Neurocognitive benchmarks following transplant for emerging cerebral adrenoleukodystrophy

Discussion

This investigation focused on a group of boys transplanted for cALD in the earliest stages of lesion development, in most cases before clinical signs of brain disease. Unlike most historical patient cohorts, familial diagnosis or other ALD symptoms (e.g., adrenal insufficiency) in these patients facilitated evaluation and monitoring prior to the development of a severe brain lesion. The cohort therefore offers insight into the cerebral involvement that may be detected during surveillance following a positive NBS. We present evidence that although disease-related neurocognitive symptoms are initially absent across the low range of the MRI severity scale, they emerge within a few years after transplantation. These findings have implications for realizing the promise of early detection through NBS: they imply that the window of watchful waiting between discovering a lesion and proceeding to transplant may be narrower than previously assumed, if neurocognitive and neuropsychiatric disease burden is to be avoided.

It is not known whether HSCT can prevent cerebral disease from emerging, but due to the inherent risk of transplantation, that study is unlikely to be conducted. The development of a gadolinium-enhancing lesion is considered evidence of active neuroinflammation and blood–brain barrier disruption, and has consistently been a clinical marker sufficient to justify moving forward with this intensive, risky therapy.¹³ Once white matter disease appears, a fairly predictable pattern of progression is observed. Demyelination typically begins in the splenium of the corpus callosum and spreads into parietal–occipital white matter (80% of patients). Less commonly (∼20% of patients), the process begins in the anterior corpus callosum and extends into frontal regions, or presents in an atypical location such as the internal capsule.¹ The current analysis suggests that as demyelination spreads beyond the corpus callosum and immediately adjacent periventricular white matter, risk heightens for further spreading of the lesion after treatment. Contrast enhancement on MRI, radiographic hypoperfusion, small volumetric lesion size at the initial scan, and young age of the patient are risk factors for more rapid progression.^14,–,16 Complicating these circumstances is emerging evidence that initial changes on MRI can be missed during clinical interpretation.¹⁷ The subtle appearance of lesions with MRI severity <2 (figure 2) highlights the importance of meticulous MRI review by an experienced neuroradiologist so that very small changes are detected. When small lesions emerge at a young age, close follow-up with imaging and preparation to facilitate swift transplantation has been recommended.^14,18

Findings from this study suggest that when lesions are small, the absence of directly quantified neurocognitive abnormalities is not a reason to delay transplant to continue monitoring by MRI. Specifically, transplantation upon first emergence of a T2 hyperintense lesion with gadolinium enhancement appears to be the most protective of functional outcomes. Across the spectrum of initially low severity lesions (i.e., MRI severity score <5), neurocognitive deficits were not detectable at the time of treatment by present standard neuropsychological measurement methodology. However, neurocognitive losses occurred in the years following HSCT for some patients, depending on lesion severity. At 2 years post-transplant, boys with the smallest pretransplant lesions (MRI severity score 0.5–2) consistently performed within the age-expected range across a diverse array of neurocognitive tasks. In comparison, boys with slightly higher pretransplant MRI severity (2.5–4.5) performed below the age-expected range (>1 SD below the normative mean) on post-transplant measures of processing speed, fine motor dexterity, and visual–motor integration. Verbal reasoning skills and working memory (short-term recall of information) remained generally stable across all patients, consistent with previous evidence that these functions can remain relatively intact even with advanced cALD.¹¹ We speculate that differences in the observability of neurocognitive deficits, i.e., with some being obvious and others being less apparent, may be the reason that patients are sometimes described as asymptomatic across this spectrum of MRI severity and higher.^14,19 Declines in visual perception or performance-based functions can be challenging to detect without repeated direct assessment. Neurocognitive testing appears to provide a much more sensitive assessment of deficiencies than neurologic or disability rating scores, or other surrogates from clinical chart review, which may not show sensitivity to functional changes until more advanced stages of cALD.

Our findings of deficits in processing speed, fine motor dexterity, and visual–motor integration have implications for learning, academic performance, and school engagement. These deficits may cause a student to struggle to keep up, avoid work, or feel inadequate. As they are invisible disabilities, they can cause affected students to appear unmotivated or noncompliant. Furthermore, the magnitude of changes observed in patients in the current study can be considered clinically meaningful. Standard methods for detecting a minimum clinically important difference (MCID) in neurocognitive scores and other quality of life assessments typically suggest that changes exceeding 0.5 SD (i.e., 7.5 points for an IQ score) or 2 standard errors of measurement (SEM; typically around 3–6 points for index scores on the Wechsler scales) constitute a meaningful difference.^20,21 Applying the criterion of 0.5 SD for the MCID at the group level, observed declines from baseline to 2 years post-transplant could be considered clinically meaningful for the LS group in 4 neurocognitive domains: visual reasoning, processing speed, fine motor dexterity, and visual–motor integration. In contrast, no declines meeting this threshold were observed in the VLS group. Broadly speaking, preservation of a patient's full cognitive potential should be a key goal of successful treatment for neurologic disease, to maximize quality of life and independent functioning throughout the lifespan.

Another notable aspect of this study is the characterization of the neuropsychiatric status of our patients. Symptoms such as hyperactivity, attention problems, and mood/anxiety disturbance can hinder day-to-day functioning and warrant consideration in analyzing group-level post-treatment outcomes among boys with cALD. Certainly, receiving the diagnosis of a potentially fatal condition and confronting a high-risk intensive therapy creates stress that could manifest as emotional or behavioral challenges. Nevertheless, our analysis also indicates that caregiver-reported neuropsychiatric symptoms (in particular, problems with poor attention and hyperactive behaviors) are associated with the extent of the MRI lesion. This finding suggests increased mental health risk as cALD spreads, which can be underappreciated in this population and merits further prospective investigation.

The findings of the current study delineate key benchmark data against which to compare outcomes of novel interventions for cerebral disease in boys diagnosed with ALD by NBS. They also have implications for the timing of outcome evaluations employing neurocognitive endpoints. Among the domains most vulnerable to change (e.g., processing speed, fine motor dexterity), measurable declines were observed beyond 1 year post-transplant, especially for boys with greater-than-minimal disease at treatment. As such, we recommend that clinical research studies utilize a minimum trial length of 2 years following treatment, with consideration of extended follow-up, as deficits can become more pronounced over time.^11,22 Further, it should be noted that clinical evaluation of neuropsychological function can be an important tool not only to collect trial endpoints, but also to provide educational recommendations and support families.

The Loes MRI severity scoring system, while widely used in the field, may not be as sensitive to small changes as volumetric analysis.¹⁴ Since our patient cohort was limited to those with early cALD lesions, we did not distinguish among different cerebral patterns of disease; some research indicates that boys with posterior (parietal–occipital) pattern of disease have more favorable outcomes with higher MRI severity than patients with frontal pattern or other rare demyelination patterns.²³ Patients with frontal disease pattern in our cohort may have skewed psychiatric outcomes (i.e., inattentive or hyperactive behaviors). However, the proportion of patients with frontal-predominant presentation was low (6%). In order to study the impact of regional pattern on psychiatric outcomes more extensively, it would be ideal to compare patients with frontal pattern alongside patients with the classic posterior pattern who are matched for lesion severity or volume. Given the relative rarity of the frontal presentation, such an analysis may require a multicenter effort. As a final point, use of neurocognitive tools within this cohort depended on the ability to combine datasets across decades, which restricted the breadth and depth of neurocognitive domains examined.

Our data provide evidence that there are clear risks in not moving forward expeditiously toward a definitive intervention for patients with early-identified cerebral disease. A better understanding of the natural history of this disease before the lesion develops and more sensitive indicators of disease onset are needed to optimize surveillance methods. Identification and development of new, performance-based neurocognitive tests may hold promise for improved sensitivity to early-stage cALD or facilitate identification of deficits that coincide with or precede the development of a visible MRI lesion. Clinical trials of newer, safer therapies capable of minimizing disease progression would be of great benefit, not only in advanced disease, but also in those with emergent disease.