Tumour-like presentation of atypical posterior reversible encephalopathy syndrome with prominent brainstem involvement

Abstract

Typical posterior reversible encephalopathy syndrome (PRES) is a clinical-neuroradiological entity characterised by bilateral white matter oedema, which is usually symmetrical and totally reversible in 2–3 weeks. A 46-year-old man presented with a persistent headache and visual blurring in the right eye. On admission, the clinical examination revealed minimal unsteadiness of gait and elevated blood pressure. A brain MRI showed a hyperintense signal on T2-weighted sequences in the whole brainstem, extended to the spinal cord (C2–C6), the left insula and the right cerebellum. When his blood pressure was controlled, his symptoms gradually improved. The follow-up MRI scan at 3 weeks revealed a dramatic regression of the hyperintense lesions on T2-weighted sequences. The differential diagnosis of PRES is very wide, especially in the case of conspicuous brainstem involvement. Treatable causes of white matter oedema should be always kept in mind to avoid misdiagnosis and prevent complications, such as intracranial haemorrhage.

Background

Typical posterior reversible encephalopathy syndrome (PRES) is a clinical-neuroradiological entity characterised by subcortical vasogenic oedema, with preferential involvement of the posterior brain regions.¹ The most common clinical findings include headache, altered mental status, seizures, vomiting and visual disturbance.^2–6 MRI demonstrates bilateral and symmetrical white matter oedema, which is usually reversible in 2–3 weeks.⁷ The diagnosis requires both clinical and radiological criteria and normalisation of the neuroimaging at follow-up. It has been proposed that several clinical conditions may play a role in triggering PRES: hypertension, immunosuppressive drugs, chemotherapy, transplantation, eclampsia, renal failure, sepsis and autoimmune diseases such as systemic lupus erythematosus or polyarteritis nodosa.^{1 8 9} Breakdown of the blood–brain barrier and endothelial dysfunction are considered the principal underlying mechanisms.¹ However, the exact pathogenesis of PRES remains incompletely understood.⁸

We report an atypical case of PRES in a 46-year-old man with prominent brainstem involvement suggestive of malignancy.

Case presentation

A 46-year-old man was admitted with a month-long history of headache and visual blurring in the right eye. His medical history mentioned mononucleosis (the year before), gastro-oesophageal reflux, renal colic, frequent urination and appendectomy. He reported a family history of cardiovascular diseases (hypertension, ischaemic heart disease and cerebral ischaemia). He had not been on any regular medications. He was not a chronic alcohol user and he also denied smoking and sexual promiscuity.

On admission, the neurological examination revealed minimal unsteadiness of gait with no other cerebellar signs neither focal neurological deficits. Physical examination was unremarkable, except for elevated blood pressure (200/140 mm Hg).

Investigations

A brain MRI showed a hyperintense signal on T2-weighted sequences in the whole brainstem, extended to the spinal cord (C5–C6), the left insula and the right cerebellum (figure 1). Diffusion-weighted imaging (DWI) sequences demonstrated a vasogenic oedema. An intraparenchymal haemorrhage was found at the pontomedullary junction. There were patchy areas of signal enhancement in the pons as well as spinal leptomeningeal enhancement following the injection of contrast material on T1-weighted sequences (figure 1). Time-of-Flight Magnetic Resonance Angiography (MRA) was unremarkable, with no signs of vasculopathy. Neuroimaging data were consistent with a space-occupying lesion of the whole brainstem extended to the cervical spinal cord and supratentorial regions.

Figure 1.

MRI performed during hospitalisation. MRI performed during hospitalisation shows a hyperintense signal in the medulla oblongata (A), pons (B) and left insula (C) in FLAIR sequences; in (D) normal findings on MRI spectroscopy; hyperintense signal in the medulla oblongata to C5-6 in T2-weighted sequences (E); spinal leptomeningeal enhancement following the injection of contrast material on T1-weighted sequences (F). FLAIR, fluid attenuated inversion recovery.

Blood investigations showed polyglobulia, presence of serum anti-hepatitis C virus (HCV) antibodies and HCV-RNA positivity (830 000 UI/ml). There were no abnormalities in serum electrolytes, blood sugar, renal and liver function, thyroid function, urine analysis and coagulation profile. HIV infection was ruled out. ECG was in sinus rhythm.

An ophthalmological examination demonstrated a grade 3 hypertensive retinopathy. Visual field examination revealed centrocecal defects and a nasal scotoma in the right eye. Visual evoked potentials showed a bilateral prolongation of the latency of P100 waves.

Differential diagnosis

Possible differential diagnoses of T2-hyperintense brainstem lesions extended to the spinal cord include tumours (glioma and lymphoma), vasculitis, infections, osmotic demyelination syndrome, toxic leukoencephalopathy and neuromyelitis optica spectrum disorders (NMOSD).

The clinical presentation and MRI findings (figure 1) in our patient were consistent with an initial hypothesis of a space-occupying lesion. Then, he was referred to a neurosurgeon, who hypothesized a low-grade glioma; however, he did not recommend performing a biopsy, due to the localisation of the lesion. In addition, the initial diagnosis was questioned after MRI-spectroscopy (figure 1), which was not consistent with glioma. Infectious processes were excluded because of negativity of biochemical markers of inflammation. Osmotic demyelination syndrome and toxic leukoencephalopathy were also ruled out, since there was no history of electrolyte imbalance, correction of hyponatraemia or toxic agents’ exposure. Central nervous system (CNS) vasculitis linked to HCV infection was considered, but there were no mural thickening or vessel wall contrast enhancement on MRA; cryoglobulins were not assessed, but antinuclear antibodies and anti-neutrophil cytoplasmic antibodies were negative. Visual impairment and longitudinal-extended transverse myelitis with rostral involvement of the brainstem may be signs of NMOSD. However, our patient did not show increased signal within the optic nerves on T2-weighted sequences and did not fully meet the diagnostic criteria for NMOSD.¹⁰ Since the suspicion was too low, acquaporin-4 and myelin oligodendrocyte glycoprotein antibodies were not assessed.

Reversible cerebral vasoconstriction syndrome was also considered due to headache and focal intracerebral haemorrhage, but it seemed unlikely in absence of diffuse vasoconstriction on MRA.⁶

Recovering of symptoms after blood pressure control and improvement of the hyperintense T2-weighted lesions on a repeated MRI allowed a diagnosis of PRES associated with accelerated hypertension. In fact, even without typical symptoms of PRES, except for visual loss, clinical–radiological findings disappeared after normalisation of blood pressure.⁶

Treatment

On the first day of admission, the patient was started on ramipril 10 mg once a day. However, he had persistently elevated blood pressure and was still symptomatic. So that, 4 mg doxazosin and 30 mg nifedipine once daily were added. When his blood pressure was controlled, his symptoms gradually disappeared. Renal, renovascular and endocrine causes of secondary hypertension were excluded.

Outcome and follow-up

Blood pressure was controlled by day 8 of admission. Headache gradually improved as well as other clinical signs.

At 3-week follow-up the neurological examination was normal. A repeated brain MRI showed an almost complete resolution of the T2-hyperintense lesions. In particular, there were only some persistent centropontine alterations (figure 2). No enhancement was seen following contrast administration. The pontomedullary haemorrhage was seen again. These findings confirmed the diagnosis of atypical PRES with coincidental intraparenchymal haemorrhage.

Figure 2.

MRI at follow-up. MRI shows regression of the hyperintense lesions on T2-sequences, with complete resolution of the oedema and only a few persistent centro-pontine alterations (A, B).

At 2-year follow-up, the patient presented clinical and radiological stability. He was on ramipril 10 mg once daily and his blood pressure was within normal limits.

Discussion

The present paper describes an atypical case of PRES with prominent brainstem involvement in a 46-year-old man.

MRI is the gold standard for the diagnosis of PRES and should be performed as soon as possible. Since the first description in 1996,¹ several radiological patterns of PRES have been reported,⁵ including asymmetrical and unilateral variants^{3 11} or involvement of atypical regions, such as brainstem and cerebellum.^12–17 In typical PRES, neuroimaging usually reveals symmetric oedema in the subcortical white matter of parietal–occipital regions. Sparing of the calcarine and paramedian occipital lobe structures distinguishes PRES from bilateral infarction of the posterior cerebral artery.^{18 19} A key point is choosing the correct time to perform neuroimaging in order to demonstrate the presence of T2-hyperintense lesions, which disappear after removal of the causal factor. Many studies describe normal or non-specific findings when MRI is performed too early.⁴ On the other hand, if neuroimaging is abnormal, a too early repeated MRI could fail in highlighting a regression of the T2-hyperintensities.³ Symptoms of PRES usually resolve in 3–8 days, but MRI alterations may persist for several weeks. The ideal time of repeated brain imaging to document recovery is not clear.³ It seems advisable to repeat brain MRI at least 3 weeks after removing the causal factor of PRES.

Contrast enhancement can be variably present (figure 1). Since contrast enhancement is associated with the breakdown of the blood-brain barrier, it is especially expected in patients who are taking endothelium-toxic drugs, such as immunosuppressants.²⁰ No relevant associations have been found between contrast enhancement and clinical outcome, so intravenous gadolinium-based contrast seems not necessary to evaluate the severity or extent of PRES.²⁰ The presence or absence of contrast enhancement could be linked to the stage of the lesion, with cases lacking enhancement possibly being in a stage in which the blood–brain barrier has regained its integrity.²⁰

The diagnosis of PRES can be complex in atypical cases (2%–10%) involving the brainstem, which have to be differentiated from other diseases, for example posterior circulation stroke.⁶ In these cases DWI sequences on brain MRI help to distinguish cytotoxic oedema, typical of ischaemic lesions, from vasogenic oedema, typical of PRES: cerebral infarction shows hyperintensity on DWI with low signal on the corresponding apparent diffusion coefficient (ADC) map while PRES shows the exact opposite.⁶ However, alterations in DWI sequences may also occur incase of PRES: an increase in T2 signal caused by increased water within regions of vasogenic oedema can cause slight DWI hyperintensity (the so-called T2-shine through). However, the ADC maps, which are not influenced by the T2 component, show normal or elevated signal intensity, as expected in vasogenic oedema.²¹

Concomitant brainstem or cerebellar involvement in PRES occurs in as many as 70% of patients, whereas only brainstem or cerebellar involvement is reported uncommonly.^{15 22} In these cases, despite the presence of extensive MRI abnormalities, patients usually show mild symptoms or signs of brainstem or cerebellar dysfunction.²² Although PRES typically occurs in the fifth and sixth decades of life, brainstem variants have been reported even in younger subjects in the fourth decade.²²

Consistent with the literature data, our patient showed mild clinical symptoms associated with prominent MRI abnormalities, which initially led to a misdiagnosis of low-grade glioma. However, rapid reversibility of symptoms after controlling blood pressure aided in ruling out this hypothesis. Misdiagnosis of PRES as a brain tumour could be very dangerous and lead to unnecessary and invasive investigations, such as lumbar puncture, cerebral angiography, brain biopsy or even surgery.^23–28

Wide varieties of medical conditions have been suggested as causes of PRES.⁷ We believe that accelerated hypertension was the triggering factor in our patient. In fact, even if he had no history of hypertension, ophthalmological examination revealed a hypertensive retinopathy, hinting a chronic hypertensive insult. Sustained and persistent hypertension may exceed the brain vessels’ autoregulatory reserve, leading to vasodilatation and vasoconstriction with increased permeability of the blood–brain barrier and consequent vasogenic oedema.^{29 30} However, 15%–20% of patients with PRES are normotensive or hypotensive and, among patients who are hypertensive, less than 50% have a mean arterial blood pressure above the upper limit of cerebral blood flow autoregulation.²⁹ So that, some authors have suggested that endothelial dysfunction caused by hypertension or circulating toxins could have a pathogenic role in the syndrome.³¹ For example, cytokine release in immune disorders leads to increased vascular permeability, which possibly causes vasogenic oedema.²⁹ It has been proposed that posterior cerebral circulation might be more vulnerable to a failure in autoregulation, due to less sympathetic innervation, thus explaining the frequent bilateral posterior involvement in PRES.^{29 30}

Even when a possible triggering factor is found, the cause of PRES remains uncertain and the exact mechanism is still unknown.³²

PRES can appear as a severe clinical condition, but recovery is usually rapid and complete.⁷ Nevertheless, in some cases PRES could have secondary complications due to reactive vasoconstriction. In a series by Lee et al follow-up neuroimaging after 2 weeks demonstrated residual foci of abnormalities, suggestive of small residual infarcts, in approximately one-fourth of patients.³ Lesions compatible with transient white matter oedema may evolve into persistent areas of leukomalacia, especially when treatment is delayed.³³ Haemorrhages are considered an uncommon complication in PRES, ranging from 5% to 17% of cases.^{3 34} No significant difference in haemorrhage frequency has been found in patients having normal, mildly elevated or severely elevated blood pressure. The pathological mechanism of bleeding is still not understood. It has been proposed that haemorrhages could be the result of pial vessels rupture in severe hypertension or reperfusion injury in vasoconstriction.³⁴

Permanent neurological deficits and even death have been reported, questioning the complete reversibility of this clinical entity.^{29 34} In this regard, our patient remained asymptomatic during the follow-up period. Intracranial haemorrhage on repeated brain MRI was the only sequel of the syndrome. Furthermore, recurrent PRES episodes can present in about 4% of cases.³⁵

In conclusion, neuroimaging and clinical characteristics have a key role in making the correct and timely diagnosis of PRES, in order to avoid unnecessary investigations and prevent possible complications, such as intracranial haemorrhages.

It is important to exclude other possible differential diagnosis, especially in atypical cases of conspicuous brainstem involvement. In these circumstances, brain and spinal cord MRI is mandatory. When hypertension is concomitant to PRES, the management involves continuous blood pressure monitoring and rapid control of systemic blood pressure. Some authors recommend to treat ‘any degree of hypertension’ in the attempt to reduce the patient’s risk of complications.³¹ In the initial phase, blood pressure should be lowered no more than 25% in order to avoid ischaemic events.³⁰ Labetalol and nircadipine are usually administered as first-line treatments in intensive care units; nitroglycerin should be avoided due to possible worsening of vasogenic oedema.^{29 36}

When PRES occurs in normotensive patients, treatment consists of removing the possible triggering factor (ie, correcting metabolic abnormalities) and administering anticonvulsive medications if seizures occur.

There are no recommendations for specific anticonvulsive drugs or optimal duration of anticonvulsive therapy.²⁹

Learning points.

• Typical posterior reversible encephalopathy syndrome (PRES) is a clinical–neuroradiological entity with subcortical vasogenic oedema and preferential involvement of the posterior brain regions. MRI demonstrates bilateral widespread white matter alterations, which are reversible in 2–3 weeks.

• Atypical variants of PRES could involve the brainstem and cervical spine, mimicking neoplastic lesions. To confirm a diagnosis of PRES, it is useful to repeat a brain MRI, in order to demonstrate an expected improvement of T2-weighted hyperintensities.

• When hypertension is concomitant to PRES, the treatment involves continuous blood pressure monitoring and rapid control of systemic blood pressure.