW Jr. Diagnostic brain biopsy: a series of 50 cases and a review. Neurosurgery. 1979;4(2):129136.

  • 7

    MacGregor DL, Humphrey RP, Armstrong DL, Becker LE. Brain biopsies for neurodegenerative disease in children. J Pediatr. 1978;92(6):903905.

    • Search Google Scholar
    • Export Citation
  • 8

    Venkateswaran S, Hawkins C, Wassmer E. Diagnostic yield of brain biopsies in children presenting to neurology. J Child Neurol. 2008;23(3):253258.

    • Search Google Scholar
    • Export Citation
  • 9

    Richards O, Sivakumar G, Goodden J, et al. Non-oncological biopsy—does it make a difference? Paper presented at: 47th Annual Meeting of the International Society for Pediatric Neurosurgery; October 20–24, 2019; Birmingham, UK.

    • Search Google Scholar
    • Export Citation
  • 10

    Tonder LV, Foster M, Hennigan D, et al. Non tumour brain biopsies in Alder Hey paediatric neurosurgery. In: ABN/SBNS Joint Annual Meeting; September 19–21, 2018; London, UK. Abstract TP1-10.

    • Search Google Scholar
    • Export Citation
  • 11

    Brett EM, Berry CL. Brain biopsy in infancy and childhood. Dev Med Child Neurol. 1968;10(2):263264.

  • 12

    Javedan SP, Tamargo RJ. Diagnostic yield of brain biopsy in neurodegenerative disorders. Neurosurgery. 1997;41(4):823830.

  • 13

    Josephson SA, Papanastassiou AM, Berger MS, et al. The diagnostic utility of brain biopsy procedures in patients with rapidly deteriorating neurological conditions or dementia. J Neurosurg. 2007;106(1):7275.

    • Search Google Scholar
    • Export Citation
  • 14

    Warren JD, Schott JM, Fox NC, et al. Brain biopsy in dementia. Brain. 2005;128(Pt 9):20162025.

  • 15

    Brown JR, Morfopoulou S, Hubb J, et al. Astrovirus VA1/HMO-C: an increasingly recognized neurotropic pathogen in immunocompromised patients. Clin Infect Dis. 2015;60(6):881888.

    • Search Google Scholar
    • Export Citation
  • 16

    Sa M, Hacohen Y, Alderson L, et al. Immunotherapy-responsive childhood neurodegeneration with systemic and central nervous system inflammation. Eur J Paediatr Neurol. 2018;22(5):882888.

    • Search Google Scholar
    • Export Citation
  • 17

    Sa M, Green L, Abdel-Mannan O, et al. Is chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) in children the same condition as in adults? Dev Med Child Neurol. 2019;61(4):490496.

    • Search Google Scholar
    • Export Citation
  • 18

    Kramer U, Chi CS, Lin KL, et al. Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children. Epilepsia. 2011;52(11):19561965.

    • Search Google Scholar
    • Export Citation
  • 19

    Wunderli W, Meerbach A, Güngör T, et al. Astrovirus infection in hospitalized infants with severe combined immunodeficiency after allogeneic hematopoietic stem cell transplantation. PLoS One. 2011;6(11):e27483. Published correction in PLoS One. 2012;7(1). doi:10.1371/annotation/8371c305-a69c-4225-83ae-b0b414eca31a

    • Search Google Scholar
    • Export Citation
  • 20

    Morfopoulou S, Brown JR, Davies EG, et al. Human coronavirus OC43 associated with fatal encephalitis. N Engl J Med. 2016;375(5):497498.

  • 21

    Morfopoulou S, Mee ET, Connaughton SM, et al. Deep sequencing reveals persistence of cell-associated mumps vaccine virus in chronic encephalitis. Acta Neuropathol. 2017;133(1):139147.

    • Search Google Scholar
    • Export Citation
  • 22

    Dammers R, Haitsma IK, Schouten JW, et al. Safety and efficacy of frameless and frame-based intracranial biopsy techniques. Acta Neurochir (Wien). 2008;150(1):2329.

    • Search Google Scholar
    • Export Citation
  • 23

    Woodworth GF, McGirt MJ, Samdani A, et al. Frameless image-guided stereotactic brain biopsy procedure: diagnostic yield, surgical morbidity, and comparison with the frame-based technique. J Neurosurg. 2006;104(2):233237.

    • Search Google Scholar
    • Export Citation
  • 24

    Rice CM, Gilkes CE, Teare E, et al. Brain biopsy in cryptogenic neurological disease. Br J Neurosurg. 2011;25(5):614620.

  • 25

    Burns JD, Cadigan RO, Russell JA. Evaluation of brain biopsy in the diagnosis of severe neurologic disease of unknown etiology. Clin Neurol Neurosurg. 2009;111(3):235239.

    • Search Google Scholar
    • Export Citation
  • 26

    Gilkes CE, Love S, Hardie RJ, et al. Brain biopsy in benign neurological disease. J Neurol. 2012;259(5):9951000.

Illustration from Guida et al. (pp 346–352). Copyright Lelio Guida. Published with permission.

Contributor Notes

Correspondence Sebastian M. Toescu: Great Ormond Street Hospital for Children, London, United Kingdom. sebastian.toescu@ucl.ac.uk.

INCLUDE WHEN CITING Published online July 3, 2020; DOI: 10.3171/2020.4.PEDS19783.

H.L.H. and S.M.T. share first authorship of this work.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

  • View in gallery

    A: Bar plot of presenting symptoms and signs and their frequencies. B: Density plot of duration of symptoms prior to biopsy in patients who had a diagnosis reached on biopsy and those who did not. Dashed vertical lines show the mean symptom duration for the 2 groups, values indicated. The p value is shown for the Mann-Whitney U-test (data markedly positively skewed). Figure is available in color online only.

  • View in gallery

    A: Preoperative CT scan obtained in a 12-year-old girl who presented with a 4-week history of headaches, vomiting, and constitutional symptoms. Imaging was consistent with a diagnosis of tuberculous meningitis. Brain biopsy ruled out malignancy—and was thus contributory to clinical management—but did not show typical tuberculous lesions. The causative Mycobacterium sp. was not identified on tissue culture, stains, or PCR. The patient was started on empirical antituberculous therapy, and her condition improved clinically. B: Axial T2-weighted MR image obtained in a 16-year-old boy with a bone marrow transplant who presented with fevers and generalized seizures. Biopsy of the left parietal focal abnormality revealed toxoplasmosis. C–F: Coronal FLAIR MR images obtained in a 14-year-old boy with a complex history of neonatal meningitis, epilepsy, and bone marrow transplantation 7 years earlier. He presented with headaches and arm weakness. Initially, the imaging differential was of multifocal demyelination (C). Serial imaging showed progression of changes in the right diencephalon with an evolving differential toward neoplastic disease (D). The biopsy revealed gliomatosis cerebri, which can be appreciated on a images obtained 9 months postbiopsy (E and F). Coronal FLAIR MR image showing infiltration in the temporal and deep frontal lobes and right superior cerebellar peduncle (E). Sagittal T1-weighted postcontrast MR image showing enhancing lesions in the cerebellum, temporal lobe, and thalamus (F).

  • View in gallery

    Examples of the pathology found at biopsy. A: A biopsy that revealed a CNS embryonal tumor composed of diffuse sheets of hyperchromatic cells. B: A dural biopsy showing granulomatous inflammation characterized by necrosis (black arrowhead), epithelioid histiocytes (white arrowhead), and giant cells (arrow). C and D: Brain biopsy showing Toxoplasma gondii cysts (C, arrow) confirmed on immunohistochemical analysis (D). E and F: Brain biopsy obtained a patient with a fungal infection characterized by granulomatous inflammation, shown by the frequent giant cells (E, arrow) and fungal hyphae on Grocott staining (F). Bar = 50 μm.

  • 1

    Hall WA. The safety and efficacy of stereotactic biopsy for intracranial lesions. Cancer. 1998;82(9):17491755.

  • 2

    Kim JE, Kim DG, Paek SH, Jung H-W. Stereotactic biopsy for intracranial lesions: reliability and its impact on the planning of treatment. Acta Neurochir (Wien). 2003;145(7):547555.

    • Search Google Scholar
    • Export Citation
  • 3

    Tilgner J, Herr M, Ostertag C, Volk B. Validation of intraoperative diagnoses using smear preparations from stereotactic brain biopsies: intraoperative versus final diagnosis—influence of clinical factors. Neurosurgery. 2005;56(2):257265.

    • Search Google Scholar
    • Export Citation
  • 4

    Bai HX, Zou Y, Lee AM, et al. Diagnostic value and safety of brain biopsy in patients with cryptogenic neurological disease: a systematic review and meta-analysis of 831 cases. Neurosurgery. 2015;77(2):283295.

    • Search Google Scholar
    • Export Citation
  • 5

    Boltshauser E, Wilson J. Value of brain biopsy in neurodegenerative disease in childhood. Arch Dis Child. 1976;51(4):264268.

  • 6

    Kaufman HH, Catalano LW Jr. Diagnostic brain biopsy: a series of 50 cases and a review. Neurosurgery. 1979;4(2):129136.

  • 7

    MacGregor DL, Humphrey RP, Armstrong DL, Becker LE. Brain biopsies for neurodegenerative disease in children. J Pediatr. 1978;92(6):903905.

    • Search Google Scholar
    • Export Citation
  • 8

    Venkateswaran S, Hawkins C, Wassmer E. Diagnostic yield of brain biopsies in children presenting to neurology. J Child Neurol. 2008;23(3):253258.

    • Search Google Scholar
    • Export Citation
  • 9

    Richards O, Sivakumar G, Goodden J, et al. Non-oncological biopsy—does it make a difference? Paper presented at: 47th Annual Meeting of the International Society for Pediatric Neurosurgery; October 20–24, 2019; Birmingham, UK.

    • Search Google Scholar
    • Export Citation
  • 10

    Tonder LV, Foster M, Hennigan D, et al. Non tumour brain biopsies in Alder Hey paediatric neurosurgery. In: ABN/SBNS Joint Annual Meeting; September 19–21, 2018; London, UK. Abstract TP1-10.

    • Search Google Scholar
    • Export Citation
  • 11

    Brett EM, Berry CL. Brain biopsy in infancy and childhood. Dev Med Child Neurol. 1968;10(2):263264.

  • 12

    Javedan SP, Tamargo RJ. Diagnostic yield of brain biopsy in neurodegenerative disorders. Neurosurgery. 1997;41(4):823830.

  • 13

    Josephson SA, Papanastassiou AM, Berger MS, et al. The diagnostic utility of brain biopsy procedures in patients with rapidly deteriorating neurological conditions or dementia. J Neurosurg. 2007;106(1):7275.

    • Search Google Scholar
    • Export Citation
  • 14

    Warren JD, Schott JM, Fox NC, et al. Brain biopsy in dementia. Brain. 2005;128(Pt 9):20162025.

  • 15

    Brown JR, Morfopoulou S, Hubb J, et al. Astrovirus VA1/HMO-C: an increasingly recognized neurotropic pathogen in immunocompromised patients. Clin Infect Dis. 2015;60(6):881888.

    • Search Google Scholar
    • Export Citation
  • 16

    Sa M, Hacohen Y, Alderson L, et al. Immunotherapy-responsive childhood neurodegeneration with systemic and central nervous system inflammation. Eur J Paediatr Neurol. 2018;22(5):882888.

    • Search Google Scholar
    • Export Citation
  • 17

    Sa M, Green L, Abdel-Mannan O, et al. Is chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) in children the same condition as in adults? Dev Med Child Neurol. 2019;61(4):490496.

    • Search Google Scholar
    • Export Citation
  • 18

    Kramer U, Chi CS, Lin KL, et al. Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children. Epilepsia. 2011;52(11):19561965.

    • Search Google Scholar
    • Export Citation
  • 19

    Wunderli W, Meerbach A, Güngör T, et al. Astrovirus infection in hospitalized infants with severe combined immunodeficiency after allogeneic hematopoietic stem cell transplantation. PLoS One. 2011;6(11):e27483. Published correction in PLoS One. 2012;7(1). doi:10.1371/annotation/8371c305-a69c-4225-83ae-b0b414eca31a

    • Search Google Scholar
    • Export Citation
  • 20

    Morfopoulou S, Brown JR, Davies EG, et al. Human coronavirus OC43 associated with fatal encephalitis. N Engl J Med. 2016;375(5):497498.

  • 21

    Morfopoulou S, Mee ET, Connaughton SM, et al. Deep sequencing reveals persistence of cell-associated mumps vaccine virus in chronic encephalitis. Acta Neuropathol. 2017;133(1):139147.

    • Search Google Scholar
    • Export Citation
  • 22

    Dammers R, Haitsma IK, Schouten JW, et al. Safety and efficacy of frameless and frame-based intracranial biopsy techniques. Acta Neurochir (Wien). 2008;150(1):2329.

    • Search Google Scholar
    • Export Citation
  • 23

    Woodworth GF, McGirt MJ, Samdani A, et al. Frameless image-guided stereotactic brain biopsy procedure: diagnostic yield, surgical morbidity, and comparison with the frame-based technique. J Neurosurg. 2006;104(2):233237.

    • Search Google Scholar
    • Export Citation
  • 24

    Rice CM, Gilkes CE, Teare E, et al. Brain biopsy in cryptogenic neurological disease. Br J Neurosurg. 2011;25(5):614620.

  • 25

    Burns JD, Cadigan RO, Russell JA. Evaluation of brain biopsy in the diagnosis of severe neurologic disease of unknown etiology. Clin Neurol Neurosurg. 2009;111(3):235239.

    • Search Google Scholar
    • Export Citation
  • 26

    Gilkes CE, Love S, Hardie RJ, et al. Brain biopsy in benign neurological disease. J Neurol. 2012;259(5):9951000.

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