Disappearing corticospinal tract on routine MRI: dynamic signal evolution in primary lateral sclerosis

Summary

Primary lateral sclerosis (PLS) may show corticospinal tract (CST) hyperintensity on fluid-attenuated inversion recovery and motor cortex hypointensity on susceptibility-weighted imaging (SWI); however, its longitudinal evolution remains poorly understood. Here, we describe two cases with definite PLS, who were followed up for 15 and 6 years and assessed using qualitative visual magnetic resonance imaging (MRI) scores. Both patients initially exhibited CST hyperintensity. Despite progressive clinical deterioration due to wheelchair/walker dependence, serial MRI demonstrated complete CST normalisation (score 0/16). Concurrently, SWI revealed progressive motor cortex hypointensity, consistent with iron deposition. These cases illustrate a possible dissociation between conventional and susceptibility-based MRI markers, suggesting dynamic pathophysiological processes and potentially early inflammation followed by gliotic remodelling, although technical factors cannot be excluded. A normal-appearing CST should not exclude advanced PLS, and progressive motor cortex hypointensity may provide a more stable marker. Prospective studies with standardised protocols are required to validate these observations.

Background

Primary lateral sclerosis (PLS) is a rare motor neuron disorder characterised by progressive degeneration of the upper motor neuron (UMN) without involvement of the lower motor neurons. Diagnosis requires isolated UMN signs for at least 4 years and the exclusion of amyotrophic lateral sclerosis (ALS)-mimicking conditions.¹

On routine magnetic resonance imaging (MRI), corticospinal tract (CST) hyperintensity on T2/fluid-attenuated inversion recovery (FLAIR) sequences is observed in 17%–78% of patients with motor neuron disease, with a higher prevalence in the PLS.^{2 3} Histopathological studies have demonstrated that CST hyperintensity could correspond to myelin pallor, axonal vacuolisation, macrophage infiltration and gliosis in the posterior limb of the internal capsule.^{4 5}

The temporal evolution of the CST signals remains largely unexplored, and limited longitudinal data are available. Early, even presymptomatic, CST hyperintensity has been documented, suggesting initial axonal degeneration with increased water content.⁵ Limited longitudinal studies on ALS have shown variable evolution of CST hyperintensity, with either persistence or further increase over time⁶ and, in a case report, subsequent signal attenuation or ‘pseudonormalisation’ in advanced disease.⁷ This possible paradoxical normalisation may reflect the histopathological transition from active axonal degeneration and inflammatory changes to chronic dense gliosis, which could theoretically reduce the interstitial water content and T2/FLAIR conspicuity.⁴ While this dynamic pattern has been observed in ALS, longitudinal PLS data are absent. However, the extended survival characteristics of patients with PLS provide a unique opportunity to document such imaging changes over a long follow-up period.

Several scoring systems have been developed to assess imaging markers systematically. In routine clinical practice, quantitative methods for evaluating neurodegenerative changes are often unavailable because of technical and time constraints. Visual and semiquantitative analyses have proven to be reliable and feasible alternatives in this setting.8,10 For CST hyperintensity on FLAIR sequences, semiquantitative visual scores evaluate signal intensity at different anatomical levels.⁸ For motor cortex iron deposition in the motor cortex, the Motor Cortex Susceptibility (MCS) score and related frameworks were used to assess the degree of cortical hypointensity in susceptibility-weighted sequences.^{9 10} While these scoring systems provide systematic approaches for evaluating imaging changes, their application in monitoring long-term evolution remains unexplored.

We report two patients with PLS who were followed up at the SARAH Network of Rehabilitation Hospitals, Rio de Janeiro, with serial clinical MRIs over 5–15 years, demonstrating complete normalisation of CST hyperintensity despite ongoing clinical progression, as assessed using systematic visual scoring methods.

Case presentation

Case 1

A woman in her mid-50s presented with a 2-year history of progressive right-sided motor dysfunction. Symptoms began insidiously with weakness and stiffness in the right upper limb, gradually extending to the right lower limb. Examination revealed spastic hemiparesis with hyperreflexia, clonus and Babinski signs on the right side. No bulbar symptoms or signs of lower motor neuron involvement were observed.

Investigations

Brain MRI examinations were performed at our institution and at external imaging centres using multiple scanner platforms over the observation period (table 1). All MRI examinations were conducted on clinical scanners with magnetic field strengths of ≥1.5 T. The imaging protocols included FLAIR sequences for CST assessment and susceptibility-weighted imaging (SWI) or T2* gradient-echo sequences for motor cortex evaluation. All images were exported directly from the Digital Imaging and Communications in Medicine database using identical lookup tables and consistent global display adjustments for each sequence type. Because identical numerical window/level settings yielded markedly different contrasts across vendors, fixed values were not imposed. No selective or region-specific enhancement was applied, and no artificial highlighting was used.

Table 1. Longitudinal MRI findings and clinical scores.

Patient	Date	Exam location	Scanner model	Field strength (T)	Corticospinal tract-fluid-attenuated inversion recovery score	Motor Cortex Susceptibility score
1	Year 1	External	GE Signa Excite	1.5	6	0
1	Year 2	Index Hospital	GE Signa HDxt	3.0	12	1
1	Year 15	Index Hospital	Siemens Magnetom Sola	1.5	0	6
2	Year 1	External	Philips Achieva	1.5	10	0
2	Year 6	Index Hospital	Siemens Magnetom Sola	1.5	0	9

Note: Complete technical parameters and detailed regional scores are provided in online supplemental table S1.

.GE, General Electric.

Two readers independently assessed all images, blinded to the clinical data and temporal sequence and reached a consensus regarding discrepancies.

FLAIR-CST hyperintensity scoring was based on the study by Hecht et al,⁸ in which we scored the signal intensity at four bilateral anatomical levels (subcortical precentral, centrum semiovale, internal capsule and cerebral peduncle) from 0 (absent) to 2 (marked hyperintensity), for a maximum of 16 points.

For motor cortex hypointensity (SWI/T2*) scoring, we used the MCS score described by Conte et al⁹ and Lo Russo et al¹⁰ adapted for conventional axial imaging. The six bilateral motor cortex subregions (lower limb, upper limb and bulbar) were scored from 0 (absent) to 2 (marked hypointensity), with a maximum score of 12 points. The two independent readers achieved 91% agreement for the FLAIR-CST scores and 94% agreement for the MCS scores.

Detailed acquisition parameters and total scores are presented in online supplemental table S1.

Extensive investigations excluded ALS mimics; serologies for HIV, human T-lymphotropic virus, syphilis and antiglutamic acid decarboxylase antibodies were negative. Cerebrospinal fluid analysis was unremarkable. Genetic testing excluded ATXN2 and C9orf72 expansions. Serial electromyography performed 2, 4, 5 and 12 years after symptom onset consistently showed no acute or chronic denervation.

Differential diagnosis

Over the initial 2.5 years, the patient exhibited predominantly hemiplegic progression (Mills syndrome variant), with gradual contralateral involvement initially limited to mild spasticity and hyperreflexia. Subsequently, the disease generalised and led to spastic quadriplegia and dysarthria with pseudobulbar effects. The patient met the consensus criteria for definite primary lateral sclerosis 4 years after onset. By year 15, she was wheelchair-dependent with unintelligible speech but remained cognitively intact.

Initial brain magnetic resonance imaging (year 1 after onset) revealed bilateral CST hyperintensity on FLAIR sequences involving the centrum semiovale, internal capsule and cerebral peduncles (FLAIR-CST score: 6/16). The T2* gradient echo showed no hypointensity in the motor cortex (MCS score: 0/12).

A repeat MRI at 2 years demonstrated increased CST hyperintensity involving the juxtacortical precentral region (FLAIR-CST score: 12/16). Minimal hypointensity was observed in the motor cortex (MCS score: 1/12).

Outcome and follow-up

Follow-up MRI at year 15 revealed complete resolution of the corticospinal tract hyperintensity at all anatomical levels (FLAIR-CST score: 0/16), despite severe clinical deterioration. SWI demonstrated marked bilateral motor cortex hypointensity, predominantly in the upper limb representations (MCS score: 6/12) (figure 1).

Figure 1. Patient 1: Longitudinal evolution of MRI findings over 15 years. 12 axial brain MR images illustrating CST signal changes. Columns A, B and C represent MR images acquired at year 1 (GE Signa Excite 1.5T), year 2 (GE Signa HDxt 3.0T) and year 15 (Siemens Magnetom Sola 1.5 T) from symptom onset, respectively. Images A1–A3, B1–B3 and C1–C3: Axial FLAIR sequences at three anatomical levels of the CST: the subcortical precentral region, centrum semiovale and posterior limb of the internal capsule. Bilateral CST hyperintensity was present at 1 and 2 years (columns A and B, arrow) and was completely absent at 15 years (column C). Images A4, B4 and C4: Axial susceptibility-weighted sequences in the precentral gyrus. At year 1 (T2*-GRE, (A4), no hypointensity was observed. At 2 years (T2*-GRE, (B4), mild hypointensity emerged bilaterally (arrowhead). At 15 years of age (susceptibility-weighted imaging), (C4) marked hypointensity was observed at the posterior margin of the precentral gyri (arrowheads), consistent with the motor band sign, indicative of chronic upper motor neuron degeneration. Images were exported from DICOM and Communications in Medicine with consistent global display parameters, and no selective or region-specific contrast manipulation was applied. CST, corticospinal tract; FLAIR, fluid-attenuated inversion recovery; GE, general electric.

Case 2

A woman in her mid-40s presented with an 8-month history of slurred speech and gait instability. Examination revealed spastic dysarthria and spastic quadriplegia predominantly attributable to severe spasticity, with preserved strength (Medical Research Council grade 5, except for hip flexion grade 4). Generalised hyperreflexia was present, with bilateral Hoffmann and Babinski signs. Spasticity was moderate in the upper limbs and severe in the lower limbs (Modified Ashworth Scale 2–3/4). No muscular atrophy, fasciculation or dysphagia was observed.

Investigations

Investigations excluded mimics: HIV, human T-lymphotropic virus and syphilis serology were negative. The metabolic screening results (long-chain fatty acids, beta-galactosidase, arylsulphatase A and galactocerebrosidase) were normal. Genetic testing excluded ATXN2, C9orf72 and other pathogenic variants from the comprehensive ALS gene panel. Creatine kinase levels were normal. Spinal MRI revealed no abnormalities.

Serial electromyography at 1, 3 and 6 years after symptom onset consistently showed no denervation. The patient met the criteria for definite PLS at year 4.

Functionally, she remained ambulatory and worked full-time in year 1. By year 6, she required a walker indoors and a motorised scooter for longer distances but remained independent for self-care and continued working on-site.

Brain MRI year 1 after onset showed corticospinal tract hyperintensity on FLAIR, involving the centrum semiovale, internal capsule and cerebral peduncles (FLAIR-CST score: 10/16). SWI revealed no hypointensity in the motor cortex (MCS score: 0/12).

Repeat MRI at 6 years revealed complete normalisation of the CST signal (FLAIR-CST score: 0/16) despite clinical progression. SWI revealed extensive bilateral motor cortex hypointensity involving all motor subregions (MCS score: 9/12) (figure 2).

Figure 2. Patient 2: Longitudinal evolution of MRI findings over 6 years. Eight axial brain MR images are arranged in columns representing examinations at year 1 (column A, Philips Achieva 1.5 T) and year 6 (column B, Siemens Magnetom Sola 1.5 T) from symptom onset. Rows 1–3: Axial FLAIR sequences at three anatomical levels: subcortical precentral region (row 1), centrum semiovale (row 2) and posterior limb of the internal capsule (row 3). The bilateral CST hyperintensity present at year 1 (column A, arrows) was completely absent at year 6 (column B). Row 4: Axial susceptibility-weighted imaging of the precentral gyrus. No hypointensity in the motor cortex is evident at year 1 (A4). Extensive bilateral hypointensity consistent with the motor band sign developed by year 6 (B4, arrowheads), indicating progressive iron deposition despite CST signal normalisation. Images exported from DICOM with consistent global display parameters; no selective or region-specific contrast manipulation was applied. CST, corticospinal tract; FLAIR, fluid-attenuated inversion recovery; GE, general electric.

Discussion

We report two patients with PLS with complete normalisation of CST hyperintensity on FLAIR despite ongoing clinical progression over 6–15 years. Concurrently, both patients developed progressive hypointensity of the motor cortex on susceptibility-weighted sequences, suggesting a dissociation between these imaging markers.

This paradoxical normalisation challenges the assumption that CST hyperintensity is a stable marker of UMN degeneration. Previous studies have described CST hyperintensity in 17%–78% of patients with motor neuron disease,^{2 3} but longitudinal data are scarce. One case report of ALS described possible ‘pseudonormalisation’ of the signal on magnetisation transfer imaging,⁷ and limited longitudinal studies have shown variable signal evolution.⁶ Our cases extend these observations by documenting possible complete signal normalisation over longer follow-up periods, unique to PLS survival.

Temporal evolution may reflect underlying histopathological changes. Early CST hyperintensity may reflect axonal degeneration, oedema and inflammation,^{4 5} whereas late-stage disease shows dense gliosis that could reduce the T2/FLAIR signal intensity.⁴ However, technical factors cannot be excluded, as different scanner platforms may influence signal characteristics despite our standardised visual assessment. In this context, interscanner variability and magnetic field strength may influence the conspicuity of CST hyperintensity on FLAIR and motor cortex hypointensity on susceptibility-based sequences. Nevertheless, CST hyperintensity was identified early across different platforms in both cases, and marked motor cortex hypointensity remained detectable even on routine 1.5 T examinations at later disease stages, supporting a biological rather than purely technical contribution.

Progressive hypointensity in the motor cortex likely represents iron accumulation, a recognised marker of UMN degeneration that appears to be more stable than changes in the CST.9,12 This finding across scanner changes supports its biological, rather than technical, basis. Susceptibility-based imaging studies in motor neuron diseases have suggested an association between motor cortex hypointensity, predominant UMN involvement and greater clinical burden, providing a relevant conceptual framework for PLS. In contrast, prospective longitudinal quantitative susceptibility mapping studies with short follow-up intervals (eg, 6 months) have demonstrated relative stability of motor cortex susceptibility measures, suggesting that iron-related changes may evolve slowly and may not be detectable over brief observation periods. In this context, the extended follow-up available in our two PLS cases (6–15 years) allows a description of long-term qualitative signal evolution on routine MRI, which is rarely documented in the literature.

Our observations align with the recent meta-analytical evidence of the divergent behaviour of these imaging markers. A systematic review found that motor cortex hypointensity (primarily on SWI/T2*) showed substantially higher specificity for motor neuron disease (OR 10.85, 95% CI 3.74 to 31.44) compared with CST hyperintensity on T2/FLAIR (OR 2.21, 95% CI 1.40 to 3.49), despite acknowledged heterogeneity and risk-of-bias concerns across studies.² This differential specificity may reflect the more dynamic or transient nature of CST hyperintensities, whereas motor cortex iron deposition appears to progressively increase. The persistent SWI hypointensity observed across different scanner platforms suggests that it reflects the underlying iron-related pathology rather than technical variability, supporting its role as a stable biomarker for chronic UMN degeneration. These findings reinforce the notion that a normal-appearing CST on conventional MRI should not exclude a PLS diagnosis, even in advanced disease.

Normal CST appearance should not exclude a PLS diagnosis in advanced disease. The dissociation between imaging normalisation and clinical progression underscores the need for a multimodal assessment that combines clinical evaluation, electrophysiology and multiple MRI sequences.

Some limitations must be considered. Different scanner platforms, small sample sizes and lack of quantitative measurements limit the ability to draw definitive conclusions regarding biological versus technical factors. In case 1, susceptibility imaging transitioned from T2* GRE to SWI over time, which may have contributed to perceived differences in cortical hypointensity, which were mitigated by sequence-specific, globally consistent display and by replication of the pattern in case 2. Differences in scanner platforms and field strengths may influence signal conspicuity, limiting the ability to fully disentangle biological evolution from technical variability.

Patient’s perspective.

Patient 1: ‘When weakness started on my right side, I hoped it would stay limited to that area. Looking at the disease spreading to my whole body is devastating. Understanding the MRI findings helped me accept what was happening, though it was confusing when later scans looked “normal” while I felt progressively worse. Now I am a wheelchair user, but I remain close to my family. I agree with the publication because I wanted other doctors to understand that a normal-looking MRI does not mean that the disease is absent. Do not dismiss patients based on imaging alone; listen to their symptoms’.

Patient 2: ‘My slurred speech and leg stiffness began years ago. I still work full time, but now I need a walker for my mobility. I was surprised to learn that my brain images changed dramatically over time, even as my symptoms worsened steadily. The disappearance of some abnormalities while new abnormalities appeared was unexpected. Sharing my case might help doctors recognise that PLS does not follow predictable MRI patterns. Every patient’s journey is unique, and imaging is only one piece of the puzzle. I hope this will help others to be diagnosed more quickly’.

Learning points.

• Corticospinal tract (CST) hyperintensity on fluid-attenuated inversion recovery (FLAIR) can normalise over 5–15 years in primary lateral sclerosis (PLS) despite clinical progression.

• Susceptibility-weighted imaging (SWI) motor cortex hypointensity progresses in parallel with disability and may be a more stable biomarker.

• A normal CST on MRI should not exclude PLS in advanced stages.

• Serial MRI interpretation must weigh biological evolution and interplatform variability.

• Combined qualitative FLAIR+SWI analysis offers complementary insight into upper motor neuron degeneration.