Pediatric Acute Toxic Leukoencephalopathy: Prediction of the Clinical Outcome by FLAIR and DWI for Various Etiologies

DISCUSSION

PATL is an uncommon clinicoradiologic diagnosis characterized by cerebral WM injury on DWI. This entity should be considered in the differential diagnosis of a child who presents with a recent onset of neurologic deficit and a known exposure to an external toxin, such as medications (most common in this cohort).⁵ Recognition of this condition is crucial because it is potentially reversible on prompt removal of the underlying etiology with supportive treatment. However, the clinical outcome varies between the etiologies, as found in the current study. Of note, prior studies of adult ATL have similarly found that a heterogeneous variety of causes has been defined that can lead to toxic leukoencephalopathy with similar clinical and imaging presentations.^10,15 Thus, this study may be the first to both describe a common appearance of PATL on DWI and FLAIR shared by such various entities and assess whether DWI and FLAIR differ in outcome.

Thus, this study attempted to determine variations in the DWI and FLAIR imaging appearances, to evaluate the severity of PATL in these different etiologies, and to assess their clinical outcomes using both DWI and FLAIR severity scoring. Thus, higher %ADCR values were found to be associated with adverse outcomes, and strong correlations were observed between the FLAIR and DWI severity with clinical outcome. Such observations likely highlight the significance of discerning early cases of PATL to initiate prompt therapy. Thus, the presence of a correlation between the MR imaging findings and clinical outcome suggests that the MR imaging severity may reflect the prognosis in PATL. This possibility suggests that there may be several important reasons to identify the early MR imaging findings of PATL in children presenting with acute symptoms. First, a minority of these patients continue to deteriorate; hence, the patients may deteriorate and even die after persistent exposure to a toxic agent, as described previously with chemotherapeutic agents.^18,19 Second, PATL may present with rather nonspecific-but-severe symptoms and thus can be confused clinically with other irreversible syndromes (eg, hypoxic-ischemic encephalopathy or PRES); consequently, the window for effective treatment could be missed.²⁰ Third, prompt recognition of PATL can prevent inappropriate treatment with potential iatrogenic complications in patients suspected of having another or underlying disorder.

Many etiologies have been documented anecdotally to cause PATL, including a variety of chemotherapeutic and immunosuppressive medications, BMT, and perhaps other etiologies such as uremia and sepsis.^4,10 Accordingly, in this larger study, half of the cases of PATL were caused by chemotherapy, with methotrexate being the most common (37%), as well as fludarabine (16%). Regarding these etiologies, the current study attempted to attribute etiologies to determine whether they have different outcomes in PATL. Overall, the DWI and FLAIR severity scoring appears prognostic, while the %ADCR was only moderately prognostic in predicting outcomes. Notably, fludarabine-related PATL had the worst clinical outcome, being the most common cause of death from PATL, in accordance with prior results in adults.^3,21 Thus, in PATL, the presence of characteristic regions of involvement on DWI and FLAIR, combined with quantitative ADC analysis in the appropriate clinical setting, may allow early diagnosis and potentially help determine the prognosis in children with PATL.¹⁸

Regarding intergroup comparisons of outcome, the DWI and FLAIR severity was worse in chemotherapy-related PATL, which also had worse clinical outcomes, despite the potentially reversible nature of PATL. In comparison, immunosuppression-related PATL had milder MR imaging severity and better clinical outcomes than the other subgroups, in accord with a recent study of adult ATL.¹¹ Thus, chemotherapy-related PATL having relatively strong correlations between the imaging severity and outcome suggests that more diffuse brain involvement in PATL tends to result in neurologic sequelae.

The basic pathophysiologic mechanisms leading to PATL and reduced diffusion are unknown but are likely multifactorial, being thought related to BBB dysfunction and endothelial injury. For example, chemotherapeutic agents such as methotrexate and fludarabine have been shown to directly injure the microvasculature and can also have indirect excitotoxic effects.²² Meanwhile, immunosuppressive medications, such as tacrolimus, cyclosporine, and mycophenolate are thought to cause capillary endothelial injury, leading to BBB dysfunction and occasional WM injury; thus, such injury from these agents may manifest as PRES (more commonly) or ATL (less commonly) based on prior studies.^3,13,23 Hence, the cause of reduced diffusion in the PVWM in PATL likely varies by etiology but may arise from intramyelinic edema, cytotoxicity via capillary endothelial injury, and/or direct toxic demyelination. Accordingly, histopathologic studies have corroborated such insults by discovering WM injury with axonal and oligodendroglial swelling, and also macrophage infiltration.^1,15

Limited studies used DWI in children with PATL, being mostly anecdotal.^4,24,25 DWI is more sensitive than T2WI or FLAIR in depicting the abnormalities of PATL; DWI can also help to determine the age of lesions, such as whether they are acute.²⁶ Another benefit of DWI is the ability to measure quantitative ADC values; thus, pathologic foci on DWI can be objectively measured on the ADC maps to exclude T2 shine through effects, which can mimic the reduced diffusion of acute lesions.²⁷

The main limitation of this study is its retrospective nature. For example, the clinical outcomes were based on the retrospective assessment of the medical record, in which long-term follow-up was not available in some patients; thus, the relatively small number of patients from a single tertiary care center may limit the number of etiologies evaluated and thus potentially affect the outcome analysis. Another limitation is that PATL is becoming slowly-but-increasingly recognized during the past 15–20 years; therefore, the frequency of this disorder may not be as uncommon as reported in this study, perhaps being underreported. Additionally, serial imaging was not performed routinely in the current study; therefore, the potential reversibility or progression of the brain injury could not be entirely assessed in each patient.

Another potential limitation is the differences in the physiologic MR imaging signal of WM structures between the pediatric and adult brain that may result in differences in the MR imaging findings and clinical outcomes between pediatric and adult ATL.²⁸ For example, during the first year of life, WM signal intensity decreases with time on T2WI via the physiologic process of myelination, which is mostly completed in the second year of life. To prevent this possible confounding factor, children younger than 12 months of age were not included in the study. This is largely due to the difficulty in measuring the effects of WM maturation on MR imaging signal intensity within the first 2 years, when the modeling of these variables would be highly complex; hence, a statistical correction cannot be readily applied to quantify the effects of PATL in infants.

Another possible limitation is the differing MR imaging scanner field strengths, with some children being imaged on a 1.5T scanner and others at 3T; notably, the differences in appearances and ADC values between these field strengths were not evaluated in this study. Nevertheless, this scenario mimics what often happens in routine clinical practice across centers and is also a consequence of the retrospective nature of this study. Most interesting, some authors have observed no statistically significant differences in ADC values comparing various regions of PVWM between magnetic field strengths (1.5 and 3T), so it is uncertain whether this observation would affect the results of the current study.¹⁵ Hence, this is another reason that the relative ADC measurements of affected WM (compared with NAWM) were used rather than using absolute ADC measurements. Hence, a prospective study is needed that incorporates control patients, obtains PATLs at regular intervals with a single MR imaging scanner, and implements advanced MR imaging applications such as DTI, to confirm the findings of our study of affected regions based on visual inspection.²⁹