Reversible brainstem hypertensive encephalopathy (RBHE): Clinicoradiologic dissociation

Clinical Neurology and Neurosurgery 110 (2008) 1047–1053

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Case report

Reversible brainstem hypertensive encephalopathy (RBHE): Clinicoradiologic dissociation Shuzo Shintani a,∗ , Tarou Hino a , Shouichirou Ishihara a , Saneyuki Mizutani a , Tatsuo Shiigai b a Department of Neurology, Toride Kyodo General Hospital, 2-1-1 Hongoh, Toride City, Ibaraki 302-0022, Japan b Department of Internal Medicine, Toride Kyodo General Hospital, 2-1-1 Hongoh, Toride City, Ibaraki 302-0022, Japan

a r t i c l e

i n f o

Article history: Received 9 February 2008 Received in revised form 18 June 2008 Accepted 21 June 2008 Keywords: Brainstem Hypertension Vasogenic edema MRI

a b s t r a c t We report two cases of reversible brainstem hypertensive encephalopathy (RBHE) with unusual magnetic resonance (MR) findings. Patient 1, an 85-year-old man without a history of hypertension, developed acute severe hypertension and mild consciousness disturbance as the only symptoms. Patient 2, a 46year-old man with an untreated hypertension, presented with extremely high blood pressure and general fatigue, vertigo, and mild dysarthria as the initial manifestations. In these patients, fluid-attenuated inversion recovery (FLAIR) and T2-weighted MR images revealed diffuse hyperintensities in the brainstem. Diffusion-weighted imaging (DWI) findings were normal, and apparent diffusion coefficient (ADC) values were increased in the brainstem. The supratentorial regions were largely spared, and mildly diffuse hyperintensities were noted in the white matter. There were no accompanying changes in the occipital lobe and cerebellum. The lesions completely resolved after stabilization of blood pressure. The normal DWI findings and high ADC values were consistent with vasogenic edema due to severe hypertension. The characteristics of RBHE are a very high blood pressure, mild clinical and neurologic symptoms, rapidly improved MR findings after initial treatment with the control of hypertension, and a marked clinicoradiologic dissociation. © 2008 Elsevier B.V. All rights reserved.

1. Introduction

2. Case reports

Hypertensive encephalopathy (HE) is characterized by severe hypertension, confusion, visual complaints, headache, stupor, and seizures [1]. Because computed tomography (CT) and magnetic resonance imaging (MRI) frequently show edema in the occipital regions, the term “reversible posterior leukoencephalopathy syndrome (RPLS)” has been used [1–4]. CT or MRI usually show transient, predominantly posterior white matter involvement that rapidly improves with the control of hypertension. We report here the cases of two patients with severe brainstem involvement without accompanying occipital lobe changes, and describe the precipitating factors, clinical course, neuroimaging characteristics, outcome, and pathophysiology of “reversible brainstem hypertensive encephalopathy (RBHE)” syndrome.

2.1. Patient 1

∗ Corresponding author. Tel.: +81 297 74 5551; fax: +81 297 74 2721. E-mail address: [email protected] (S. Shintani). 0303-8467/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2008.06.012

An 85-year-old man was admitted to our hospital with a mild facial injury sustained during a fall in his garden. Neurological examination revealed no abnormalities except for a mild consciousness disturbance. He was able to talk to us. His cranial nerves were intact, and motor paresis was absent. Deep tendon reflexes and cerebellar functions were normal. Physical examination showed no abnormalities. His blood pressure was 221/112 mmHg, and his heart rate was 88 beats per minute with a regular rhythm. His medical and family histories were unremarkable. He had not a history of hypertension. Laboratory examinations on admission showed the following: red blood cell count, 301 × 104 mm−3 ; hemoglobin concentration, 9.9 g/dl; white blood cell count, 10,600 mm−3 ; and platelet count, 20.8 × 104 mm−3 . Hepatic function test showed normal results, and the serum blood glucose concentration was 105 mg/dl. The concentrations of blood urea nitrogen (BUN) and serum creatinine were 28 mg/dl and 1.5 mg/dl, respectively. The serum electrolyte

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concentrations (Na, 142 mEq/l; K, 4.5 mEq/l; Ca, 9.2 mg/l) were normal. Immunologic studies showed no abnormalities including the concentrations of the following: antinuclear factor, antibodies to native DNA, antibodies to ribonucleoprotein, antibodies to smooth muscle (Sm), SS-A (anti-Ro antibody), SS-B (anti-La antibody), serum IgG, IgA, or IgM, C3, C4, and serum immunocomplex. An antihuman immunodeficiency virus (HIV) antibody was not detected. His cerebrospinal fluid (CSF) was clear and showed the following: opening pressure, 105 mm H2 O; protein content, 62 mg/dl; 4 leukocytes/mm3 ; and glucose content, 68 mg/dl. Cultures of CSF were negative for pathogens, including acid-fast bacilli (AFB) and fungi. A chest roentgenogram and an electrocardiogram showed no abnormalities. Brain MRI (1.5-T, Siemens Symphony) on admission showed normal diffusion-weighted imaging (DWI) findings, increased apparent diffusion coefficient (ADC) values, and diffuse hyperintensities in fluid-attenuated inversion recovery (FLAIR) and T2-weighted images of the brainstem (Fig. 1a and b). The supratentorial regions were largely spared, and mildly diffuse hyperintensities were noted in the white matter. There were no accompanying changes in the occipital lobe and cerebellum (Fig. 3a). Magnetic resonance angiography (MRA) revealed no abnormalities in the trunk vessels including vertebrobasilar circulation (Fig. 1c). We immediately started the administration of antihypertensive medicines (Temocapril and Amlodipine), and 20 days later the systolic and diastolic pressures stabilized at 120–150 and 70–90 mmHg, respectively. His consciousness rapidly became clear, and the brainstem lesions completely resolved, as shown in FLAIR and T2-weighted images, after stabilization of his blood pressure (Fig. 1b). 2.2. Patient 2 A 46-year-old man was admitted to the emergency room of our hospital with general fatigue, vertigo, dysarthria, and marked hypertension. Neurological examination revealed no abnormalities except for mild dysarthria. Consciousness was clear. His cranial nerves were intact, and motor paresis was absent in the upper and lower extremities. Deep tendon reflexes and cerebellar functions were normal. Physical examination showed no abnormalities. His blood pressure was 244/150 mmHg, and his heart rate was 100 beats per minute with a regular rhythm. He had untreated hypertension and chronic renal failure (CRF) since he was 20 years old. Laboratory examinations on admission showed the following: red blood cell count, 344 × 104 mm−3 ; hemoglobin concentration, 10.7 g/dl; white blood cell count, 10,000 mm−3 ; and platelet count, 9.2 × 104 mm−3 . Hepatic function test showed normal results, and the serum blood glucose concentration was 139 mg/dl. The concentrations of BUN and serum creatinine were 36 and 4.1 mg/dl, respectively. The serum electrolyte concentrations were the following; Na, 124 mEq/l; K, 3.3 mEq/l; and Ca, 9.6 mg/l. The intake of salt (NaCl) was 0.26–1.47 g/day, and the serum concentration of antidiuretic hormone (ADH) was 1.9 pg/ml (normal range: 0.3–3.5) on admission. Immunologic studies showed no abnormalities including the concentrations of the following: antinuclear factor, antibodies to native DNA, antibodies to ribonucleoprotein, antibodies to Sm, SS-A, SS-B, serum IgG, IgA, or IgM, C3, C4, and serum immunocomplex. An anti-HIV antibody was not detected. His CSF was clear and showed the following: protein content, 49 mg/dl; 1 leukocyte/mm3 ; and glucose content, 72 mg/dl. Myelin basic protein (MBP) was within the normal range, and oligoclonal IgGs were not detected in CSF.

Brain MRI on admission showed normal DWI findings, increased ADC values, and diffuse hyperintensities in FLAIR and T2-weighted images of the brainstem (Fig. 2a and b). The supratentorial regions were largely spared, and mildly diffuse hyperintensities were noted in the white matter. There were no accompanying changes in the occipital lobe and cerebellum (Fig. 3b). MRA revealed no abnormalities in the trunk vessels including vertebrobasilar circulation (Fig. 2c). We immediately started the administration of antihypertensive medicines (Olmesartan and Amlodipine), but his refractory hypertension did not stabilize. The concentrations of BUN and serum creatinine increased, and on day 7 he was started on hemodialysis. Three weeks later, the systolic and diastolic pressures stabilized at 150–160 and 80–90 mmHg, respectively. His vertigo and dysarthria disappeared, and the brainstem lesions completely resolved, as shown in FLAIR and T2-weighted images, after stabilization of his blood pressure (Fig. 2b). 3. Discussion Our two patients had persistent extremely high blood pressure for over 1 week. Systolic and diastolic pressures were 200 and 100 mmHg or more, respectively. Patient 1 had a mild CRF without a history of hypertension. On the other hand, Patient 2 had a severe CRF requiring hemodialysis. On admission, they presented with mild lethargy, vertigo, and dysarthria of several days associated with marked hypertension. Visual complaints were conspicuously absent, and clear-cut brainstem symptoms were not noted. Abnormal neurologic and physical findings were limited. Rapid improvement of several symptoms followed the lowering of blood pressure. This characteristic clinical evolution, accompanied by rapid improvement of radiologic abnormalities, strongly suggests hypertension-induced encephalopathy. Involvement of the posterior cerebral region is a hallmark in HE, and visual deficits are common. In our patients, MRI showed that the brainstem was predominantly involved, whereas the occipital lobes were spared. Differential diagnosis included brainstem infarction, tumor, encephalitis, central pontine myelinolysis (CPM), neuro-Behcet disease, and acute disseminated encephalomyelitis (ADEM). Brainstem infarction can be ruled out by the lack of major brainstem signs, rapid clinical recovery, and the absence of signal changes in DWI. Infectious brainstem encephalitis is unlikely because of the normal CSF findings and rapid recovery without specific treatment. The rapidity of the clinical evolution should help differentiate their condition from tumor. The patients lacked cutis and eye symptoms, aphtha, and definitive brainstem symptoms, so we excluded neuroBehcet disease. ADEM is perhaps the most difficult condition to exclude, but our patients did not show inflammatory CSF changes. CPM may produce a similar radiologic picture, but our patients presented no remarkable changes in serum electrolyte concentrations. In Patient 2, the concentrations of serum Na+ changed between 124 and 138 mEq/l during the MRI follow-up period. The velocity of change was not rapid enough to produce remarkable CPM lesion in the brainstem. The NaCl intake was very low (0.26–1.47 g/day) on admission, and the concentration of ADH was normal. The dehydration and renal failure, but not a syndrome of inappropriate secretion of ADH (SIADH), might result in the hyponatremia in Patient 2. In addition, DWI usually demonstrates positive hyperintense legion in the patient with acute phase of demyelinating disease, such as CPM. We reviewed the previously reported 20 patients with RBHE (Table 1). The mean age at onset was 51.3 ± 16.0 years, and 13 were men. The mean systolic and diastolic blood pressures on admission were 213.2 ± 29.7 and 127.6 ± 25.6 mmHg, respectively. Headache

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Fig. 1. (a) MRI on admission showed normal diffusion-weighted imaging (DWI) findings (left) and increased apparent diffusion coefficient (ADC) values (right) in the brainstem in an 85-year-old man (Patient 1) with a reversible brainstem hypertensive encephalopathy (RBHE). There were no accompanying changes in the occipital lobe and cerebellum. (b) Twenty days later in Patient 1, the brainstem lesions on admission (a and b) completely resolved, as shown in fluid-attenuated inversion recovery (FLAIR) images, after stabilization of his blood pressure (c and d). (c) Magnetic resonance angiography (MRA) on admission revealed no abnormalities in the trunk vessels (left) including vertebrobasilar circulation (right) in Patient 1.

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Table 1 Characteristics of 20 patients with reversible brainstem hypertensive encephalopathy (RBHE) Year

Age

Gender

Medical history

Systolic pressure

Diastolic pressure

Physical symptoms

Neurologic symptoms

Recent therapy for HT before developing RBHE

1 2 3

Chang [14] Chang [14] Chang [14]

1999 1999 1999

54 22 49

F F M

Chronic HT HT, SLE HT

210 213 211

144 133 156

Mild right hemiparesis None Diffuse weakness

Poor Chronic HT Chronic HT

4 5

de Seze [5] de Seze [5]

2000 2000

41 52

M F

HT, pheochromocytoma Unknown

220 220

120 150

Mild headache, confusion, nausea Drowsy, tonic-clonic seizure Headache, vomiting, confusion, nausea Headache, blurred vision Headache, blurred vision

Appropriate Unknown

6 7 8

Chu [15] Kumai [16] Yasuda [17]

2001 2002 2003

48 73 45

F M M

None None HT, CRF

180 300 250

100 160 160

None Cerebellar symptoms, nystagmus Left-side weakness Right-side hemiparesis None

9 10

Tada [18] Cruz-Flores [19]

2004 2004

73 38

M M

Renovascular HT HT, CRF sickle cell disease

200 280

120 160

Chronic HT Chronic HT

11

Cruz-Flores [19]

2004

30

F

HT, SLE, CRF cardiomyopathy

230

150

Headache, agitated, nausea, tonic-clonic seizure

12 13

Nagata [20] Karasawa [21]

2004 2004

67 63

M M

HT, CRF, DM HT, DM, tuberculosis

230 240

122 80

Edema, drowsy, visual disturbance None

14 15 16

Fujiwara [22] Ono [23] Kanazawa [24]

2005 2005 2005

38 67 75

M F M

HT DM Unknown

240 204 200

180 106 120

Poor No history of HT Unknown

17 18

Kanazawa [24] Doi [13]

2005 2006

76 35

M M

HT CRF

230 180

100 118

None None

Chronic HT No history of HT

19 20

Doi [13] Gamanagatti [25]

2006 2006

52 60

F M

HT, CRF None

200 220

130 150

Headache, visual blurring Stuporous Headache, stupor, generalized convulsion Relapse of generalized convulsion Headache, nausea, blurred vision, skin purpura Headache, drowsy Unconscious state

Ataxia Dysarthia, limitation of upper gaze, mild VII paresis, positive Babinski sign Blindness → cardiac arrest → death due to sepsis Diffuse weakness Ataxia of upper and lower limbs None None None

None None

Poor No history of HT

Drowsy Drowsy, disoriented Dizziness, lethargic, blurred vision, confusion Drowsy Headache, drowsy, disoriented nausea, vomiting, blurred vision

M: male, F: female, HT: hypertension, DM: diabetes mellitus, CRF: chronic renal failure, SLE: systemic lupus erythematosus; Unit of blood pressure, mmHg.

No history of HT No history of HT Untreated

Chronic HT

Poor Chronic HT

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Fig. 2. (a) MRI on admission showed normal DWI findings (left) and increased ADC values (right) in the brainstem in a 46-year-old man (Patient 2) with RBHE. There were no accompanying changes in the occipital lobe and cerebellum. (b) Three weeks later in Patient 2, the brainstem lesions on admission (a and b) completely resolved, as shown in FLAIR images, after stabilization of his blood pressure (c and d). (c) MRA posterior–anterior (left) and lateral views (right) revealed no abnormalities in the trunk vessels including vertebrobasilar circulation in Patient 2.

(10 of 20, 50%), blurred vision (7 of 20, 35%), nausea and vomiting (5 of 20, 25%), and seizure (4 of 20, 20%) were the most frequently reported physical symptoms at onset. Neurological examinations revealed that 12 (60%) had mild consciousness disturbance alone;

the rest had comorbidities, including ataxia (3), mild hemiparesis (3), blindness (1), and dysarthria with facial paresis (1) (Table 1). Medical records on recent therapy for hypertension before developing RBHE in 20 patients revealed that five (25%) had

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Fig. 3. (a) and (b) MRI on admission showed no accompanying signal changes in the parieto-occipital lobe in fluid-attenuated inversion recovery (FLAIR) images in Patients 1 (a) and 2 (b).

no history of hypertension, two (10%) had unknown history of hypertension, one (5%) had appropriately treated hypertension with an antihypertensive drug (Ramipril), seven (35%) had chronic hypertension, and five (25%) with poorly treated hypertension. Surprisingly, eight (40%) patients did not present with hypertension immediately before developing RBHE (Table 1). Several mechanisms have been proposed to try to account for MRI-demonstrated abnormalities in HE. De Seze et al. proposed three hypotheses [5]. The first hypothesis was edema. The rapid increase in blood pressure may affect the blood–brain barrier, leading to increased permeability and extravasation of proteins and fluid, resulting in cerebral edema [6–8]. Second, abnormally increased sensitivity of vessels to circulating vasoactive agents or endothelial cell dysfunction has also been suggested [3,4,9]. Third, an autoregulatory vasoconstriction in the brain, in response to a marked increase in blood pressure, may induce hypoperfusion, leading to focal and diffuse areas of ischemia [4,8–11]. The brainstem lesion in RBHE is considered to be a basogenic edema rather than a cytotoxic edema because of the absence of hyperintense signal in DW images [5]. The review of previously reported cases of patients with RBHE revealed that eight individuals (40%) did not present with hypertension immediately before developing RBHE (Table 1). Our Patient 1 also had no history of hypertension. Although the brainstem is not vulnerable in hypertensive condition, an unexpected extremely rapid increase in blood pressure may induce brainstem involvement. No clear explanation has been suggested for the prominence of brainstem lesions over occipital lesions. Both parieto-occipital and brainstem lesions are within the territory of the vertebrobasilar artery and its branches. The posterior circulation has significantly less sympathetic innervation than the carotid circulation [12]. More severe and longer-lasting malignant hypertension is unlikely to cause predominantly infratentorial lesions rather than supratentorial lesions. Doi et al. proposed two mechanisms [13]: extensive fluid leakage in the brainstem may spare the parieto-occipital regions in the distal portion of the vertebrobasilar artery system; or a relatively rich sympathetic nerve innervation occur in the parieto-occipital region, which is mainly supplied via the posterior communicating artery (PCoA) from the anterior circulation. The definitive mechanism underlying the development of RBHE without occipital lesions has remained unknown.

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