By Mary L. Vo, MD, PharmD

Assistant Professor of Neurology,Weill Cornell Medical College

Dr. Vo reports she is an advisory board member for CSL Behring, is a consultant and advisory board member for Alexion Pharmaceuticals, and receives grant/research support from Takeda Pharmaceuticals.

SYNOPSIS: The current study characterizes novel patterns of abnormalities on muscle magnetic resonance imaging (MRI) in patients with amyotrophic lateral sclerosis and spinobulbar muscular atrophy. Further, MRI changes correlate with disease severity.

SOURCE: Klickovic U, Zampedri L, Sinclair CDJ, et al. Skeletal muscle MRI differentiates SBMA and ALS and correlates with disease severity. Neurology 2019;93:e895-e907.

Magnetic resonance imaging (MRI) of skeletal muscle has been used to discern patterns of muscular fatty infiltration and edema associated with acute denervation in various neuromuscular diseases. However, there is limited experience with muscle MRI in motor neuron disease.

In this prospective cross-sectional study, Klickovic et al assessed head and lower limb (LL) MRI in 21 men with spinobulbar muscular atrophy (SBMA), 21 men and women with at least clinically possible amyotrophic lateral sclerosis (ALS), and 16 healthy controls seen at two specialty neuromuscular clinics in the United Kingdom between 2015 and 2017. They used the ALS Functional Rating Scale-Revised (ALSFRS-R), SBMA Functional Rating Scale (SBMA-FRS), and adult myopathy assessment tool (AMAT) to assess disease severity. All subjects underwent 3T MRI of head-neck, thigh, and calf regions. A semiquantitative MRI analysis was performed to assess muscle fat infiltration and edema seen on T1-weighted and fat-suppressed T2-weighted short tau inversion recovery (STIR) images, respectively. Quantitative fat fraction maps and functional remaining muscle area for muscle compartments in the thighs and calves were calculated. Data from four patients with SBMA, three patients with ALS, and one healthy control were excluded due to incomplete imaging or insufficient image quality. Statistical analysis was performed using Kruskal-Wallis tests, two-sample t tests, and Mann-Whitney U tests for intergroup comparisons with an α level of 0.05. Correlations of MRI data with clinical measures were established with Spearman (ρ) or Pearson coefficients.

T1-weighted MRI images of the thigh muscles showed that the SBMA group had significantly greater muscle fat infiltration compared to controls (P < 0.001). In the SBMA group, there was a distinct pattern of severe fatty infiltration in the anterior and posterior muscle compartments of the thigh and the superficial and deep muscle compartments of the calf. In contrast, ALS patients did not demonstrate significant differences in thigh muscular fat infiltration compared to matched controls. There was moderate fatty infiltration of lateral calf muscles in the ALS patients. STIR-weighted imaging of lower extremity muscles showed increased hyperintensity in both SBMA and ALS groups, with the most marked abnormalities in calf muscles of the ALS group.

T1-weighted MRI sequences of head and neck musculature showed moderate to severe fatty infiltration of intrinsic and extrinsic tongue muscles in both SBMA and ALS groups. SBMA patients had moderate to severe fatty infiltration of masticatory and swallowing muscles. In comparison, the ALS group showed mild to moderate involvement of these muscles. Quantitative analysis confirmed significant severe fatty infiltration of bulbar muscles in the SBMA group relative to controls (P < 0.001) with the genioglossus being the most severely affected muscle. There were no significant differences in the overall fatty fraction of bulbar muscles in the ALS group compared to control.

There was a strong negative correlation between fatty infiltration of muscle and disability in patients with SBMA (ρ = -0.86; P < 0.001) and with ALS (ρ = -0.47; P = 0.04).

Although fatty infiltration was not a prominent feature of ALS, muscle atrophy measured by functional remaining muscle area (fRMA) correlated strongly with ALSFRS-R LL subscales. Similarly, combined thigh and calf fRMA correlated strongly with SBMA-FRS LL subscales and with AMAT scores.

In summary, the authors found significant fat infiltration of bulbar and limb muscles in SBMA and marked STIR hyperintensities in lower limb muscles in ALS sufficient to differentiate the two conditions. MRI abnormalities correlated significantly with clinical scales of disease severity in ALS and SBMA.

COMMENTARY

SBMA is a rare, slowly progressive form of motor neuron disease presenting with dysarthria, facial weakness, and limb weakness. It is an X-linked disorder caused by CAG repeat expansion on the androgen receptor gene. In contrast, ALS is a fatal complex neurodegenerative disorder characterized by relentless progression of upper and lower motor neuron weakness and cognitive degeneration.

Clinical assessment, electrophysiologic testing, genetic testing, and brain imaging are the main strategies used to distinguish SBMA from ALS. Diagnosis can be challenging, particularly early in the disease course. The distinct MRI signatures described in the study illustrates a pattern of prominent fatty infiltration of bulbar and lower limb muscles in patients with SBMA in contrast to patients with ALS, who demonstrated marked STIR hyperintensities and reduced functional muscle area in calves.

One limitation of traditional assessment tools is that they do not capture the extent or progression of disease. Some advantages of skeletal MRI include evaluation of muscles that are inaccessible to traditional clinical and electrophysiologic assessments and the ability to quantify disease and monitor disease progression.1,2 As the role of skeletal muscle MRI in motor neuron disease continues to emerge, it demonstrates the potential to be a sensitive research biomarker and may inform
the development of future therapeutic
targets.

REFERENCES

  1. Jenkins TM, Alix JJP, David C, et al. Imaging muscle as a potential biomarker of denervation in motor neuron disease. J Neurol Neurosurg Psychiatry 2018;89:248-255.
  2. Bede P, Querin G, Pradat PF. The changing landscape of motor neuron disease imaging: The transition from descriptive studies to precision clinical tools. Curr Opin Neurol 2018;31:431-438.