A Novel Radiographic and Genetic Variant of Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Case Report

Abstract

Background

The differential for acute onset progressive leukoencephalopathy in adults is broad. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is a rare genetic white matter disorder with typical onset around 40 years. Variability in clinical presentation can often lead to misdiagnosis with other neurodegenerative disorders, underscoring the importance of taking a detailed medical history, obtaining comprehensive diagnostic evaluations, and considering timely genetic testing.

Case presentation

A 53-year-old woman with a medical history of systemic lupus erythematosus and marginal zone B-cell lymphoma in remission presented with subacute onset fatigue, confusion, and slurred speech following SARS-CoV2 infection. Diagnostic testing was unremarkable except for elevated CSF interleukin-6, tumor necrosis factor, and myelin basic protein levels. The patient was diagnosed with presumed post-infectious encephalitis. Over the next 2 months, the patient’s clinical syndrome progressed to include bradykinesia, hypophonia, dysphagia and resting tremor. Pathology and genetic testing revealed a rare diagnosis of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

Conclusions

This case illustrates a stepwise process for constructing a comprehensive differential diagnosis for acute onset of progressive leukoencephalopathy and a general management strategy. We also report a novel radiographic finding and genetic variant in the CSF1R gene associated with ALSP.

Keywords

adult-onset leukoencephalopathy with axonal spheroids and pigmented glia leukoencephalopathy microglia CSF1R neurogenetics

Introduction

Leukoencephalopathies encompass a heterogenous group of genetic and acquired white matter diseases with varying presentations.¹ In adults, clinical features may range from motor impairment, neuropsychiatric and cognitive symptoms, movement disorders, and seizures.² The differential diagnosis for acute adult-onset progressive leukoencephalopathy is thus broad and includes infectious, inflammatory, toxic-metabolic, malignant, small-vessel vascular, and genetic etiologies. This report presents the diagnostic odyssey and management of a case of adult-onset leukoencephalopathy, which led to a diagnosis of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), including a novel genetic variant and radiographic features. This case highlights the importance of taking a detailed medical history, obtaining comprehensive laboratory and imaging, and considering timely genetic testing in the evaluation of adult-onset leukoencephalopathy.

Case Description

A 53-year-old woman with past medical history of systemic lupus erythematosus (SLE), marginal zone B-cell lymphoma in remission, and unremarkable family history presented with 1 week of fatigue, confusion, and slurred speech in setting of recent coronavirus disease (COVID-19). Her neurological exam was notable for hypophonia, hypomimia, mild cognitive slowing, inability to complete Luria sequence, and positive glabellar reflex. MRI brain revealed extensive confluent and symmetric T2 fluid attenuated inversion recovery (FLAIR) hyperintensities throughout the cerebral white matter, posterior limbs of the internal capsule, and cerebellar white matter (Figure 1). These findings were new compared to a normal MRI brain performed 2 months prior which was performed for a 6-month history of headache.

Figure 1.

(A) Diffusion Weighted Imaging of the Bilateral Frontoparietal White Matter on First Presentation; (B) ADC Sequence; (C) T2-FLAIR Sequence; (D) DWI Sequence of the Bilateral Cerebellar Regions on First Presentation, (E) ADC Sequence, (F) T2FLAIR

Complete blood count, complete metabolic panel, urinalysis and rheumatological lab were reassuring as compared to priors (Table 1). On the second day of admission, lumbar puncture was done with normal opening pressure. Cerebrospinal fluid (CSF) studies revealed normal white blood cells (WBC), red blood cells (RBC), glucose, and total protein counts. Cytopathology and flow cytometry were negative for atypical or malignant cells, and Gram stain revealed no organisms. Oligoclonal bands were negative, and immunoglobulin G (IgG) index was normal. Autoimmune and paraneoplastic antibody panels were negative. CSF lactate was within normal limits. Myelin basic protein (19.10 ng/mL, normal 0-5.50 ng/mL), interleukin-6 (IL-6) (8.3 pg/mL, normal ≤7.5 pg/mL) and tumor necrosis factor (9.0 pg/mL, normal ≤1.7 pg/mL) were elevated in the CSF. Patient was discharged from the hospital as her exam improved close to baseline without any intervention.

Table 1.

Summary of Key Diagnostic Findings

Symptoms	Fatigue, confusion, slurred speech, progressing to bradykinesia, hypophonia, dysphagia, and rest tremor
Laboratory	Bloodwork: Unremarkable, including metabolic, drug, and infectious metagenomics testing CSF: Normal WBC, RBC, glucose, total protein. Negative cytopathology, flow cytometry, infectious studies, autoimmune and paraneoplastic antibody panels. Elevated MBP, IL-6, and TNF
Radiology	MRI brain: Confluent and symmetric T2 fluid attenuated inversion recovery (FLAIR) hyperintensities throughout the cerebral white matter, posterior limbs of the internal capsule, and cerebellar white matter MR spectroscopy brain: Negative PET scan whole body: negative CT of whole body: negative
Genetic testing	mtDNA sequencing: Negative Whole genome testing: Heterozygous VUS in the CSF1R gene, c.2833_2835del, p.(Glu945del)
Pathology	Bone marrow: Negative Brain: H&E and neurofilament stain with axonal spheroids with no pigmented glia

Unfortunately, over the following 2 months, the patient developed subacute symptoms of parkinsonism including bradykinesia, hypophonia, dysphagia, and rest tremor. Repeat MRI showed new increased T1 and T2 signal and diffusion restriction within the bilateral gangliocapsular regions and redemonstrated the confluent T2/FLAIR/diffusion hyperintensities in the white matter and deep brain nuclei. She was re-admitted for progressive decline in functional status with weight loss secondary to dysphagia.

She was diagnosed with SLE 20 years ago and currently well-controlled on hydroxychloroquine monotherapy with stable disease markers. Thus, NPSLE was less likely. Her B-cell lymphoma was treated with rituximab 10 years prior to presentation without subsequent immunosuppressive therapy, making chemotherapy-induced neurotoxicity and PML unlikely. She was ultimately diagnosed with COVID-19 leukoencephalopathy and was empirically treated with intravenous (IV) steroids for presumed COVID-19 leukoencephalopathy with mild improvement and discharged from the hospital.

Two months later she was sent back to the hospital by her rheumatologist given significant function decline in the setting of steroid tapering. Subsequently, the patient was admitted with expanded work up. Recreational drug history, urine drug studies, and heavy metal screening were negative. Repeat lumbar puncture revealed similar results as well as brain MRI (Figure 2). Repeat infectious work-up was negative, including metagenomics panel.

The workup for CNS lymphoma given her clinical history of B-cell lymphoma including MRI spectroscopy, positron emission tomography (PET)/computer tomography (CT) whole body scan, and bone marrow biopsy was unremarkable. Metabolic testing, including copper, ceruloplasmin, magnesium, urine organic acids, plasma amino acids, serum lactate, and pyruvate were normal. A multidisciplinary decision was made to proceed with brain biopsy, which showed some axonal spheroids but no pigmented glia (Figure 3). Whole genome sequencing (GeneDx) revealed a heterozygous variant of unknown significance (VUS) in the CSF1R gene, c.2833_2835del, p.(Glu945del). Buccal swab mitochondrial DNA (mtDNA) sequencing and deletion did not show additional variants of interest.

Figure 2.

(A) DWI Sequence of the Subcortical White Matter at Progression of Symptoms (B) ADC, (C) T2-FLAIR, (D) DWI of the Cerebellar, Finding at Progression of Symptoms (E) ADC, (F) T2-FLAIR

Figure 3.

Histopathological Findings of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (A–D). (A) and (B). H&E stained sections show white matter with innumerable varyingly sized vacuoles, some of which are traversed by axons. Reactive astrocytes and subtle microglia and macrophages are also encountered. An axonal spheroid (arrow) can be seen in (B) and (C). A luxol fast blue with a PAS counterstain shows diminished myelin staining intensity in vacuolated regions but not total myelin loss. Macrophages have granular PAS positive cytoplasm (arrows). (D). A neurofilament stain labels some longitudinally sectioned axonal varicosities and a swollen dystrophic axonal ovoid (arrow). Magnification 40x.

Symptom management included initiating carbidopa-levodopa for tremor, gastrostomy-tube (G-tube) placement for nutritional optimization, and physical and occupational therapies. Empiric management included a mitochondrial cocktail of alpha-lipoic acid, biotin, creatine, ubiquinol, and Vitamin B complex. Tocilizumab was given empirically to treat potential inflammatory etiology given the elevated CSF IL-6 marker. At 12-month post-discharge follow-up visit, the patient still has a parkinsonism gait but can ambulate without assistance for a short distance. Her tremors are controlled with carbidopa-levodopa. Her hypophonia improved, and her cognition remains intact. She can eat 70% by mouth, using G-tube for nutritional supplementation and medications only.

Discussion

The patient’s clinical syndrome, genetic testing, and brain pathology were indicative of a diagnosis of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia, a subtype of adult-onset diffuse leukoencephalopathy. The differential for adult-onset diffuse leukoencephalopathy is broad (Table 2). Notable diagnoses pertaining to the patient’s medical history were neuropsychiatric systemic lupus erythematosus (NPSLE) was considered, with possible secondary cerebral vasculitis and posterior reversible encephalopathy syndrome (PRES), post COVID-19 leukoencephalopathy, chemotherapy-related neurotoxicity, progressive multifocal leukoencephalopathy (PML), and lymphomatosis cerebri, a rare infiltrating form of primary central nervous system (CNS) lymphoma. The presence of bilateral symmetrical diffusion restriction narrows down the differential diagnosis to conditions such as some tRNA synthetase disorders such as AARS2-associated leukoencephalopathy, and other rare genetic leukodystrophies³

Table 2.

Differential Diagnosis for Adult-Onset Diffuse Leukoencephalopathy

Category	Examples
Inflammatory	NPSLE Cerebral vasculitis PRES
Infectious	COVID-19-related leukoencephalopathy PML HIV/AIDS
Neoplastic	Lymphomatosis cerebri
Genetic	Genetic vasculopathies (CADASIL, CARASIL) Fabry disease Cerebrotendinous xanthomatosis Primary mitochondrial disorder-related leukoencephalopathies ARS2-related leukoencephalopathies CLCN2-associated leukoencephalopathy Adult polyglucosan body disease Adrenoleukodystrophy Metachromatic leukodystrophy Pelizaeus Merzbacher disease Alexander disease Canavan disease
Toxicity	Chemotherapy Heroin inhalation “chasing the dragon” Methamphetamine Carbon monoxide Toluene

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare adult-onset genetic white matter disorder. Previously, it was thought to have a familial form (hereditary diffuse leukoencephalopathy with axonal spheroids) and a sporadic form (pigmented orthochromatic leukodystrophy). These entities were subsequently integrated under a singular diagnostic terminology given their shared clinical presentations and genetic findings. Based on genome-wide linkage analyses and exome sequencing, variants in the colony stimulator factor 1 receptor (CSF1R) gene have been associated with ALSP.⁴ The gene for CSF1R encodes a tyrosine kinase receptor expressed primarily in microglia, which plays a critical role in immune regulation of the central nervous system.⁵

The typical age of onset for ALSP is around 40 years. The most common clinical presentations are subacute neuropsychiatric symptoms ranging from executive dysfunction and behavior changes to dementia and parkinsonism.⁶ Variability in clinical presentation can often lead to misdiagnosis with other neurodegenerative disorders. This presents a diagnostic challenge for providers and underscores the importance of considering a broad differential. White matter changes, rapid progression, and younger age of onset are clinical features that would not be expected in Parkinson’s disease and Parkinson’s plus disorders.

Diagnosis is ascertained with neuroimaging, biopsy findings, genetic testing, and correlating clinical phenotype. As in our patient’s case, cerebrospinal fluid studies are often unremarkable.^6,7,8 A case series of magnetic resonance imaging (MRI) findings from 16 participants showed findings ranging from brain atrophy to confluent white matter disease in both cerebral hemispheres, predominantly affecting frontoparietal regions. Interestingly, the cerebellum was spared; another four-patient case series reported cerebellar involvement.^9,13 However, these imaging features are not unique to ALSP and may be similar in other genetic white matter disorders.

Brain biopsy and genetic testing can help narrow the diagnosis further. Brain biopsy typically demonstrates axonal spheroids and pigmented glia in the affected areas. In the literature, the presence of pigmented glia can be variable, and its presence is not a diagnostic criterion. With recent advances in next generation genome sequencing, diagnosis of these rare disorders is becoming more accessible. A positive finding for CSF1R mutations is considered a hallmark of ALSP.¹⁰

This case also highlights rare radiographic findings and a previously unreported variant in the CSF1R gene. Our patient’s MRI brain showed T2/FLAIR hyperintensities throughout the cerebral white matter, posterior limbs of the internal capsule, and cerebellar white matter, with more extensive white matter disease than previously reported, especially in the cerebellum, in addition to that lack of cobblestone calcification. She interestingly had an in-frame deletion of 1 amino acid in exon 22 of CSF1R (c.2833_2835del, p.(Glu945del). In The Genome Aggregation Database (gnomAD), the deletion is present with a frequency of 0.02% (no homozygotes) and does not result in a frameshift. It has not been previously reported in the literature, thereby resulting in its VUS classification.

It is interesting that our patient had a prior history of immune dysregulation with her lupus diagnosis and marginal zone B-cell lymphoma. There is evidence of immune dysregulation in CSF1R-related ALSP affecting peripheral macrophage and microglial function. Proinflammatory cytokines and granulocyte macrophage colony stimulating factor (GM-CSF) were shown to be upregulated in the grey matter of post-mortem tissue in patients with ALSP.¹⁰ Abnormal migration and adhesion of peripheral monocytes suggest widespread immune dysfunction. If related to the CSF1R gene, then both innate and humoral mechanisms may be involved in this disease.

There are currently no standardized treatments for ALSP. Allogenic hematopoietic stem cell transplant has been tried, in two-patient case series, radiographic stabilization and slow clinical progression were noted at about 2 years follow-up.^11,12 Symptomatic management can include pharmacologic treatment for cognitive, behavioral, and motor symptoms, along with speech, physical, and occupational therapy. A multidisciplinary approach with a team of specialists is recommended given the management complexity. Investigations are underway to validate biomarkers for ALSP, including neurofilament light chain, tau protein, and glial fibrillary acid.¹⁰

Recent translational advances have shown promise in microglial replacement as a novel therapeutic strategy.¹⁰ CSF1R shares similar signaling pathways with human triggering receptor expressed on myeloid cells 2 (TREM2) through DNAX-activation protein 12 (DAP12) and spleen tyrosine kinase (SYK) phosphorylation. ALSP is thought to be driven by haploinsufficiency of the CSF1R gene resulting in reduced function of the tyrosine kinase domain. Unfortunately, a recent clinical trial evaluation TREM2 modulatory treatment did not meet its primary endpoint . There is also an ongoing natural history study to better understand ALSP (NCT05020743).

In conclusion, the diagnosis of ALSP may be missed due to its rarity and non-specific neuroimaging findings. Diagnosis can be particularly challenging in cases with a comorbid medical history and a variety of presenting symptoms. Genetic testing should be considered when diagnostic evaluation for more common infectious and toxic/metabolic etiologies are unrevealing. In these rare cases, brain biopsy can provide additional immunohistochemical evidence. Earlier diagnosis may allow for more rapid interdisciplinary management strategies and consideration for targeted treatments. Key clinical features in this case include the subacute neurological decline with parkinsonism following SARS-CoV2 infection, neuroimaging findings consistent with a diffuse bilateral diffusion restriction affecting the cerebellum and lack of typical cobblestone calcifications, biopsy findings of axonal spheroids without pigmented glia, and a novel variant in CSF1R.

Footnotes

Acknowledgements

We thank our patient and her family for their permission to publish this case as an educational resource. We also thank Dr Jason Handwerker, associate professor in the Department of Radiology at the University of California, San Diego, for his teaching regarding this diagnosis.

ORCID iDs

Angeline B. Ngo

Meshari Alharthi

Consent for Publication

Written informed consent was provided by the patient for publication of the case details.

Author Contributions

A.A.N. wrote the initial draft with support from A.B.N., M.A., M.O., S.R., and J.H.Y. K.H. prepared the pathology sections. All authors provided edits to the manuscript. All authors read and approved the final manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

Data is provided within the manuscript.*

Appendix

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