- Email: [email protected]
The diagnosis of posterior reversible encephalopathy syndrome
Correspondence
The diagnosis of posterior reversible encephalopathy syndrome In their comprehensive Review,1 Jennifer Fugate and Alejandro Rabinstein discuss how posterior reversible encephalopathy syndrome (PRES) is sometimes inappropriately regarded as a radiological diagnosis and rightly emphasise the importance of correlating clinical history in the diagnostic process.1 However, we believe that an important differential diagnosis has been omitted. Mitochondrial disorders are among the most common forms of inherited neurological disease and present with a frequency of 1:4300 in the adult population.2 The acute neurological symptoms associated with PRES are frequently non-specific, including seizures, encephalopathy, headache, and visual disturbances.1 These symptoms also characterise stroke-like episodes associated with mitochondrial disease, often recognised in the context of the mitochondrial DNA mutation 3243A→G or mutations in the nuclear POLG gene.3,4 In our clinical experience of a cohort of 37 patients harbouring the 3243A→G mutation and presenting with stroke-like episodes, PRES was frequently the initial working diagnosis before consideration of a mitochondrial disorder. Although hypertension frequently accompanies PRES, studies5 suggest that 15–20% of patients with PRES are in fact normotensive or even hypotensive. Moreover, PRES is suggested to be recurrent in 5–10% of cases.1 Particularly in the absence of the known predisposing conditions for PRES, such as an autoimmune disorder, immunosuppressive or cytotoxic drug treatment, or eclampsia, both normotension and recurrent episodes together with neurological and radiological features suggestive of PRES warrant consideration of a possible underlying mitochondrial
disorder. Importantly, the brain MRI abnormalities associated with PRES can be very similar to those encountered in patients with mitochondrial stroke-like episodes. We wish to point out that in patients presenting acutely with any combination of seizures, encephalopathy, headache, and visual disturbances, particularly when brain MRI reveals features suggestive of PRES, the possibility of a mitochondrial disorder should be considered. Useful clinical pointers to discern mitochondrial disease from PRES include: the presence of seemingly unrelated multisystem diseases such as bilateral sensorineural hearing loss, diabetes mellitus, cardiomyopathy, and gut dysmotility, which are common in 3243A→G mutation carriers; the presence of cerebellar ataxia or axonal polyneuropathy, which are suggestive of POLG-associated mitochondrial disease; and in the case of mitochondrial disease caused by mutations in mitochondrial DNA, a detailed family history might reveal features compatible with a maternal inheritance pattern. Genetic testing for the 3243A→G mutation and the common POLG mutations are at present noninvasive, inexpensive, and readily available.6 Moreover, establishment of a diagnosis of mitochondrial disease mimicking PRES has important practical implications, not only from a prognostic perspective, but also in relation to therapeutic strategies (such as avoidance of sodium valproate in POLG-related mitochondrial disease due to the associated risk of fulminant hepatic failure) and the need for detailed family tracing of at-risk individuals. We declare no competing interests.
Yi Shiau Ng, Grainne S Gorman, Doug M Turnbull, *Mika H Martikainen [email protected] Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle NE2 4HH, UK
www.thelancet.com/neurology Vol 14 November 2015
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Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol 2015; 14: 914–25. Gorman GS, Schaefer AM, Ng Y, et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol 2015; 77: 753–59. Mancuso M, Orsucci D, Angelini C, et al. The m.3243A>G mitochondrial DNA mutation and related phenotypes. A matter of gender? J Neurol 2014; 261: 504–10. Engelsen BA, Tzoulis C, Karlsen B, et al. POLG1 mutations cause a syndromic epilepsy with occipital lobe predilection. Brain 2008; 131: 818–28. Rabinstein AA, Mandrekar J, Merrell R, Kozak OS, Durosaro O, Fugate JE. Blood pressure fluctuations in posterior reversible encephalopathy syndrome. J Stroke Cerebrovasc Dis 2012; 21: 254–58. McFarland R, Taylor RW, Turnbull DM. A neurological perspective on mitochondrial disease. Lancet Neurol 2010; 9: 829–40.
Posterior reversible encephalopathy syndrome (PRES) was first described by Hinchey and colleagues1 in 1996 as a clinical and radiological syndrome characterised by a reversible, predominantly posterior, leukoencephalopathy associated with a cluster of signs and symptoms, including “headache, vomiting, confusion, seizures, cortical blindness, other visual abnormalities, and motor signs”. Jennifer Fugate and Alejandro Rabinstein2 summarised the main clinical symptoms of PRES in adults: encephalopathy (50–80%), seizures (60–75%), headache (50%), visual disturbances (33%), focal neurological deficit (10–15%), and status epilepticus (5–15%). In the paediatric population, seizures are reported to be the most common presenting symptom, occurring in more than 90% of children, and encephalopathy (eg, visual disturbances, headache, and focal neurological deficits) seems to be the second most frequent presentation. We have been carefully monitoring PRES at our institution over the years.3 Between 2006 and 2013, we recorded 24 cases consistent with the clinical and neuroradiological criteria of PRES. In 11 of them, we were able to obtain an electroclinical documentation of PRES through 1073
The diagnosis of posterior reversible encephalopathy syndrome In their comprehensive Review,1 Jennifer Fugate and Alejandro Rabinstein discuss how posterior reversible encephalopathy syndrome (PRES) is sometimes inappropriately regarded as a radiological diagnosis and rightly emphasise the importance of correlating clinical history in the diagnostic process.1 However, we believe that an important differential diagnosis has been omitted. Mitochondrial disorders are among the most common forms of inherited neurological disease and present with a frequency of 1:4300 in the adult population.2 The acute neurological symptoms associated with PRES are frequently non-specific, including seizures, encephalopathy, headache, and visual disturbances.1 These symptoms also characterise stroke-like episodes associated with mitochondrial disease, often recognised in the context of the mitochondrial DNA mutation 3243A→G or mutations in the nuclear POLG gene.3,4 In our clinical experience of a cohort of 37 patients harbouring the 3243A→G mutation and presenting with stroke-like episodes, PRES was frequently the initial working diagnosis before consideration of a mitochondrial disorder. Although hypertension frequently accompanies PRES, studies5 suggest that 15–20% of patients with PRES are in fact normotensive or even hypotensive. Moreover, PRES is suggested to be recurrent in 5–10% of cases.1 Particularly in the absence of the known predisposing conditions for PRES, such as an autoimmune disorder, immunosuppressive or cytotoxic drug treatment, or eclampsia, both normotension and recurrent episodes together with neurological and radiological features suggestive of PRES warrant consideration of a possible underlying mitochondrial
disorder. Importantly, the brain MRI abnormalities associated with PRES can be very similar to those encountered in patients with mitochondrial stroke-like episodes. We wish to point out that in patients presenting acutely with any combination of seizures, encephalopathy, headache, and visual disturbances, particularly when brain MRI reveals features suggestive of PRES, the possibility of a mitochondrial disorder should be considered. Useful clinical pointers to discern mitochondrial disease from PRES include: the presence of seemingly unrelated multisystem diseases such as bilateral sensorineural hearing loss, diabetes mellitus, cardiomyopathy, and gut dysmotility, which are common in 3243A→G mutation carriers; the presence of cerebellar ataxia or axonal polyneuropathy, which are suggestive of POLG-associated mitochondrial disease; and in the case of mitochondrial disease caused by mutations in mitochondrial DNA, a detailed family history might reveal features compatible with a maternal inheritance pattern. Genetic testing for the 3243A→G mutation and the common POLG mutations are at present noninvasive, inexpensive, and readily available.6 Moreover, establishment of a diagnosis of mitochondrial disease mimicking PRES has important practical implications, not only from a prognostic perspective, but also in relation to therapeutic strategies (such as avoidance of sodium valproate in POLG-related mitochondrial disease due to the associated risk of fulminant hepatic failure) and the need for detailed family tracing of at-risk individuals. We declare no competing interests.
Yi Shiau Ng, Grainne S Gorman, Doug M Turnbull, *Mika H Martikainen [email protected] Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle NE2 4HH, UK
www.thelancet.com/neurology Vol 14 November 2015
1
2
3
4
5
6
Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol 2015; 14: 914–25. Gorman GS, Schaefer AM, Ng Y, et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol 2015; 77: 753–59. Mancuso M, Orsucci D, Angelini C, et al. The m.3243A>G mitochondrial DNA mutation and related phenotypes. A matter of gender? J Neurol 2014; 261: 504–10. Engelsen BA, Tzoulis C, Karlsen B, et al. POLG1 mutations cause a syndromic epilepsy with occipital lobe predilection. Brain 2008; 131: 818–28. Rabinstein AA, Mandrekar J, Merrell R, Kozak OS, Durosaro O, Fugate JE. Blood pressure fluctuations in posterior reversible encephalopathy syndrome. J Stroke Cerebrovasc Dis 2012; 21: 254–58. McFarland R, Taylor RW, Turnbull DM. A neurological perspective on mitochondrial disease. Lancet Neurol 2010; 9: 829–40.
Posterior reversible encephalopathy syndrome (PRES) was first described by Hinchey and colleagues1 in 1996 as a clinical and radiological syndrome characterised by a reversible, predominantly posterior, leukoencephalopathy associated with a cluster of signs and symptoms, including “headache, vomiting, confusion, seizures, cortical blindness, other visual abnormalities, and motor signs”. Jennifer Fugate and Alejandro Rabinstein2 summarised the main clinical symptoms of PRES in adults: encephalopathy (50–80%), seizures (60–75%), headache (50%), visual disturbances (33%), focal neurological deficit (10–15%), and status epilepticus (5–15%). In the paediatric population, seizures are reported to be the most common presenting symptom, occurring in more than 90% of children, and encephalopathy (eg, visual disturbances, headache, and focal neurological deficits) seems to be the second most frequent presentation. We have been carefully monitoring PRES at our institution over the years.3 Between 2006 and 2013, we recorded 24 cases consistent with the clinical and neuroradiological criteria of PRES. In 11 of them, we were able to obtain an electroclinical documentation of PRES through 1073