MRI characteristics of globus pallidus infarcts in isolated methylmalonic acidemia

Abstract

Background: Bilateral infarcts confined to the globus pallidus are unusual and occur in conjunction with only a few disorders, including isolated methylmalonic acidemia, a heterogeneous inborn error of metabolism. On the basis of neuroradiographic features of metabolic strokes observed in a large cohort of patients with methylmalonic acidemia, we have devised a staging system for methylmalonic acidemia-related globus pallidus infarcts.

Materials and methods: Forty patients with isolated methylmalonic acidemia and neurologic symptoms underwent clinical brain MR imaging studies, which included 3D-T1WI. Infarcted globus pallidus segments were neuroanatomically characterized, and infarct volumes were measured.

Results: Globus pallidus infarcts were present in 19 patients; all were bilateral, and most were left-dominant. A neuroanatomic scoring system based on the infarct patterns was devised; this revealed a 5-stage hierarchical susceptibility to metabolic infarct, with the posterior portion of the globus pallidus externa being the most vulnerable. Globus pallidus infarct prevalence by methylmalonic acidemia class was the following: cblA (5/7, 71%), cblB (3/7, 43%), mut(o) (10/22, 45%), and mut- (1/4, 25%). Tiny lacunar infarcts in the pars reticulata of the substantia nigra, previously unrecognized in methylmalonic acidemia, were found in 17 patients, 13 of whom also had a globus pallidus infarct.

Conclusions: The staged pattern of globus pallidus infarcts in isolated methylmalonic acidemia suggests a nonuniform, regionally specific cellular susceptibility to metabolic injury, even for patients having milder biochemical phenotypes. In support of this hypothesis, the delineation of lacunar infarcts in the pars reticulata of the substantia nigra, a tissue functionally and histologically identical to the globus pallidus interna, supports the concept of cell-specific pathology.

Trial registration: ClinicalTrials.gov NCT00078078.

Fig 1.

Progression of a GP infarct. This 16-month-old patient was known to have MMA due to the cblB defect that had been diagnosed 6 months previously. Within 24 hours after onset of symptoms from gastroenteritis, she became lethargic and was taken to the emergency department. A, CT at the time of admission to the hospital appears to have normal findings. B, CT scan 35 hours later shows distinct hypoattenuating abnormalities involving the entirety of each GP. DWI performed 1 week later showed restricted diffusion in each GP (image not available). C, High-resolution MPRAGE image and D, T2-weighted image (b=0 image from DTI) acquired 7.5 years later demonstrate bilateral complete GP infarcts.

Fig 2.

Laterality of GP infarcts. A, Most GP infarcts were left-dominant. A few were nearly symmetrical (5 were within ±10%), and 2 were right-dominant. The average laterality index was −0.13, and the median was −0.17. B, An example of a left-dominant infarct. The laterality index in this case is −0.20.

Fig 3.

Volume of GP infarcts. The range of GP infarct volumes is 9–1021 μL. Laterality of the infarcts is apparent when infarcts are segregated into left and right columns for each of the MMA classes. Group means (indicated by the heavy bar) differ between classes. Application of a t test suggests that there is a statistically significant difference in infarct size between the 2 mut subtypes together (mut- and mut^o), the 2 cbl classes together (cblA and cblB) (P = .01), and the mut^o subtype alone versus the 2 cbl classes together (P = .02). There was a statistically significant difference between the mut- subtype alone and each of the other categories (P = .01 versus mut^o, P < .01 versus cblA, and P = .02 versus cblB). There was a statistically significant difference between the left and right for the cblA class (P = .04).

Fig 4.

GP infarct segments. A, Normal anatomy of the dorsal pallidum, also known as the globus pallidus. The thin line indicates the medial medullary lamina; the thick line, the boundary of the globus pallidus. Surrounding structures include the anterior limb of the internal capsule (IC ant) and the posterior limb of the internal capsule (IC post). The putamen, thalamus, and head of the caudate nucleus are also labeled. The external medullary lamina separates the putamen from the GPe. B, Infarct segments 1–5. Segment 1 seems to be the most sensitive to metabolic infarct in MMA, followed by segment 2, then segment 3; segments 4 and 5 are the least sensitive and usually infarct together. C, An example of a segment 1 infarct (posterior GPe). D, An example of an infarct of segments 1 + 2 (posterior and middle GPe). E, An example of an infarct of segments 1 + 2 + 3 (whole GPe). F, An example of an infarct of segments 1 + 2 +3 + 4 + 5 (complete GP, both externa and interna). Note that the medial medullary lamina (a white matter tract) remains intact and can be seen separating the GPe and GPi.

Fig 5.

Graphic depiction of all 38 GP infarcts. Infarcted segments are shown in black (follows the rule) or gray (exception to the rule). The segments appear to follow a rule in which the likelihood of infarct is 1 > 2 > 3 > 4 = 5. Five infarcts (in 3 different patients) do not follow the segment-ordering rule. Infarcts can be staged by counting the number of infarcted segments, regardless of the order. In 16 of 19 patients, right and left infarcts are of the same stage, even if the volumes differ (as described in Fig 2). The location of the segments is shown in Fig 4.

Fig 6.

Lacunar infarcts of the SNr. Due to the small size of the cell clusters that form the SNr (near or below the lower limit of MR imaging resolution), detection of these infarcts can be difficult. A, Tiny bilateral infarcts of the SNr are seen on a bFFE image. The resolution of this image is 0.6 × 0.6 × 1.0 mm per voxel. The infarcts measure approximately 1 mm. Both are found in the anterior location. B, Slightly larger bilateral infarcts of the SNr are seen on an MPRAGE image with a resolution of 0.9 × 0.9 × 1.0 mm per voxel. These infarcts are in the middle location. C, Bilateral infarcts at 2 sites (anterior and posterior) in the SNr are seen on an MPRAGE image. SNr infarcts were found in only 3 distinct locations, which we are designating by their relative positions; the anterior location was the most common (20 infarcts), followed by the posterior location (9 infarcts). The middle location was the least common (5 infarcts).