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. 2017 Feb;38(2):376-382.
doi: 10.3174/ajnr.A4978. Epub 2016 Oct 20.

MRI Brain Volume Measurements in Infantile Neuronal Ceroid Lipofuscinosis

E H Baker  1 , S W Levin  2 , Z Zhang  2 , A B Mukherjee  2
Affiliations

MRI Brain Volume Measurements in Infantile Neuronal Ceroid Lipofuscinosis

E H Baker et al. AJNR Am J Neuroradiol. 2017 Feb.

Abstract

Background and purpose: Infantile neuronal ceroid lipofuscinosis is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase 1 deficiency, which impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury, resulting in rapid neurodegeneration and childhood death. As part of a project studying the treatment benefits of a combination of cysteamine bitartrate and N-acetyl cysteine, we made serial measurements of patients' brain volumes with MR imaging.

Materials and methods: Ten patients with infantile neuronal ceroid lipofuscinosis participating in a treatment/follow-up study underwent brain MR imaging that included high-resolution T1-weighted images. After manual placement of a mask delineating the surface of the brain, a maximum-likelihood classifier was applied to determine total brain volume, further subdivided as cerebrum, cerebellum, brain stem, and thalamus. Patients' brain volumes were compared with those of a healthy population.

Results: Major subdivisions of the brain followed similar trajectories with different timing. The cerebrum demonstrated early, rapid volume loss and may never have been normal postnatally. The thalamus dropped out of the normal range around 6 months of age; the cerebellum, around 2 years of age; and the brain stem, around 3 years of age.

Conclusions: Rapid cerebral volume loss was expected on the basis of previous qualitative reports. Because our study did not include a nontreatment arm and because progression of brain volumes in infantile neuronal ceroid lipofuscinosis has not been previously quantified, we could not determine whether our intervention had a beneficial effect on brain volumes. However, the level of quantitative detail in this study allows it to serve as a reference for evaluation of future therapeutic interventions.

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Conflict of interest statement

The authors report no conflicts of interest.

Figures

Fig 1.
Fig 1.
MR imaging findings in end-stage INCL. T1-weighted (A) and T2-weighted (B) images in the plane defined by the anterior and posterior commissures. These images demonstrate findings that include extreme atrophy, near-complete lack of gray matter, extensive abnormal signal in the white matter, loss of internal landmarks separating the basal ganglia, and subdural effusions.
Fig 2.
Fig 2.
Thalamus volume measurements in patients with INCL. Due to lack of visible boundaries of the thalamus (secondary to disease-related alterations in intrinsic contrast), an ellipsoidal approximation to the volume was made on the basis of brain surface landmarks. Thalamus volumes were out of the normal range by the time of our earliest measurements and further decreased with time. The equation for the best curve fit is shown. We did not detect a difference between INCL in boys and girls (P = .98). The normal curve reflects thalamus volumes measured on 23 healthy volunteers 1.1–9.6 years of age participating in other studies at our institution; for the healthy volunteers, we did not find a statistical difference between boys and girls (P = .89) or between right and left (P = .86) (dark line = mean, light lines = ±2 SDs). For comparison, the onset ages of major clinical findings (mean and 95% CI) observed in our patients are plotted below the volume curve. A indicates developmental regression; B, cerebral atrophy noted in clinical MR imaging report; C, myoclonic jerks and seizures; D, loss of vision; E, deceleration of head growth; F, isoelectric visual-evoked potentials; and G, isoelectric EEG or electroretinogram.
Fig 3.
Fig 3.
Brain stem volume measurements in patients with INCL. Brain stem volumes decreased with time, dropping below the 2.5th percentile before 3 years of age. The equation for the best curve fit is shown. We did not detect a difference between INCL in boys and girls (P = .88). We defined the brain stem as including the cerebral peduncles, midbrain, pons, and medulla. The normal curve reflects brain stem volumes measured on 23 healthy volunteers 1.1–9.6 years of age participating in other studies at our institution; for the healthy volunteers, we did not find a statistical difference between boys and girls (P = .94) (dark line = mean, light lines = ±2 SDs). For comparison, the onset ages of major symptoms (mean and 95% CI) observed in our patients are plotted below the volume curve. A indicates developmental regression; B, cerebral atrophy noted in clinical MR imaging report; C, myoclonic jerks and seizures; D, loss of vision; E, deceleration of head growth; F, isoelectric visual-evoked potentials; and G, isoelectric EEG or electroretinogram.
Fig 4.
Fig 4.
Cerebellum volume measurements in patients with INCL. Cerebellar volumes were initially near normal but decreased with time and dropped below the 2.5th percentile by about 2.5 years of age. The equation for the best curve fit is shown. We did not detect a difference between INCL in boys and girls (P = .94). We included the cerebellar peduncles in our measurement of cerebellar volume. The normal curve reflects cerebellum volumes measured on 23 healthy volunteers 1.1–9.6 years of age participating in other studies at our institution; for the healthy volunteers, we did not find a statistical difference between boys and girls (P = .91) (dark line = mean, light lines = ±2 SDs). For comparison, the onset ages of major symptoms (mean and 95% CI) observed in our patients are plotted below the volume curve. A indicates developmental regression; B, cerebral atrophy noted in clinical MR imaging report; C, myoclonic jerks and seizures; D, loss of vision; E, deceleration of head growth; F, isoelectric visual-evoked potentials; and G, isoelectric EEG or electroretinogram.
Fig 5.
Fig 5.
Cerebrum volume measurements in patients with INCL. Even our earliest measurements of cerebral volumes were lower than normal, and volumes decreased dramatically with time. The equation for the best curve fit is shown. We did not detect a difference between INCL in boys and girls (P = .94). We defined the cerebrum as including the deep nuclei but not the cerebral peduncles. The normal curve reflects cerebrum volumes measured on 23 healthy volunteers 1.1–9.6 years of age participating in other studies at our institution; for the healthy volunteers, we did not find a statistical difference between boys and girls (P = .78) (dark line = mean, light lines = ±2 SDs). For comparison, the onset ages of major symptoms (mean and 95% CI) observed in our patients are plotted below the volume curve. A indicates developmental regression; B, cerebral atrophy noted in clinical MR imaging report; C, myoclonic jerks and seizures; D, loss of vision; E, deceleration of head growth; F, isoelectric visual-evoked potentials; and G, isoelectric EEG or electroretinogram.
Fig 6.
Fig 6.
Total brain volume measurements in patients with INCL. Total brain volumes (dominated by the cerebral volume) were initially lower than normal and decreased dramatically with time. The equation for the best curve fit is shown. We did not detect a difference between INCL in boys and girls (P = .96). The normal curve reflects total brain volumes measured on 23 healthy volunteers 1.1–9.6 years of age participating in other studies at our institution; for the healthy volunteers, we did not find a statistical difference between boys and girls (P = .80) (dark line = mean, light lines = ±2SD). For comparison, the onset ages of major symptoms (mean and 95% CI) observed in our patients are plotted below the volume curve. A indicates developmental regression; B, cerebral atrophy noted in clinical MR imaging report; C, myoclonic jerks and seizures; D, loss of vision; E, deceleration of head growth; F, isoelectric visual-evoked potentials; and G, isoelectric EEG or electroretinogram.
Fig 7.
Fig 7.
Relative segmental volumes in patients with INCL. A, In INCL, the cerebellum is large relative to the cerebrum, reflecting the observation that volume loss begins earlier and progresses faster in the cerebrum than elsewhere in the brain. The ratio initially rises as cerebral loss outpaces cerebellar loss and decreases later because the cerebrum reaches asymptotic volume earlier than the cerebellum. B, In INCL, the thalamus becomes somewhat large relative to the cerebrum for a while, reflecting the tight linkage between the volumes of these structures with a bit of a delay in involvement of the thalamus relative to the cerebrum. C, In INCL, the brain stem is also large relative to the cerebrum, with a later peak relative to both the thalamus/cerebrum ratio and cerebellum/cerebrum ratio, indicating that the brain stem is involved last among the structures that we measured. In all plots, the equation describes the best curve fit to the INCL results. We did not detect a difference between boys and girls for either patients with INCL or healthy volunteers. The normal curves reflect volume ratios measured on 23 healthy volunteers 1.1–9.6 years of age participating in other studies at our institution (dark line = mean, light lines = ±2 SDs).
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