SNAPSHOT Metabolic Stroke Identifying underlying causes of metabolic stroke is essential for prompt appropriate treatment. By Divakar Mithal, MD, PhD and Tracy Gertler, MD, PhD

Metabolic occur when Thromboembolic Stroke decompensation of an underly­ ing caused by In homocystinuria, elevation of plasma homocysteine and a stressor (eg, intercurrent illness result in a predisposition to thromboembolic or fasting) results in acute neuro­ events, approximately 30% of which affect the nervous sys­ logic deficits. Individuals with tem.1 The classic form of homocystinuria is an autosomal metabolic disorders are at risk for classical thromboembolic recessive disorder caused primarily by missense variants in arterial strokes, stroke-like episodes (SLE), and diffuse sym­ cystathionine β-synthase (CBS). These missense mutations metric lesions (DSL) (Table). Clinicians providing care for those reduce activity of cystathionine β-synthase, a pyridoxine with underlying metabolic disorders who have known pre­ (B6)-dependent critical for metabolism of dietary disposition to metabolic stroke should maintain a high index methionine. Homocystinuria can be identified on newborn of suspicion in the setting of acute neurologic change and screening and is also associated with , act accordingly. Although there are few evidence-based prac­ ectopia lentis, and skeletal abnormalities leading to a mar­ tices for diagnosis and treatment, a prompt and thoughtful fanoid habitus. A relative state of homocystinuria can also approach may minimize long-term sequelae of stroke episodes. be acquired through severe cobalamin ( B12) defi­

TABLE. DISTINGUISHING CHARACTERISTICS OF METABOLIC DISORDERS WITH INCREASED STROKE RISK Disease Genetic cause Imaging findings Treatment Metabolic , MT-TL1 (>80%), other mtDNA Discrete ischemic changes, not Intravenous (acute and and stroke- confined to specific vascular potentially preventive), taurine like episodes (MELAS)4-7 territories (preventive) Leigh syndrome14-17 >75 genes (monogenic) Diffusion or necrosis of bilateral Supportive care (chronic) deep nuclei Fabry disease21 a-galactosidase (GLA) Small lesions in close proximity Enzyme replacement (chronic) to pre-existing white matter lesions Propionic acidemia11 propionyl CoA carboxylase Diffuse, bilateral restricted dif- Dialysis for metabolite toxic- (PCC) (Type A or B) fusion, preferentially affecting ity (acute), low protein diet (chronic) Congenital disorder of phosphomannomutase-2 (PMM2) Supportive care (chronic) glycosylation12,13 (Type 1a) Glutaric aciduria19,20 glutaryl coenzyme A dehydrogenase Bilateral striatal necrosis /-restricted (GCDH) (Type 1) (Type 1) diet (chronic) electron transfer flavoprotein (ETF) A, B, and DH (Type 2) Homocysteinuria1,3 cystathionine b-synthase (CBS) Diffusion restriction in punctae Restrict methionine, supple- or along a vascular territory ment with folate, cobalamin, and pyridoxine (chronic)

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ciency or other genetic/metabolic enzyme deficiencies in the attributable to arginine, although cases progressed similarly same pathway (eg, MTHFR deficiency or cobalamin trans­ to the natural history of MELAS.6 porter deficiency). The enzyme deficiency results in elevated Chronic management of MELAS with appropriate anti­ levels of serum homocysteine and methionine, conferring a seizure medications (ASMs) and infection prophylaxis remains relative hypercoagulable state, although how this leads to the best approach to avoiding SLEs. Because the pathogenic increased stroke risk remains unclear.2 Primary preventive m.A3243G variant may undergo posttranslational modifica­ strategies include folate, cobalamin, and pyridoxine supple­ tion by taurine in healthy individuals, a study investigated tau­ mentation and dietary restriction of methionine. Up to 50% rine supplementation to determine if this might prevent met­ of untreated individuals will have a life-altering thromboem­ abolic decompensation for MELAS patients. The study was bolic event before age 30 that can be significantly reduced an open-label 52-week study and demonstrated reduction in with appropriate dietary therapy—underscoring the need for the frequency of clinically defined strokes for participants who prompt identification and treatment.3 Further research into had 2 or more strokes in the 1.5 years before the study. No the causal relationship between homocysteine metabolism significant acute or long-term side effects were noted.7 and thromboembolic stroke is needed. Disorders of Nuclear DNA. People with almost any form of , including those of nuclear genetic Stroke-Like Episodes etiology, may develop SLE.5 The most common, although Mitochondrial Disease still rare, are SLE-associated with genetic variants in DNA Disorders of Mitochondrial DNA. Metabolic encephalopa­ polymerase γ (POLG1), a gene more classically linked to thy, lactic acidosis and stroke-like episodes (MELAS) is the intractable epilepsy in Alpers-Huttenlocher syndrome.8 The prototypical metabolic disorder that presents with acute met­ fact that SLE universally occur during periods of metabolic abolic stroke. In approximately 80% of cases, MELAS is caused decompensation underscores the importance of aggressive by a missense variant of the MT-TL1 mitochondrial gene fluid and glucose management as well as avoidance of any (m.A3243G). The remainder of cases are caused by other vari­ drugs toxic to mitochondria and that may precipitate iatro­ ants in MT-TL1 or in other mitochondrial genes.4 The mecha­ genic SLE.9 If a mitochondrial syndrome is suspected, the nism of injury in MELAS is reversed from traditional arterial genetic etiology may be less important than recognizing the stroke; instead of poor blood flow causing injury, brain need for acute management. tissue involved in a metabolic stroke is stressed by increased . Generally identified in infancy because metabolic demand (eg, febrile illness), and localized swelling of vomiting, lethargy, and , propionic acidemia is secondarily restricts blood flow, resulting in further ischemic caused by defects in propionyl CoA carboxylase (PCC), a key injury. As such, the SLE lesions seen in MELAS typically do not enzyme in breaking down amino acids. Once identified, propi­ conform to a vascular territory.5 A primary diagnostic crite­ onic acidemia is treated with a low protein diet. In rare cases, rion for MELAS is the presence of SLE on MRI, because over metabolic decompensation may present as a focal neurologic 90% of people with MELAS will experience SLE during their deficit or change in mental status suggestive of a stroke.10 lifetime (Figure 1). Seizures often occur in conjunction with Typical imaging findings show bilateral basal ganglia lesions, SLE and may be difficult to control. As increased blood flow but lesions may also be seen in the bilateral cortex or subcor­ and electrical hypersynchrony escalate metabolic demand, tical white matter.11 Central goals of care include fluid resus­ further stressing and extending the injured area, seizure activ­ citation, electrolyte balance, and, if needed, dialysis to remove ity can spread and persist in tissue along the penumbra. buildup of propionic acid and secondary . Acute treatment of SLE in MELAS, as with most metabolic Congenital Disorder of Glycosylation Type 1a. Caused by disorders, remains focused on identifying and managing deficiency of phosphomannomutase-2 (PMM2-CDG), con­ stressors such as infections or seizures. An aspect of SLE may genital disorder of glycosylation type 1a is the most com­ be related to poor vasodilation, which some have suggested mon congenital disorder of glycosylation. A wide variety of can be addressed by providing precursors like neurologic phenotypes are associated with PMM2-CDG, arginine. Data for intravenous arginine as a specific therapy including SLE presenting as focal weakness in 15% to 50% for SLE in MELAS comes from a 9-year prospective study of cases. Some studies have shown MRI to be negative in a that has shown strong potential.6 Arginine was administered majority of patients, but when present, MRI findings have urgently during periods of neurologic decline with MRI- focal diffusion restriction akin to MELAS.12,13 A broad dif­ confirmed SLE. Treatment reduced seizure intensity and ferential is needed to identify treatable triggers for each pre­ frequency during acute illness. Arginine also appeared to sentation, because in addition to head trauma and infection, decrease headaches, visual disturbances, and impaired con­ there may be hypoglycemia in a fasting state, coagulopathy sciousness. There were no long-term consequences directly if liver dysfunction is present, or susceptibility to seizures.13

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A C

B D

Figure 1. Imaging Findings for Stroke-Like Episodes. Stroke-like episodes (SLE) in metabolic encephalopathy, lactic acidosis and stroke-like episodes (MELAS) (A, B) and congenital disorder of glycosylation type 1a (PMM2-CDG) (C, D). Separate instances of SLE in the same person are shown. Axial diffusion-weighted imaging shows bright areas (white arrows) indicating acute injury. Lesions are not restricted to vascular territories. For MELAS, both lesions are in cortical gray matter, but for PMM2-CDG both superficial and deep gray are involved.

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Diffuse Symmetric Lesions During acute periods of neurologic injury, fluid support, Mitochondrial Disease metabolic support and treatment of underlying triggers . The most common form of pediatric is crucial. At present there are no mitochondrial-targeted mitochondrial disease, Leigh syndrome (LS) is character­ therapies, and there remains no evidence for the use of ized by psychomotor regression, seizures, respiratory fail­ arginine in the acute management of LS. ure, and bilateral diffuse ischemic lesions on MRI.14 Also Glutaric Aciduria. A progressive autosomal recessive termed subacute necrotizing encephalopathy, LS is most disorder, glutaric aciduria is characterized by often caused by pathogenic variants in nuclear genes in an with delayed development, punctuated by periods of autosomal recessive pattern. There is significant genetic severe metabolic decompensation resulting in hypotonia, and phenotypic variability, however, with over 75 mono­ encephalopathy, and seizures.18 The genetic deficiency is in genic causes and few reliable genotype-phenotype correla­ glutaryl coenzyme A dehydrogenase (GCDH), a mitochon­ tions.15 The neurologic symptoms of LS are often severe drial matrix protein. Absence of GCDH causes a selective early life phenotypes, including rapid neurodegeneration abnormality metabolism resulting in buildup and intractable epilepsy.16 of glutaric acid. Dietary management is crucial, including Symmetric MRI findings include diffusion-restricted avoidance of lysine- and tryptophan-containing foods and lesions that have a predilection for the basal ganglia, supplementation with L-. For unclear reasons, brainstem, and cerebellum (Figure 2). During acute illness, the striatum is at particular risk and undergoes necrotic there are often new neurologic findings as well as progres­ changes that are notable on MRI (Figure 2). Retrospective sion of previous MRI abnormalities that can culminate in studies have suggested that the selective vulnerability of bilateral necrotic lesions of the deep gray nuclei. Of note, the striatum may be evident on imaging even before clini­ arterial spin labeling shows a counterintuitive hyperperfu­ cal symptoms are present.19 sion within lesions,17 perhaps signifying a state of increased Glutaric aciduria type 2 is an autosomal recessive disor­ metabolic demand more substantial than cytotoxic edema. der of fatty acid β-oxidation and amino acid metabolism

A B

Figure 2. Imaging Findings for Diffuse Symmetric Lesions. Diffuse symmetric lesions (DSL) for glutaric aciduria type 1 and leigh syndrome. Images represent initial presentation of disease for each person affected. Axial diffusion-weighted imaging shows bright areas (white arrows) consistent with acute injury. Brain MRI from an infant with glutaric aciduria type 1 shows classic bilateral stria- tal injury (A). Brain MRI from an infant with Leigh syndrome demonstrates increased signal with central necrosis in the bilateral caudate and putamen (B).

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1. Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. caused by impaired assembly of the electron transfer fla­ Am J Hum Genet. 1985;37(1):1-31. voprotein (ETF), another mitochondrial matrix protein. 2. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002;288(16):2015-2022. It is significantly more rare than type 1 disease, although 3. Yap S, Boers GH, Wilcken B, et al. Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase strokes have also been reported in children.20 Treatment is deficiency treated chronically: a multicenter observational study. Arterioscler Thromb Vasc Biol. 2001;21(12):2080-2085. 4. El-Hattab AW, Adesina AM, Jones J, Scaglia F. MELAS syndrome: clinical manifestations, pathogenesis, and treatment empiric, consisting of a high-carbohydrate diet and carni­ options. Mol Genet Metab. 2015;116(1-2):4-12. tine supplementation. 5. Finsterer J. Mitochondrial metabolic stroke: Phenotype and genetics of stroke-like episodes. J Neurol Sci. 2019;400:135– 141. 6. Koga Y, Povalko N, Inoue E, et al. Therapeutic regimen of L-arginine for MELAS: 9-year, prospective, multicenter, clinical Fabry Disease research. J Neurol. 2018;265(12):2861-2874. 7. Ohsawa Y, Hagiwara H, Nishimatsu SI, et al. Taurine supplementation for prevention of stroke-like episodes in MELAS: a Fabry disease is characterized by extensive, symmet­ multicentre, open-label, 52-week phase III trial. J Neurol Neurosurg Psychiatry. 2019;90(5):529-536. ric white matter injury due to an X-linked disorder of 8. Brinjikji W, Swanson JW, Zabel C, Dyck PJ, Tracy JA, Gavrilova RH. Stroke and stroke-like symptoms in patients with mutations in the POLG1 gene. JIMD Rep. 2011;1:89-96. sphingolipid metabolism People with Fabry disease carry 9. Finsterer J, Segall L. Drugs interfering with mitochondrial disorders. Drug Chem Toxicol. 2010;33(2):138-151. a variant in α-galactosidase (GLA) resulting in impaired 10. Scholl-Bürgi S, Haberlandt E, Gotwald T, et al. Stroke-like episodes in propionic acidemia caused by central focal metabolic decompensation. Neuropediatrics. 2009;40(2):76-81. lysosomal function and sphingolipid accumulation. The 11. Pfeifer CM, Van Tassel DC, Miller JH. Unique neuroradiological findings in propionic acidemia. Radiol Case Rep. course is variable, and the most common clinical presenta­ 2018;13(6):1207-1211. 12. Pearl PL, Krasnewich D. Neurologic course of congenital disorders of glycosylation. J Child Neurol. 2001;16(6):409-413. tion is pain crisis. Given normal life expectancy, a variety of 13. Izquierdo-Serra M, Martínez-Monseny AF, López L, et al. Stroke-like episodes and cerebellar syndrome in symptoms do not present until later in life. Stroke is one phosphomannomutase deficiency (PMM2-CDG): evidence for hypoglycosylation-driven . Int J Mol Sci. 2018;19(2):619. such symptom, which has median age of first occurrence 14. DiMauro S, De Vivo DC. Genetic heterogeneity in Leigh syndrome. Ann Neurol. 1996;40(1):5-7. around age 40 and affects approximately 5% of all individ­ 15. Lake NJ, Compton AG, Rahman S, Thorburn DR. Leigh syndrome: one disorder, more than 75 monogenic causes. Ann Neurol. 2016;79(2):190-203. uals with Fabry disease, requiring a workup that includes 16. Morava E, van den Heuvel L, Hol F, et al. Mitochondrial disease criteria: diagnostic applications in children. Neurology. sequencing of GLA. Findings on MRI usually demonstrate 2006;67(10):1823–1826. 17. Whitehead MT, Lee B, Gropman A. Lesional perfusion abnormalities in Leigh disease demonstrated by arterial spin extensive white matter lesions at baseline, and individuals labeling correlate with disease activity. Pediatr Radiol. 2016;46(9):1309–1316. with a new, acute neurologic deficit may only demonstrate 18. Strauss KA, Puffenberger EG, Robinson DL, Morton DH. Type I glutaric aciduria, part 1: natural history of 77 patients. Am J Med Genet C Semin Med Genet. 2003;121C(1):38-52. progression of the white matter lesions. Rarely, there may 19. Nunes J, Loureiro S, Carvalho S, et al. Brain MRI findings as an important diagnostic clue in glutaric aciduria type 1. be subtle new imaging findings, but large new asymmetric Neuroradiol J. 2013;26(2):155-161. 20. Testai FD, Gorelick PB. Inherited metabolic disorders and stroke part 2: homocystinuria, organic acidurias, and urea lesions are rare. Acute therapy should again be focused cycle disorders. Arch Neurol. 2010;67(2):148-153. on stabilizing metabolism, along with fluid and electrolyte 21. Sims K, Politei J, Banikazemi M, Lee P. Stroke in Fabry disease frequently occurs before diagnosis and in the absence of management. For chronic treatment, enzyme replacement other clinical events: natural history data from the Fabry Registry. Stroke. 2009;40(3):788-794. therapy may be an option. Divakar Mithal, MD, PhD Conclusion Instructor Metabolic stroke is a high-morbidity complication for Department of Pediatric Neurology many metabolic disorders. Prompt appropriate metabolic Ann and Robert H. Lurie Children’s Hospital of Chicago support and supportive care are necessary to minimize Chicago, IL long-term sequelae. Practitioners should maintain a high index of suspicion for SLE if people with metabolic dis­ Tracy Gertler, MD, PhD ease present with acute neurologic deficits or depressed Instructor mental status. For those with variants in MT-TL1, in addi­ Department of Pharmacology tion to correction of fluid and electrolyte imbalances Northwestern University, Feinberg School of Medicine and addressing metabolic stressors, consideration is also Department of Pediatric Neurology warranted for both acute and chronic treatment with Ann and Robert H. Lurie Children’s Hospital of Chicago amino acid therapy, based on availability, feasibility, and Chicago, IL physician comfort. Thromboembolic and diffuse symmet­ ric lesions are also complications of metabolic disorders Disclosures and should be on the differential for acute neurologic DM and TG report no disclosures symptoms. Familiarity with the differences between stroke column editor subtypes associated with specific diseases may aid in rapid Waimei Amy Tai, MD diagnosis and treatment. Long-term prevention is directly Attending Neurologist related to disease-specific treatments, but significant Christiana Care Health System research is still needed to identify efficacious therapies for Newark, DE most metabolic disorders. n

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