Cytotoxic not Vasogenic Edema is the Cause for Stroke-Like Episodes in Propionic Acidemia

Dear Editors,

Stroke-like episodes are a recognized feature of inherited metabolic disorders, including propionic acidemia [1]. In their article Broomfield et al. [2] describe a metabolic stroke-like episode in an 8-month-old patient with propionic acidemia. However, due to the lack of imaging sequences, they are unable to differentiate between a cytotoxic and vasogenic edema.

Recently, we had the opportunity to follow a similar case, and can answer this question. The now 4-year-old boy is the third child of healthy parents. Propionic acidemia was diagnosed in parallel through appearing symptoms (lethargy, feeding difficulties) and a positive newborn screening at the age of 1 week. The boy is treated with a protein restricted diet, l-carnitine supplementation and β-blockers and diuretics due to a dilated cardiomyopathy. His gross motor development is slightly retarded showing a broad based gait and muscular hypotonia. However, cognition and speech development are adequate for age.

At the age of 4 years and 2 months he had a prolonged gastrointestinal infection. 2 weeks after demission he showed noticeable behavioural changes with regression, especially in speech, confusion and abnormal reaction to people and objects well known to him (unable to recognize objects or people, aggressive, unfriendly reactions to family members). There were no motor symptoms like ataxia or hemiplegia. EEG showed bilateral diffuse slowing of background activity with right-sided accentuation, and with sharp wave foci bilaterally over the temporo-occipital regions.

Cerebral MRI was performed using a whole-body 1.5 Tesla MR scanner (Magnetom TimSyphony, Siemens Erlangen, Germany) and a 12-channel head coil. We performed a double-echo T₂/proton density fast spinecho sequence, permitting the calculation of T₂ relaxation maps, and a diffusion-weighted sequence with 12 diffusion-sensitizing gradients and b-factors of 0 and 1000 s/mm².

In our patient, T₂-weighted images and T₂ relaxation maps showed a clear signal increase within the caudate nucleus, the putamen as well as the cerebellum, which can indicate vascular edema or gliosis. Gliosis is a reactive process due to neuronal loss and results in a disruption of the highly organized neuronal architecture. Gliotic processes lead to an increase in ADC (apparent diffusion coefficient), because a disruption of neuronal architecture raises the degree of freedom for water diffusion. Signal increases in diffusion-weighted imaging are commonly produced by cytotoxic factors, but can be also caused by an effect called T₂-shine-through and is based on a high T₂ signal. In order to distinguish T₂-shine-through, ADC maps have to be evaluated. T₂-shine-through also generates an increase in ADC, as visible in the caudate nucleus of our patient. However, ADC is rather slightly decreased within the putamen and the cerebellum of our patient, indicating the presence of cytotoxic edema (see [Fig. 1] – images and arrows).

Fig. 1 Cerebral MRI of a 4-year-old patient with propionic acidemia and behavioural changes: Slices of the basal ganglia (a–d) and the cerebellum (e–h) are shown. The putamen and the caudate nucleus are marked with a white arrow and the cerebellum with a white bold arrow. For each slice position, a collection of an ADC map (a, e), a diffusion-weighted image (b, f), a T₂-weighted image (c, g) as well as a T₂ relaxation map (d, h) is provided. The slices show a signal increase in T₂ and T₂ relaxation time within the putamen, the caudate nucleus and cerebellum. However, the signals are also increased in diffusion-weighted imaging (DWI), whereby no concomitant ADC increase is visible within the putamen and the cerebellum. This finding indicates that the DWI signal increase within these regions cannot be explained by T₂-shine-through effects, but by the presence of cytotoxic edema.

After the general anesthesia given for imaging, the EEG changes resolved and with a regimen of glucose and l-carnitine infusion the boy recovered within a couple of days.

This case illustrates that part of the pathogenesis in propionic academia is due to a cytotoxic damage to the CNS, probably caused both by trapping of organic acids [3] and lack of anaplerotic substances for the Krebs cycle [4].

D. Karall, E. Haberlandt, M. Schimmel, M. Schocke, K. Gautsch, U. Albrecht, S. Baumgartner Sigl, S. Scholl-Bürgi

• References

• 1 Scholl-Bürgi S, Haberlandt E, Gotwald T et al. Stroke-like episodes in propionic acidemia caused by central focal metabolic decompensation. Neuropediatrics 2009; 40: 76-81
• 2 Broomfield A, Gunny R, Prabhakar P et al. Spontaneous rapid resolution of acute basal ganglia changes in an untreated infant with propionic academia: A clue to pathogenesis?. Neuropediatrics 2010; 41: 256-260
• 3 Sauer SW, Opp S, Mahringer A et al. Glutaric aciduria type I and methylmalonic aciduria: simulation of cerebral import and export of accumulating neurotoxic dicarboxylic acids in in vitro models of the blood-brain barrier and the choroid plexus. Biochim Biophys Acta 2010; 1802: 552-560
• 4 Brunengraber H, Roe CR. Anaplerotic molecules: current and future. J Inher Metab Dis 2006; 29: 327-331