Encephalopathy, hypertensive I67.4

Hinchey et al. first described hypertensive encephalopathy in 1996 in a total of 15 patients (Fischer 2017). At that time, the clinical picture was called RPLS = reversible posterior leukoencephalopathy syndrome. The name "posterior reversible encephalopathy syndrome (PRES)" was not given until 2002 (Schwab 2015).

PRES is an encephalopathy that occurs in the context of a hypertensive crisis (Herold 2022) or malignant hypertension. It describes a clinical syndrome (Okamoto 2017) and is usually reversible (Kasper 2015).

Hypertensive encephalopathy belongs to the "posterior reversible encephalopathy syndrome = PRES".

PRES can also be caused by a hypertensive crisis in the context of sepsis, renal disease, (pre)eclampsia, treatment with cytostatic drugs and autoimmune diseases. The latter often requires therapy with immunosuppressants, which can also trigger PRES (Fischer 2017).

Of those >70 years of age, approximately 70% suffer from arterial hypertension (Price 2014). Of these, about 1% suffer a hypertensive crisis. Of these, approximately 16% develop hypertensive encephalopathy (Schoenenberger 2009).

PRES may still be significantly underdiagnosed today. Therefore, epidemiological data should be interpreted with caution.

PRES can occur at any age, from children to older adults. However, females in young to middle adulthood are most commonly affected (Fischer 2017), even if patients with eclampsia are not included in the statistics (Gewirtz 2021).

In approximately 0.4-6%, PRES occurs after organ transplantation and / or treatment with immunosuppressants. After bone marrow transplantation (and the associated higher administration of immunosuppressants compared to organ transplantation), approximately 8% of patients are affected (Fischer 2017).

In patients with eclampsia, PRES is seen in > 90%, and in preeclampsia in approximately 20% (Fischer 2017).

Patients with covid- 19 who underwent neuroimaging develop PRES in approximately 1 - 4% (Gewirtz 2021).

- Hypertensive crisis (Herold 2015) triggered by:

- malignant hypertension

- sepsis

- renal diseases

- autoimmune diseases

- (pre)eclampsia

- Therapy with cytostatic drugs (Fischer 2017)

- Covid- 19 (Gewirtz 2021)

The exact mechanism of a PRES is unknown to date (Fischer 2017).

Currently, there are 2 leading theories on the pathophysiology of a PRES.

• 1st theory:

Here, the encephalopathy is related to the failure of cerebral blood flow autoregulation. The mean arterial pressure (MAP) is shifted by the cerebral autoregulation curve. However, the absolute value of the pressure is less important than the rate of pressure increase. This leads to vasodilation and hyperperfusion (Kasper 2015). This primarily affects the bilateral parieto-occipital region (Okamoto 2017).

This pathophysiology is particularly found in patients with malignant hypertension, autoimmune diseases, and renal diseases (Fischer 2017).

However, this theory is contradicted by the fact that approximately 30% of patients with PRES have normal or at most slightly elevated blood pressure values (Fischer 2017).

• 2nd theory:

According to the 2nd theory, PRES is caused by endothelial dysfunction caused by circulating endogenous and/or exogenous toxins (Fischer 2017). The dysfunction also primarily affects the bilateral parieto-occipital region (Okamoto 2017).

As a consequence of primary endothelial dysfunction, blood pressure elevations occur.

This pathophysiology is predominantly found in patients with eclampsia, autoimmune diseases, sepsis , and under treatment of cytostatic drugs such as chemotherapeutic agents or immunosuppressive drugs (Fischer 2017).

The onset of the disease is usually (sub) acute (Fischer 2017).

Symptoms that may be present in PRES include:

- severe arterial hypertension

- headache

- nausea

- vomiting

- confusion

- stupor

- convulsions

- coma

- Elevated protein levels in cerebrospinal fluid

- cerebral edema (Herold 2022 / Kasper 2015)

- impaired visual acuity

- visual field defects (Fischer 2017)

- nosebleeds

- but an asymptomatic course is also possible (Bopp 2021)

To date, the diagnosis of PRES is mostly a diagnosis of exclusion, as established diagnostic criteria are lacking and imaging techniques predominantly do not show specific findings (Fischer 2017).

Physical examination

- Measure blood pressure on both arms using the correct cuff size

- Obtain neuro status

- Check any visual field defects

- Check ocular fundus (retinopathy)

- check for microvascular or renal damage

- auscultate any flow sounds over the kidneys

- cardiovascular examination (Bopp 2021)

MRI

- Brain edema

MRI typically shows vasogenic (Lamy 2014) posterior (occipital > frontal) brain edema, which is usually reversible. It is referred to as "posterior leukoencephalopathy."

The radiological term "reversible posterior leukoencephalopathy (RPLE)" is now considered obsolete. Nowadays, the picture is referred to as a "posterior reversible encephalopathy syndrome = PRES" (Kasper 2015).

- Intracranial hemorrhage

At times, intracranial hemorrhages (seen as microhemorrhages in approximately 65% [Fischer 2017]) may be observed and/or sites of restricted diffusion, similar to infarction (Okamoto 2017). Microbleeds are best visualized in T2-weighted sequences (Fischer 2017).

- watershed distribution

- vasogenic edema

- Lesions of the subcortical substance (Fischer 2017), which are often symmetrically arranged (Schwab 2015)

- Involvement of frontal and parietal lobes possible (Fischer 2017).

- FLAIR sequences show white matter lesions (Bopp 2021).

However, cases with normal imaging have also been described (Kasper 2015).

Computed tomography

CT is less sensitive than MRI. Patchy hypodensity may be detectable in the affected area on CT (Kasper 2015).

EEG

EEG does not show specific changes (Schwab 2015). There may be:

- slowed delta waves

- rhythmic delta activity

- diffuse theta slowing

- sharp-slow wave activity

- focal or diffuse symmetrical slowing of background activity

- periodic lateralized epileptiform discharges (Fischer 2017).

Angiography

Angiography may reveal vasoconstriction and diffuse or focal vasospasm (Fischer 2017).

Indications of PRES are:

- Lactate dehydrogenase (LDH) elevated

- Liver function parameters increased

- Magnesium decreased (occurs during the first 48 h)

- Serum protein decreased (found in up to 85% of patients)

- Creatinine elevated (Fischer 2017)

- Thrombocytopenia

- Number of schistocytes increased (Schwab 2015).

CSF

Analysis of cerebrospinal fluid usually shows nonspecific changes (Kasper 2015).

Pathologically altered may be:

- Albumin elevated

- Albuminocytogic dissociation (Fischer 2017).

• Reversible cerebral vasoconstriction syndrome = RCVS:

Fischer (2017) refers to it as the most important differential diagnosis.

• Apoplexy:

Focal neurological deficits that do not occur in PRES are indicative of apoplexy (Bob 2021).

• Sinus vein thrombosis

Differentiable on MRI (Schwab 2015).

Since there is no specific treatment for PRES to date, therapy is purely symptomatic (Fischer 2017).

Blood pressure in patients with hypertensive encephalopathy should be lowered rapidly, but overly aggressive therapy also carries risks, e.g., in the form of apoplexy (Kasper 2015

• Blood pressure reduction

Hypertension should be lowered with first-line medications in the presence of hypertensive encephalopathy. These include labetalol and nicardipine. These should be delivered i. v. with continuous monitoring (Williams 2018).

Recommended dosage Labetalol:

Dilute 200 - 400 mg (1 - 2 ampoules of 20 ml) in isotonic basic infusion solution to a total of 200 ml and infuse at an infusion rate of 120 mg / h in the supine or left lateral position (manufacturer's information Aspen Pharma), duration of action: 4 - 6 h (Bopp 2021).

Dosage recommendation Nicardipine:

z. E.g. Antagonil 5 - 10 mg / h per infusionem (Wilhelm 2913).

Eberhardt (2017) recommends clevidipine i. v.

Dosage recommendation clevidipine:

z. E.g. Cleviprex 2 mg / h, increase by 2 mg / h every 2 min until target pressure is reached; maximum dose is 32 mg / h (Bopp 2021).

Mean arterial pressure (MAP) should be reduced by approximately 20% (Kasper 2015) within the first hour. In the next 6 h, reduce blood pressure to 160 / 100 mmHg and after 48 h normalize blood pressure (Bopp 2021).

• Anticonvulsants

Anticonvulsant therapy is not infrequently required. Here, there is no general recommendation of specific drugs. Anticonvulsant therapy can be discontinued as soon as the patient is asymptomatic and imaging reveals unremarkable findings (Fischer 2017).

• Magnesium

Since many patients have hypomagnesemia, magnesium should be substituted up to the high normal value (Fischer 2017).

On average, approximately 40% of patients with PRES require intensive care monitoring due to the severity of the disease and any complications (Fischer 2017).

The prognosis of hypertensive encephalopathy is usually favorable (Okamoto 2017). Both clinical symptoms and imaging changes are usually reversible. In individual cases, however, neurological sequelae may develop, including long-lasting epilepsy (Fischer 2017).

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