PRES secondary to autonomic dysreflexia: A case series and review of the literature

Abstract

Context: Autonomic dysreflexia (AD) is a complex syndrome seen in patients with spinal cord injuries (SCI) and can be life-threatening with a significant negative impact on the health of the individual. Posterior reversible encephalopathy syndrome (PRES) is thought to be caused, in part, by rapid elevations in blood pressure; leading to posterior cerebral circulatory edema. This can result in seizures, blindness and can progress to fatal intracranial hemorrhages.

Findings: Here we present two cases of patients with SCI who developed PRES from AD. Each patient was correctly diagnosed, leading to appropriate treatment of the factors leading to their AD and subsequent resolution of their PRES symptoms.

Conclusions/Clinical Relevance: In SCI patients who present with new seizures, visual deficits, or other neurologic signs, PRES should be considered as a part of the differential diagnosis as a good outcome relies on rapid recognition and treatment of AD.

Introduction

Autonomic dysreflexia (AD) is a syndrome seen in patients after a spinal cord injury (SCI) at or above the level of T6, though it has been described in patients with injuries as low as T12.^1–3 The syndrome largely causes symptoms secondary to an abrupt, significant rise in the systolic blood pressure (BP). As many as 90% of patients with a SCI above T6 experience AD at some point after injury, which can happen multiple times per day.^4,5 While it is not a stereotyped syndrome, it often presents with hypertension, headaches and the sensation of hot flashes. Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome characterized by seizures, altered mental status, blindness or visual changes and hyperintensities on T2 and FLAIR MRI sequences in the posterior parietal and occipital lobes.^6,7 PRES has been associated with chemotherapeutic and immunosuppressant use, eclampsia, renal disease and uremia, and is associated with an abrupt rise in systolic BP.^8,9 Here, we present a series of patients who developed AD that led to PRES. We then discuss the mechanics of BP leading to PRES and the common presenting symptoms in this population.

Case 1

A 36-year-old gentleman sustained a SCI from a motor vehicle collision 6 months prior to admission. His injury was graded as T4 American Spinal Injury Association Injury Scale (AIS)impairment score A (ISNCSCI version1.0.2).¹⁰ He presented to his local emergency department with an acute headache and a subsequent generalized seizure while watching his child’s soccer game. His BP was >200 mmHg systolic. While in the emergency department, he suffered two additional seizures. A Computed Tomography (CT) scan revealed a subarachnoid hemorrhage with hyperdensities along the convexities of the parietal and occipital lobes (Fig. 1). A CT angiogram of the intracranial vessels performed to evaluate for aneurysmal origin was suggestive of a pericallosal artery aneurysm (Fig. 2). His BP was managed medically, and he was transferred to our hospital for treatment of the pericallosal aneurysm.

Figure 1.

Brain CT without contrast demonstrated hyperdensity in the left lateral occipital and posterior temporal lobes, along with mild hypodensity of the underlying cortex (Case 1).

Figure 2.

Brain CTA was suggestive of a pericallosal aneurysm (arrow) (Case 1).

Upon arrival, he was at his neurologic baseline, with mean arterial pressure ranging from 80 to 90 mmHg; complaining only of headaches. Additional angiography of intracranial vessels did not demonstrate the previously seen pericallosal aneurysm seen on the CTA. He was diagnosed with AD based on BP parameters and symptoms and was found to have a urinary tract infection (UTI) to which his AD was attributed. Five days after his admission, he presented with headache, diaphoresis, bradycardia of 53 beats-per-minute and BP of 170/90 mmHg. He was treated with IV hydralazine, and his headache resolved with reduction of his BP to 91/47 mmHg, and HR of 85. CT of the brain did not demonstrate additional findings. Brain MRI obtained to evaluate for other causes of his headaches and seizures revealed symmetric subcortical foci of Fluid-Attenuated Inversion Recovery (FLAIR) signal centered around the left and right high central sulci, consistent with PRES (Fig. 3). He was monitored in the hospital for two additional days where his BP was seen to be stable, with no new neurologic deficits. He had no follow up at our institution.

Figure 3.

Brain MRI (a) T2 FLAIR MRI demonstrates hyperintensity along the posterior cortex. Normal findings on diffusion weighted imaging (b) (Case 1).

Case 2

An 18-year-old female with a C2 AIS A SCI she suffered seven months prior presented to the emergency department with 24 h of headache, visual field loss, nausea, light-sensitivity, and fever. In the emergency department, her BP was 152/88 mmHg with a HR 82. Her baseline BP was typically in the 100’s systolic. She complained of severe headache. She had no previous episodes of AD, but had type-1 diabetes, and previous watershed strokes from hypoperfusion during an aortic pseudoaneurysm repair, history of pressure wounds and recurrent UTIs. Upon arrival, her Glasgow Coma Scale (GCS) score was 14 due to confusion. An evaluation for new strokes, hemorrhage or meningitis was unrevealing. Brain MRI revealed T2 and FLAIR hyperintensity in a patchy cortical and subcortical distribution in the parietal lobes, extending to the occipital poles, and in the posterior temporal region on the right side. There was patchy left lateral and inferior cerebellar hyperintensity (Fig. 4A and B). She was diagnosed with PRES secondary to AD. Her BP was treated with hydralazine and a UTI was diagnosed. The remainder of her hospital stay was uneventful, and she had no further recurrence of AD.

Figure 4.

Brain MRI T2 image demonstrates hyperintensities in the left cerebellum (a) and right occipital lobe extending from the parietal lobe (b) (Case 2).

In Table 1, we have summarized the other nine reports of PRES associated with AD in the literature. A common underlying theme is an elevation in BP from the patients’ “normal” level; though many have BP elevated beyond what is normal for patients without SCI.^19,20

Table 1. Summary of cases in the literature of AD leading to PRES.

Source	Patient information	Imaging findings	Symptoms	Outcome
Phillips, A.A., et al.11	59-year-old man with T4 AIS A, 42 years prior to presentation. Baseline BP 100 systolic	MRI demonstrated subcortical T2 and FLAIR abnormalities in the posterior parietal and occipital lobes bilaterally	12 h of headaches, vision loss, nausea. BP 219/113 mm Hg and HR 59. GCS of 10, then suffered a tonic-clonic seizure resulting in GCS 3 and intubation. UTI present and treated.	Blood pressure treated with hydralazine. Extubated on hospital day 3, was at baseline by hospital day 6. At 6 months he had complete symptom.
Matias A.C., et al.12	55-year-old man with C4 AIS A SCI after a bicycle accident 2 years prior to admission. Baseline BP 90/60 mmHg	CT demonstrated cortical and subcortical hypodensities in the parieto-occipital lobes, and cerebellar hemispheres. MRI demonstrated FLAIR and T2 signal changes in the parieto-occipital lobes. Complete resolution on MRI several months later.	Generalized tonic clonic seizure; BP 130/83 mmHg. Febrile with UTI	Recurrent episode of PRES with AD 1 month later with SBP 190/85 mmHg with UTI.
	41-year-old man with C4 AIS A SCI after an MVC 10 months prior to presentation. Many episodes of AD while in rehab.	Brain MRI with FLAIR signal changes in the occipital lobes. MRI changes resolved 1 month later.	Generalized tonic clonic seizure with severe headache. BP 188/96 mm Hg. UTI present.	UTI treated and headaches resolved. MRI improved.
Chaves C.J., et al.13	55-year-old-female with C6 AIS C SCI;6 months prior.	MRI demonstrated T2 hyperintensities in the subcortical white matter of bilateral medial occipital lobes and left post-central gyrus. Complete resolution 1 month later.	Developed headache after assisted cough maneuver. SBP 213 mmHg; declined to BP 160/100 mmHg. Presented with cortical blindness.	Resolution of blindness. No infection or bowel dysfunction found. AD thought to be secondary to assisted cough.
Joa, K.L., et al.14	58-year-old-male, C5 AIS A SCI. Baseline BP 110/95 mmHg. Elevation of BP whenever bladder full (160/80 mmHg).	MRI demonstrated T2 hyperintensities in the subcortical white matter of both parieto-occipital lobes, temporal lobes, cerebellum, and basal ganglia. Complete resolution on MRI 2 months later.	Presented with somnolence and hypoventilation. BP 160/80 mmHg. Foley placed and nifedipine was administered.	Re-admitted 3 months later with PRES, suffered 3 tonic clonic seizures. Required tracheostomy, PEG, and treatment for pneumonia.
	54-year-old male with C6 AIS C SCI, history of orthostatic hypotension and frequent AD from overactive bladder. Presented with BP 160/110 mmHg (baseline 125/85 mmHg).	MRI demonstrated T2 hyperintensities in the subcortical white matter of both parieto-occipital lobes and the cerebellum. Multiple hemorrhagic foci in the lesion area were also observed. Complete resolution 1 month later	Intermittent headaches with elevated BP; developed somnolence, seizures and hypertension. Catheterized to treat overactive bladder	No neurologic or cognitive deficits resulting from PRES. Treated with oxybutynin and straight intermittent catheterization every 4–6 h.
Squair, J., et al.15	59-year-old male with T4 AIS A SCI after an MVC 42 years prior to admission. History of severe and recurrent AD with UTI.	MRI demonstrated subcortical T2 and FLAIR abnormalities in the posterior parieto-occipital lobes bilaterally, slightly more predominant on the left	12-hour history of headaches, loss of vision, nausea, altered level of consciousness, and suffered a tonic–clonic seizure. BP 219/113 mmHg, HR 56	Treated with hydralazine and propofol, BP was 100/50 mmHg. Symptoms resolved over 6 days, no recurrent seizures or other neurologic sequelae were documented at 6 month follow up
Yamashita, T., et al.16	37-year-old male with C4 AIS B SCI after MVC 10 years prior to admission. History of neurogenic bladder and cystotomy was performed with catheter being changed every 4 weeks. Urethra was injured while changing a catheter and systolic BP became elevated to 188 mmHg, Declined to 140 mmHg with treatment	CT demonstrated low density areas in the bilateral occipital and frontal lobes. Follow up CT 2 days later demonstrated hemorrhage in frontal and occipital lobes MRI demonstrated bilateral occipital and frontal high intensity areas on FLAIR	Two weeks after catheter exchange, he developed headache, visual changes, nausea, vomiting then became somnolent with GCS 8. Wide fluctuations in blood pressure with bradycardia (values not provided)	Comatose requiring mechanical ventilation and subsequent death after withdrawal of care 3 weeks after hemorrhage.
Zimering, J.H., et al.17	68-year-old female discharged home after MVC but presented two days later with AIS D SCI after C5-C6 subluxation. Mean arterial pressure was elevated to 85–100 mmHg perioperatively to maintain spinal cord perfusion using pressors, not related to AD. Underwent anterior/posterior fusion.	MRI demonstrated areas of T2 hyperintensity in bilateral occipital lobes Complete resolution on MRI two weeks later.	Immediately post operatively patient had poor neurologic exam and was ultimately found to be in status epilepticus. Seizures treated and she was extubated, discharged home.	No further symptoms from PRES, no additional seizures. Strength returned by two-year visit without any signs of previous spinal cord injury.
Rodriguez J., et al.18	65-year-old male with C4 AIS B SCI. No information on time since injury. Cause of AD not noted in the report. Long term follow up not available.	MRI demonstrated T2 and FLAIR sequences with multiple hyperintensities throughout occipital lobes.	Presented with BP of 200/100 mmHg, loss of vision in both eyes, decreasing level of consciousness, then seizure.	Report does not mention etiology of AD, nor treatment. Blood pressure was treated. The patient had relapses in symptoms when blood pressure was elevated.

Discussion

AD was initially described by Guttmann and Whitteridge in 1947 after observation of the effects of bladder distention in patients with SCI.³ They described a pattern of hypertension, bradycardia, and diaphoresis above the level of the injury. Many patients experienced feelings of anxiety, headaches, nausea, and chest tightness.^9,21 The pathophysiology of AD involves the interruption of signals descending from the supraspinal vasomotor centers and aberrant plastic changes that occur within the spinal cord and peripheral nervous system.¹¹ Noxious or non-noxious stimuli below the level of injury reach the spinal cord and result in activation of spinal circuits that have lost supraspinal inhibition. This is associated with a massive sympathetic surge from the thoraco-lumbar sympathetic preganglionic neurons, which results in peripheral vasoconstriction and hypertension. This is detected through baroreceptors (via cranial nerves IX and X), and a recent study²¹ showed that many patients have tachycardia associated with the hypertension.^2,19,22 Accordingly, patients who have clinically complete lesions have a more severe response than those with incomplete injuries; as do those with more rostral lesions when compared to more caudal lesions.²

Patients with SCI typically have baseline systolic BP (in the range of 90–110 mmHg) which is much lower than what may be otherwise considered normal.^2,23,24 Treating physicians need to recognize that a normal BP in a neurologically intact individual may not translate to a normal BP in a patient with SCI. The first patient illustrates this point as his BP was fluctuating while hospitalized, however not elevated to pressures commonly associated PRES. While the AD was initially missed leading to the development of PRES, the prompt recognition of the inciting cause was identified, and he ultimately recovered.

Prevention of AD is accomplished by establishing regular bowel programs, intermittent catheterization and preventing pressure wounds. The patient should sit up if supine, any constrictive clothing such as compression stockings or abdominal binder should be removed, the bladder should be emptied, bowels checked for stool impaction and the skin examined for wounds or any source of nociceptive stimuli.²⁵ If systolic pressures are >150 mmHg, treatment with a quick-acting, short lasting medication such as hydralazine or nitroglycerin paste should be the first priority.^2,23 The most important factor in effectively treating AD is promptly removing its trigger.²⁶

PRES can arise from multiple pathologic conditions such as eclampsia, cyclosporine after transplant, and with severe hypertension.⁶ It is characterized by sudden headache, seizure, and visual abnormalities. Brain MRI demonstrates hyperintensity on T2 and FLAIR MRI sequences.^6,7 PRES was first described in 1996 in a review of 15 cases with diverse histories, consisting of solid organ transplant, eclampsia, and uremia with renal failure⁸ though interestingly it is not always reversible nor benign.^9,14,16 Over the past two decades other clinical signs associated with PRES have been identified, including cortical blindness, hemianopsia, or blurred vision. Other reports describe diminished alertness, stupor, paucity of speech, memory impairments and vomiting. Some of these signs and symptoms such as headaches, diminished alertness, stupor and memory impairments overlap with AD which also adds to the challenge of making an accurate diagnosis in SCI patients. Radiological signs of PRES are rarely seen in the anterior circulation.⁷ AD-associated PRES is a more complex syndrome than AD alone and is believed to be the result of impaired cerebral vascular autoregulation.²⁷ Blurred vision was the most common visual symptom, followed by hemianopsia and cortical blindness. Imaging revealed T2 hyperintensities on MRI and hypodensities on CT scans in the posterior circulation. In our cases, AD was caused by UTIs and had lower BP than found in a typical hypertensive emergency.

One possible etiology of PRES is that an abrupt and severe rise in BP overcomes the brain’s ability for autoregulation, leading to edema as fluid leaks from capillaries. The resolution of symptoms with BP treatment and several animal studies support this theory.²⁷ Hypertensive encephalopathy has been documented in many other pathologic states in which systemic BP surpasses the limits of autoregulation.²⁸ Furthermore, abnormal autoregulation of cerebral vasculature seen in SCI may predispose the posterior circulation to hypoperfusion.²⁹ Conversely, some evidence exists that there is hypoperfusion and vasoconstriction, notable in patients who develop PRES in the absence of hypertension^6,30 Another theory suggests that systemic toxicity (from chemotherapeutics, infection etc) leads to endothelial cell dysfunction and hypoperfusion,²⁷ and this is supported by the diversity of conditions associated with PRES.

It is likely that it is a combination of autoregulation which is overwhelmed by hypertension along with altered endothelial permeability leads to the development of PRES. This is highlighted by the prevalence of PRES, ranging from 0.5% to 5%³¹ in patients undergoing treatment with Sirolimus, Tacrolimus and bevacizumab- all agents which compromise vascular permeability and have the potential to alter the endothelium. Others suggest that vasospasm causes endothelial breakdown, leading to cerebral edema.²⁷ Immune suppression can be caused by both AD and SCI, independent of each other^32,33 Immunosuppression combined with AD could be a key factor in the development of endothelial dysfunction and PRES. It has been noted that PRES is typically seen in patients with an underlying systemic process leading to dysregulation of the immune system and endothelial dysfunction.²⁷ The predilection for involvement of the posterior circulation has been the source of ongoing research. There may be less sympathetic innervation of the posterior circulation; however as discussed above, the anterior circulation may also be affected.^34,35

When treating AD-associated PRES, prompt diagnosis and removal of the offending agent is critical. While searching for the AD trigger, it may be necessary to administer anti-hypertensive drugs such as nitroglycerine paste and/or hydralazine.¹⁵ With rapid treatment, symptoms resolve and radiological findings reverse. If treatment is delayed deficits can become permanent or progress to hemorrhage and death.^16,36,37 It is important to educate primary responders, first line medical personnel, and SCI patients themselves about AD for early appropriate diagnosis and treatment. While rare, PRES should be considered with acute neurological compromise in SCI patients with no immediate changes of edema or hemorrhage on brain CT. Early recognition and timely intervention will lead to better outcomes for SCI patients with AD-associated PRES.

Conclusions

The two cases reported here add to the previously reported cases from the literature, which highlight the importance of including PRES on the differential diagnosis when a SCI patient shows new neurological symptoms such as seizures, visual deficits, and headache while presenting with AD. Better outcomes rely on rapid recognition and treatment of PRES.

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Contributors None.

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Conflicts of interest Authors have no conflict of interests to declare.