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Selected References

Normal Myelination and White Matter Development

Merrow C et al (eds): Diagnostic Imaging: Pediatrics, 3e. Salt Lake City, UT: Elsevier, 2017

Fogel BL et al: Clinical exome sequencing in neurogenetic and neuropsychiatric disorders. Ann N Y Acad Sci. 1366(1):49-60, 2016

Barkovich AJ, Koch BL, Moore KR (eds): Pediatric Neuroradiology, 2e. Salt Lake City, UT: Elsevier, 2015

Yang Y et al: Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med. 369(16):1502-11, 2013

Classification of Inherited Metabolic Disorders

Saudubray JM et al (eds): Inborn Metabolic Diseases: Diagnosis and Treatment. Berlin, Germany: Springer, 2016

Longo MG et al: Brain imaging and genetic risk in the pediatric population, part 1: inherited metabolic diseases. Neuroimaging Clin N Am. 25(1):31-51, 2015

Saudubray JM: Neurometabolic disorders. J Inherit Metab Dis. 32(5):595-6, 2009

Overview

Barkovich AJ: Approach to normal myelination and metabolic disease. In: Diagnostic Imaging: Pediatric Neuroradiology, 2e, edited by Barkovich AJ, Koch BL, Moore KR. Salt Lake City, UT: Elsevier, 2015, pp. I-1-38-43

Barkovich AJ, Patay Z: Metabolic, toxic, and inflammatory brain disorders. In: Pediatric Neuroimaging, 5e, edited by Barkovich AJ, Raybaud C. Philadelphia, PA: Lippincott Williams & Wilkins, 2012, pp. 81-239

Metabolic Approach

Hypomyelinating Disorders

Steenweg ME et al: Magnetic resonance imaging pattern recognition in hypomyelinating disorders. Brain. 133(10):2971-82, 2010

IMDs Predominantly Affecting Gray Matter

Jones BV: Metabolic brain disease. In: Diagnostic Imaging: Pediatrics, 3e, edited by Carl Merrow et al. Salt Lake City, UT: Elsevier, 2017, pp 1090-1095

Barkovich AJ, Koch BL, Moore KR (eds): Pediatric Neuroradiology, 2e. Salt Lake City, UT: Elsevier, 2015

IMDs Primarily Affecting Deep Gray Nuclei

Viau KS et al: Evidence-based treatment of guanidinoacetate methyltransferase (GAMT) deficiency. Mol Genet Metab. 110(3):255-62, 2013

Longo N et al: Disorders of creatine transport and metabolism. Am J Med Genet C Semin Med Genet. 157C(1):72-8, 2011

Disorders Affecting Both Gray and White Matter

Mucopolysaccharidoses

Xing M et al: Radiological and clinical characterization of the lysosomal storage disorders: non-lipid disorders. Br J Radiol. 87(1033):20130467, 2014

Zafeiriou DI et al: Brain and spinal MR imaging findings in mucopolysaccharidoses: a review. AJNR Am J Neuroradiol. 34(1):5- 13, 2013

Rasalkar DD et al: Pictorial review of mucopolysaccharidosis with emphasis on MRI features of brain and spine. Br J Radiol. 84(1001):469-77, 2011

Mitochondrial Diseases (Respiratory Chain Disorders)

Salmi H et al: Patients with organic acidaemias have an altered thiol status. Acta Paediatr. 101(11):e505-8, 2012

Leonard JV: Recent advances in amino acid and organic acid metabolism. J Inherit Metab Dis. 30(2):134-8, 2007

IMDs Predominantly Affecting White Matter

van Der Knaap MS and Valk J. Magnetic Resonance of Myelination and Myelin Disorders, 3e. New York, NY: Springer, 2005

van der Knaap MS et al. Non-leukodystrophic white matter changes in inherited disorders. Int J Neuroradiol. 1(1): 56–66, 1995

Periventricular White Matter Predominance

Butler CJ et al: Distinctive magnetic resonance imaging findings in neonatal nonketotic hyperglycinemia. Pediatr Neurol. 72:90-91, 2017

Zubarioglu T et al: Neonatal nonketotic hyperglycinemia: diffusionweighted magnetic resonance imaging and diagnostic clues. Acta Neurol Belg. 116(4):671-673, 2016

Pinto WB et al: Brain MRI features in late-onset nonketotic hyperglycinemia. Arq Neuropsiquiatr. 73(10):891, 2015

Kanekar S et al: Characteristic MRI findings in neonatal nonketotic hyperglycinemia due to sequence changes in GLDC gene encoding the enzyme glycine decarboxylase. Metab Brain Dis. 28(4):717-20, 2013

Kurtcan S et al: MRS features during encephalopathic crisis period in 11 years old case with GA-1. Brain Dev. 37(5):546-51, 2015

Mohammad SA et al: Glutaric aciduria type 1: neuroimaging features with clinical correlation. Pediatr Radiol. 45(11):1696-705, 2015

Kölker S et al: Diagnosis and management of glutaric aciduria type I--revised recommendations. J Inherit Metab Dis. 34(3):677-94, 2011

Urea Cycle/Ammonia Disorders

Enns GM: Neurologic damage and neurocognitive dysfunction in urea cycle disorders. Semin Pediatr Neurol. 15(3):132-9, 2008

Gropman AL et al: Neurological implications of urea cycle disorders. J Inherit Metab Dis. 30(6):865-79, 2007

Methylmalonic and Propionic Acidemias

Fowler B et al: Causes of and diagnostic approach to methylmalonic acidurias. J Inherit Metab Dis. 31(3):350-60, 2008

Congenital Glycosylation Disorders

Feraco P et al: The shrunken, bright cerebellum: a characteristic MRI finding in congenital disorders of glycosylation type 1a. AJNR Am J Neuroradiol. 33(11):2062-7, 2012

Akaboshi S et al: Transient extreme spindles in a case of subacute Mycoplasma pneumoniae encephalitis. Acta Paediatr Jpn. 40(5):479-82, 1998

The brain is highly susceptible to a number of acquired metabolic derangements. As occurs with inherited metabolic disorders and the toxic encephalopathies, the basal ganglia and cortex are especially vulnerable. Whereas the hemispheric white matter is less often affected, some acquired diseases such as osmotic demyelination may largely spare the gray matter and present with striking WM abnormalities.

In this chapter, we focus on acquired metabolic and systemic disorders that involve the CNS. We begin with the most common—hypertension—before turning our attention to abnormalities of glucose metabolism and thyroid/parathyroid function.

We then discuss seizure disorders, as sustained ictal activity with hypermetabolism can have profound effects on the brain. We begin with a brief delineation of normal temporal lobe and limbic anatomy as a prelude to the challenging topic of epilepsy. We finish the section by exploring the puzzling phenomena of the transient corpus callosum splenium lesion and transient global amnesia.

Finally, we consider a potpourri of acquired metabolic diseases, such as hepatic encephalopathy (both acute and chronic) and the osmotic demyelination syndromes.

Hypertensive Encephalopathies

If not recognized and treated, the effects of both acutely elevated blood pressure and chronic hypertension (HTN) on the brain can be devastating. We begin this section with a discussion of acute hypertensive encephalopathy, then delve into the CNS damage caused by HTN.

Acute Hypertensive Encephalopathy,

Posterior Reversible Encephalopathy

Syndrome

Terminology

The most common manifestation of acute hypertensive encephalopathy is posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy syndrome (RPLS). Despite the syndrome's names, lesions are rarely limited to the "posterior"

(32-1) Axial graphic shows cortical/subcortical vasogenic edemain the posterior circulation, characteristic of PRES. Petechial hemorrhage occurs in some cases but is unusual.

(parietooccipital) aspects of the brain (see below), and atypical is more common than "classical" PRES.

Etiology

General Concepts. The pathogenesis of PRES is not yet completely understood. The most common explanation is that severe HTN leads to failed cerebral autoregulation and breakthrough hyperperfusion with vasodilatation.

Excessive circulating cytokines may contribute to injury of the microvascular endothelium, increasing vascular permeability. Hydrostatic leakage and extravasation or transudation of fluid and macromolecules through damaged arteriolar walls into the adjacent brain interstitium result in vasogenic (not cytotoxic) edema (32-1). However, between 15-20% of patients with PRES are normotensive or even hypotensive, whereas less than half have a mean arterial pressure above 140-150 mm Hg.

Alternative theories for the development of PRES invoke vasculopathy with vascular endothelial injury and dysfunction. Possible mechanisms for drug-induced PRES include direct toxic effects on vascular endothelial cells with release of endothelin, prostacyclin, and thromboxane A2.

Associated Conditions. PRES is associated with a multitude of diverse clinical entities, the most common of which are eclampsia, HTN, and immunosuppressive treatment.

Other conditions associated with PRES include renal failure with hemolytic-uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), autoimmune disorders (e.g., lupus nephropathy and acute glomerulonephritis), shock/sepsis syndrome, postcarotid endarterectomy with

(32-2) Gross pathology of complicated PRES demonstrates diffuse cerebral edema with swollen gyri. Petechial hemorrhages and foci of encephalomalacia secondary to infarction are present. (Courtesy R. Hewlett, MD.)

reperfusion syndrome, endocrine disorders, and stimulant drugs, such as ephedrine and pseudoephedrine.

Less common etiologies of PRES include ingestion of food products (such as licorice) containing substances that cause mineralocorticoid excess. The triad of HTN, hypokalemia, and metabolic alkalosis is typical. Patients with excess mineralocorticoids also have impaired endotheliumdependent vascular reactivity, which may contribute to the development of PRES.

Rarely, PRES is associated with the so-called SMART syndrome (stroke-like migraine attacks after radiation therapy).

Pathology

The pathology of PRES is largely undefined, as PRES is rarely fatal and biopsied only in exceptional circumstances. Autopsied brains from patients with complicated PRES show diffuse cerebral edema. Intracranial hemorrhage complicates 15-25% of PRES cases. The most common finding is multiple bilateral petechial microhemorrhages in the occipital lobes

(32-2).

Microscopic features in PRES resemble those reported in malignant hypertensive encephalopathy. The occipital cortex, subcortical white matter (WM), and cerebellum demonstrate a range of microvascular pathology, including fibrinoid arteriolar necrosis with petechial hemorrhages, proteinaceous exudates, and macrophage infiltration along the perivascular spaces.

Pathologic evidence of partial irreversible damage has been documented in PRES despite radiographic resolution of abnormalities. Scattered microinfarcts, WM rarefaction with

subpial gliosis, and hemosiderin deposition—especially in the posterior cerebrum—have been reported.

PRES: TERMINOLOGY, ETIOLOGY, AND CLINICAL ISSUES

Terminology

•Posterior reversible encephalopathy syndrome (PRES)

•Lesions often not just posterior, not always reversible!

Etiology

•HTN-induced dysautoregulation vs. vasospasm, ↓ perfusion

•↑ ↑ BP → failed autoregulation → hyperperfusion

○Vasogenic (not cytotoxic) edema

○Endothelial dysfunction ± excessive circulating cytokines →"leaky" blood-brain barrier

○Fluid, macromolecules ± blood extravasate

•Causes (HTN typical but not invariable)

○Preeclampsia/eclampsia

○Chemotherapy, immunosuppressive drugs

○Thrombotic microangiopathies (e.g., HUS/TTP)

○Renal failure

○Shock/sepsis

○Tumor lysis syndrome

○Food/drug-induced mineralocorticoid excess

Clinical Issues

•All ages (peak = 20-40 years)

•F > > M

•BP usually ↑ ↑ but

○< 50% have mean arterial pressure > 140-50 mm Hg

○15-20% normotensive or hypotensive

•Usually resolves completely with BP normalization

Clinical Issues

Epidemiology and Demographics. Although the peak age of onset is 20-40 years, PRES can affect patients of all ages from infants to the elderly. There is a moderate female predominance, largely because of the strong association of PRES and preeclampsia.

Preeclampsia is the most common overall cause of PRES. This pregnancy-specific disorder is characterized by HTN (blood pressure exceeding 140/90 mm Hg) and proteinuria occurring after 20 weeks of gestation in a previously normotensive patient. Preeclampsia and its variants affect approximately 5% of pregnancies and remain leading causes of both maternal and fetal morbidity.

Progression from preeclampsia to eclampsia occurs in 0.5% of patients with mild and 2-3% of patients with severe preeclampsia. Eclampsia is characterized by a peak systolic pressure of 160 mm Hg or greater, diastolic BO of 100 mg or greater, impaired renal function, thrombocytopenia, and/or evidence of microangiopathic hemolytic anemia, hepatocellular injury, pulmonary edema, and neurologic disturbances (primarily seizures).

Presentation. Although 92% of patients with PRES have acutely elevated blood pressure, PRES can also occur in the absence of hypertension. There is also no statistically significant

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association of blood pressure with imaging severity, hemorrhage, and cytotoxic edema.

The most common clinical symptoms and signs in patients with PRES are encephalopathy (50-80%), seizure (60-75%), headache (50%), visual disturbances (33%), and focal neurological deficit (10-15%).

PRES-associated seizures are typically single, short, uncomplicated grand mal type that terminate spontaneously during the first 24 hours. Serial or recurrent seizures as well as status epilepticus are uncommon.

Common comorbidities reported in recent series include steroids or immunosuppressants (40%), systemic lupus erythematosus (30%), kidney disease (20-30%), eclampsia (20%), and miscellaneous disorders such as vasculitis.

Natural History and Treatment Options. Reversibility is a typical feature of PRES and is associated with good prognosis. If the inciting substances or precipitating conditions are eliminated and any existing HTN is promptly treated, PRES often resolves with minimal or no residual abnormalities.

Extensive vasogenic edema, hemorrhage, and restricted diffusion on initial imaging are associated with worse clinical outcomes.

Severe PRES can be life-threatening. In rare cases, lesions are irreversible and permanent damage occurs, typically hemorrhagic cortical/subcortical or basal ganglionic infarcts.

Imaging

General Features. Three distinct imaging patterns of PRES have been described. The most common is a dominant parietal-occipital pattern (classic or typical PRES). Two less common (atypical) patterns are a superior frontal sulcus pattern (involvement of the mid and posterior aspects of the superior frontal sulcus) and a holohemispheric watershed pattern (involvement of the frontal, parietal, and occipital lobes along the internal watershed zones). Combinations of these three patterns as well as involvement of other anatomic areas (see below) are also common.

The parietooccipital lobes are involved in over 90% of PRES cases. These areas are considered particularly vulnerable because the comparatively sparse sympathetic innervation of the posterior circulation results in less protection against the effects of severe systemic HTN.

The frontal lobes are involved in 75-77% of cases, with the temporal lobes (65%) and cerebellum (50-55%) also commonly affected. Other atypical distributions include the basal ganglia and thalami, deep white matter, corpus callosum splenium, brainstem, and cervical spinal cord (32-3).

As many PRES patients present with encephalopathy, seizure, severe headache, or visual disturbances, NECT scans are commonly obtained as an initial screening study. It is therefore extremely important to identify even subtle abnormalities that may be suggestive of PRES. If the screening NECT is normal and PRES is suspected on clinical grounds, an MR

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(32-3) Diagrammatic axial images show location and relative frequency of lesions in PRES. Although > 90% of PRES cases have lesions in the parietooccipital subcortical WM (classic PRES, shown in red), note multifocality is the rule, not the exception. Most cases of PRES also have lesions in areas other than the classic parietooccipital location. Both classic PRES (red) and the superior frontal sulcus pattern (orange) are frequently combined with additional lesions distributed along the hemispheric cortical (superficial) watershed zones (depicted in the lower right image). The cerebellum is affected in nearly half of PRES cases, whereas about one-third have basal ganglionic lesions (light blue). The pons, medulla, cervical spinal cord, and corpus callosum splenium are less common sites involved by PRES although in some cases ONLY the posterior fossa is affected. Remember: atypical PRES is actually more common than the classic isolated parietooccipital involvement! (Adapted from Ollivier et al.)

scan with DWI and T2* in addition to the routine sequences (T1 and T2/FLAIR) should be obtained.

CT Findings. Screening NECTs are normal in approximately one-quarter of all PRES cases (32-5). Subtle patchy cortical/subcortical hypodensities—usually in the parietooccipital lobes, watershed zones, and/or cerebellum—may be the only visible abnormalities on NECT

(32-4).

PRES-associated intracranial hemorrhage is uncommon, seen in only 5-15% of cases. Three different patterns of PRESassociated intracranial hemorrhage occur and are found in almost equal proportions: focal parenchymal hematoma, multifocal hemorrhages (usually less than 5 mm), and convexity subarachnoid hemorrhage.

CECT is usually negative although severe cases may show patchy, nonconfluent cortical/subcortical enhancing foci.

MR Findings. PRES has both classic and atypical (i.e., variant) MR features. Keep in mind that (1) atypical PRES is actually more common than classic (i.e., purely parietal-occipital) PRES;

(2) PRES is rarely just posterior; and (3) PRES is not always reversible.

Classic PRES demonstrates bilateral parietooccipital cortical/subcortical hypointensities that are hypointense on T1WI and hyperintense on T2/FLAIR (32-5). T2* (GRE or SWI) sequences may demonstrate hemorrhagic foci (32-7).

"Leaky" arterioles with loss of blood-brain barrier integrity may cause patchy cortical-subcortical enhancement on T1 C+ sequences.

Imaging findings in atypical PRES include involvement of the frontal lobes, watershed zones, basal ganglia and/or thalami, brainstem, cerebellum, and even the spinal cord (32-6).

Findings of both classic and atypical PRES very commonly occur together.

In unusual cases, brainstem and/or cerebellar lesions may be the only abnormality present. The spinal cord has been reported as a rare site of isolated PRES involvement.

Frank infarction is quite rare in PRES. Because most cases of PRES are caused by vasogenic—not cytotoxic—edema, DWI is usually negative. However, PRES with restricted diffusion occurs in 15-30% of cases and is usually seen as small foci of restricted diffusion within larger regions of nonrestricting vasogenic edema.

MR and CT perfusion studies have demonstrated both increased AND decreased perfusion in PRES. The most striking reported findings are in the occipital regions and cortical watershed zones.

Following blood pressure normalization, imaging findings in most cases of PRES resolve completely. Irreversible lesions are relatively uncommon, occurring in approximately 15% of cases. Imaging features associated with poor prognosis include lesions with low initial ADC, brainstem involvement, and the presence of hemorrhage on initial imaging studies.

Angiography. Vasculopathy is a common finding on CTA, MRA, or DSA in patients with PRES. Diffuse vessel constriction or narrowing, focal irregularity, and beaded appearance are typical but nonspecific angiographic findings in PRES. Whether these abnormalities reflect transient reversible vasoconstriction or vasculitis/vasculopathy is unclear.

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Differential Diagnosis

The major differential diagnoses of PRES includes acute cerebral ischemia-infarction, vasculitis, hypoglycemia, status epilepticus, sinovenous thrombosis, reversible cerebral vasoconstriction syndrome, and the thrombotic microangiopathies.

PRES rarely involves just the posterior circulation, so acute cerebral ischemia-infarction is often easily distinguished. Bilateral PCA distribution infarcts are rare in the absence of "top of the basilar" thrombosis, which typically affects other areas such as the thalami, midbrain, and superior cerebellum.

Vasculitis can resemble PRES-induced vasculopathy at angiography. The distribution of lesions in vasculitis is much more random and less symmetric, usually does not demonstrate the parietooccipital predominance seen in PRES, and more often enhances following contrast administration.

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In contrast to vasculitis, high-resolution vessel wall imaging is usually negative in PRES.

Hypoglycemia typically affects the parietooccipital cortex and subcortical WM, so the clinical laboratory findings (i.e., low serum glucose, lack of systemic HTN) are important differentiating features. Status epilepticus can cause transient gyral edema but is rarely bilateral and can affect any part of the cortex.

Less common entities that can mimic PRES include sinovenous thrombosis and reversible cerebral vasoconstriction syndrome. Thrombosis of the posterior (descending) aspect of the superior sagittal sinus can cause patchy bilateral parietooccipital cortical/subcortical edema. Hemorrhage is common (rare in PRES), and CTV easily demonstrates the occluded sinus. Reversible cerebral vasoconstriction syndrome shares some features (e.g., convexal subarachnoid hemorrhage) with PRES but is typically limited to a solitary sulcus or just a few adjacent sulci.

Thrombotic microangiopathies (TMAs) can be difficult to differentiate from PRES solely on the basis of imaging features. Primary TMAs include ADAMTS13-mediated TMA (also known as thrombotic thrombocytopenic purpura, TTP) and Shiga toxin-mediated TMA (hemolytic-uremic syndrome, HUS).

Secondary TMAs are caused by an underlying disease process and include malignant HTN (mHTN), HELLP syndrome, autoimmune disorders, and disseminated intravascular coagulopathy (DIC).

PRES is a common manifestation in all the thrombotic microangiopathies, although the distinction between PRES and mHTN may be largely academic. The presence of diffuse cerebral edema and multifocal microhemorrhages is more typical of mHTN. Atypical location (brainstem, cerebellum, basal ganglia), restricted diffusion, and generalized cerebral edema are all more common in mHTN but also occur in PRES.

PRES: IMAGING AND DDx

Three Anatomic Patterns

•Classic PRES

○Parietooccipital pattern (> 90%)

•Variant PRES

○Superior frontal sulcus pattern (70%)

○Holohemispheric watershed pattern (50%)

○Other: cerebellum (50%), basal ganglia (30%), brainstem (20%), spinal cord (< 10%)

•Combinations very common (> 90%)

CT

•Can be normal or only subtly abnormal

○If PRES suspected and CT normal, get MR!

•Posterior cortical/subcortical hypodensities

•Gross hemorrhage rare (parenchymal > cSAH)

MR

•T2/FLAIR hyperintensity (parietooccipital most common)

•T2* (GRE/SWI) shows hemorrhage in 15-25%

•DWI usually but not invariably negative

•Enhancement none/mild (unless severe PRES)

Differential Diagnosis

•Posterior circulation ischemia-infarction

○Top of the basilar syndrome

•Vasculitis

•Status epilepticus

•Hypoglycemia

•Thrombotic microangiopathy

○Primary (ADAMTS13-mediated TMA/TTP, Shiga toxin-mediated HUS)

○Secondary (mHTN, HELLP syndrome, autoimmune disorders, DIC)

•Sinovenous thrombosis

○Internal cerebral veins, vein of Galen/straight sinus

•Reversible cerebral vasoconstriction syndrome

Acute Hypertensive Encephalopathy and

Malignant Hypertension

Terminology

Hypertensive encephalopathy occurs when elevated mean arterial pressure overcomes cerebral autoregulation. With the resulting loss of control of cerebral perfusion, cerebral blood flow (CBF) rises, the brain is hyperperfused, and vasogenic edema develops.

Malignant hypertension (mHTN), sometimes termed acute hypertensive crisis, is characterized clinically by extreme blood pressure elevation and papilledema. Accelerated HTN is identified by the presence of severe retinopathy (exudates, hemorrhages, arteriolar narrowing, spasm, etc.) without papilledema. Both forms of HTN are associated with severe vascular injury to the kidneys and other end-organs.

Etiology

Any form of hypertensive disorder, regardless of etiology, can precipitate a hypertensive crisis. The abruptness of blood pressure elevation seems to be more important than the absolute level of either systolic or mean arterial blood pressure.

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(32-8A) FLAIR in an encephalopathic 34y patient with severe headache, BP 240/120 shows swollen, hyperintense pons , cerebellum .

(32-8B) T2WI in the same case with mHTN shows pontine and cerebellar confluent hyperintensity and mass effect.

(32-8C) Symmetric thalamic hyperintensities are present. DWI (not shown) was negative. Findings resolved with aggressive BP treatment.

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(32-9A) FLAIR in 54y woman with chronic renal failure, TTP, confusion shows bifrontal confluentand scattered WM hyperintensities.

(32-9B) T2* SWI shows multiple "blooming" focithroughout the white matter. The cortex is spared.

(32-9C) More cephalad T2* SWI demonstrates more blooming WM hypointensities .

mHTN in the setting of chronic hypertension is actually rare, occurring in less than 1% of all patients. Nevertheless, because the prevalence of HTN in the general population is so high, so-called essential hypertension (i.e., chronic HTN without an identifiable underlying cause) is still the most common overall condition predisposing to mHTN.

mHTN also occurs in previously normotensive individuals. Sudden onset of severe HTN can occur in children with acute glomerulonephritis and renal failure, pregnant women with eclampsia, and patients of all ages with substance abuse (e.g., cocaine). Less common causes of mHTN include pheochromocytoma crisis, clonidine withdrawal syndrome, drug interactions (e.g., monoamine oxidase inhibitor + tyramine), and autonomic overactivity in patients with spinal cord disorders.

Pathology

Macroscopically, the brain appears swollen and edematous. Gross parenchymal hematomas and perivascular petechial microhemorrhages may be present. Acute microinfarcts, especially in the basal ganglia and pons, are common.

Microscopic features of mHTN include arteriolar fibrinoid necrosis with fragmentation and loss of nuclear staining in the affected vessel walls. In HTN-associated thrombotic microangiopathy, some arterioles contain intraluminal platelet/fibrin thrombi, whereas others are surrounded by proteinaceous exudates or admixed fibrin and hemorrhage. Edema in the adjacent white matter is a typical associated finding.

Clinical Issues

Blood pressure in mHTN is severely elevated, with diastolic levels often exceeding 130-140 mm Hg. Headache with or without coexisting encephalopathy is the most frequent symptom and is often accompanied by visual disturbances, nausea, vomiting, and altered mental status. Congestive heart failure, deteriorating renal function, and anemia are common.

The complications of acute hypertensive crisis are generally reversible if the condition is diagnosed properly and appropriate therapy instituted quickly. Rapid blood pressure reduction typically results in prompt, dramatic improvement in hypertensive encephalopathy.

Imaging

Imaging findings in mHTN range from classic PRES-like features with parietooccipital predominance to "atypical" features. "Atypical" features are more common in mHTN compared with PRES. Brainstem-dominant hypertensive encephalopathy and basal ganglia and/or watershed lesions are common cerebral manifestations of mHTN (32-8). Diffuse cerebral edema may be present in especially severe cases.

Lobar and/or multifocal parenchymal microhemorrhages in the cortex, basal ganglia, pons, and cerebellum are common in mHTN and are best seen as "blooming" foci on T2* sequences (GRE, SWI) (32-9). Convexal subarachnoid hemorrhage with multiple foci of short-segment arterial stenoses resembling reversible cerebral vasoconstriction syndrome (RCVS) has been reported in a few cases of mHTN.

mHTN can cause widespread blood-brain barrier disruption with striking multifocal patchy enhancement following contrast administration (32-10). Restricted diffusion with decreased ADC values on DWI is more common in mHTN compared with classic PRES.

Differential Diagnosis

The major differential diagnosis of mHTN is PRES. TTP with brain ischemia and microhemorrhages (32-9) can appear identical on imaging studies, and the distinction is established by clinical laboratory features, not imaging findings.

ACUTE HYPERTENSIVE ENCEPHALOPATHY

Terminology

• Also known as malignant hypertension, hypertensive crisis

Etiology

•Abrupt rise in BP > absolute value of BP

•Many causes

○Idiopathic ("essential") HTN

○Eclampsia

○Drug abuse (cocaine, methamphetamine)

○Immunosuppressant neurotoxicity

○Renal (acute glomerulonephritis, HUS)

○Other thrombotic microangiopathies

○High altitude exposure

○Collagen-vascular disease (e.g., scleroderma, lupus)

○Pheochromocytoma crisis

○Autonomic instability

Imaging

•Brainstem, basal ganglia > > cortex, watershed

•Microbleeds on T2* (GRE, SWI) common

Differential Diagnosis

• Major differential diagnosis is PRES (can, often does overlap)

Chronic Hypertensive Encephalopathy

Although the clinical and imaging manifestations of posterior reversible encephalopathy syndrome (PRES) and malignant hypertension (mHTN) can be dramatic and life-threatening, the effects of longstanding untreated or poorly treated HTN on end-organ function can be equally devastating.

Pathology

The most consistent histopathologic feature of chronic hypertensive encephalopathy (CHtnE) is a microvasculopathy characterized by arteriolosclerosis and lipohyalinosis (see Chapter 10). Stenosis and occlusion of small arteries and arterioles from layers of hyaline collagen deposition cause decreased oligodendrocyte density, myelin pallor, gliosis, and spongiform WM volume loss. Multiple lacunar infarcts are common.

Clinical Issues

CHtnE is most common in middle-aged and elderly patients. CHtnE affects men more often than women and is especially prevalent in African Americans. In addition to age and chronically elevated blood pressure, smoking is an independent risk factor for CHtnE. Metabolic syndrome (impaired glucose metabolism, elevated blood pressure, central obesity, and dyslipidemia) is increasingly common and contributes significantly to the worldwide burden of CHtnE.

The most common symptom of CHtnE is nonspecific headache. Stepwise or gradual progression of cognitive dysfunction is also common and may develop into frank vascular dementia.

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(32-10A) T1 C+ FS in a patient with mHTN shows multiple patchy foci of enhancement in the cerebellar white matter.

(32-10B) More cephalad T1 C+ FS shows multifocal patchy enhancement in the parietooccipital lobes of both hemispheres.

(32-10C) T1 C+ FS through the corona radiata shows extensive patchy enhancement in the subcortical white matter of both hemispheres.

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Approximately 1-2% of patients with chronic HTN develop an acute hypertensive emergency. In these "acute-on-chronic" hypertensive cases, blood pressure rises substantially and causes end-organ dysfunction. The brain is affected in approximately 15% of cases. Headache, seizure, focal neurological signs, or depressed consciousness are common symptoms. These patients have a 5% 1-year cumulative risk of subsequent ischemic stroke or intracranial hemorrhage.

Imaging

The two cardinal imaging features of CHtnE are (1) diffuse patchy and/or confluent WM lesions and (2) multifocal microbleeds. The WM lesions are concentrated in the corona radiata and deep periventricular WM—especially around the atria of the lateral ventricles. The damaged WM appears hypodense on NECT scans and hyperintense on T2/FLAIR imaging.

Multiple petechial bleeds ("microhemorrhages") are the second most common manifestation of CHtnE. These are not usually identifiable on NECT and may be invisible on standard MR sequences (FSE T2WI and FLAIR). T2* (GRE, SWI) scans show multiple "blooming" hypointensities ("black dots") that tend to be concentrated in the basal ganglia and cerebellum

(32-11).

Imaging findings in CHtnE can also reflect "acute-on-chronic" disease. T2* scans in the majority of patients with classic basal ganglia or lobar hypertensive hemorrhages demonstrate petechial microhemorrhages. Occasionally, patients with chronic longstanding HTN develop an acute hypertensive crisis and can demonstrate features of PRES superimposed on longstanding, chronic-appearing WM disease.

Differential Diagnosis

The major differential diagnosis of CHtnE is cerebral amyloid angiopathy (CAA). The WM lesions in both diseases often