What are the differential diagnoses for Posterior Reversible Encephalopathy Syndrome (PRES)?

Differential Diagnosis for Posterior Reversible Encephalopathy Syndrome (PRES)

Primary Differential Considerations

The most critical differential diagnoses for PRES include cerebral amyloid angiopathy-related inflammation (CAA-ri/ABRA), reversible cerebral vasoconstriction syndrome (RCVS), acute disseminated encephalomyelitis (ADEM), and primary angiitis of the central nervous system (PACNS), with the key discriminating feature being clinical context and specific imaging characteristics. 1, 2

Vascular and Inflammatory Disorders

Reversible Cerebral Vasoconstriction Syndrome (RCVS)

• Recurrent thunderclap headache (TCH), and single TCH combined with either normal neuroimaging, border zone infarcts, or vasogenic edema have 100% positive predictive value for diagnosing RCVS or RCVS-spectrum disorders 2
• The key distinguishing feature is the presence of thunderclap headaches and characteristic arterial vasoconstriction on angiography that resolves within 3 months 2
• Both PRES and RCVS can coexist, making differentiation challenging in some cases 2

Cerebral Amyloid Angiopathy-Related Inflammation (CAA-ri/ABRA)

• This is the main differential diagnosis for amyloid-related imaging abnormalities (ARIA) in patients on anti-amyloid monoclonal antibody therapy 1
• The discriminating feature between CAA-ri/ABRA and ARIA is the history of anti-amyloid MAB therapy; without this history, CAA-ri should be strongly considered 1
• Both present with similar T2 FLAIR hyperintensities and microhemorrhages 1

Primary Angiitis of the Central Nervous System (PACNS)

• Must be considered in the differential diagnosis of new cerebral arteriopathies presenting with PRES-like features 2
• Requires vessel biopsy or angiographic evidence of vasculitis for definitive diagnosis 2

Infectious and Autoimmune Encephalopathies

Acute Disseminated Encephalomyelitis (ADEM)

• Can present with identical clinical and radiological features to PRES, creating significant diagnostic dilemma 2
• Advanced imaging techniques such as MR spectroscopy or positron emission tomography (PET) can provide additional information to distinguish ADEM from PRES 2
• ADEM typically follows viral infection or vaccination and shows more extensive white matter involvement 2

Chronic Infectious and Autoimmune Meningoencephalitis

• Must be systematically excluded in cirrhotic patients presenting with neurological symptoms that could mimic PRES 1
• CSF analysis is essential when infectious etiology is suspected 1

Metabolic and Toxic Encephalopathies

Hepatic Encephalopathy

• In cirrhotic patients, complete medical history including recent infections, trauma, withdrawal and psychotropic drugs must be obtained 1
• Blood tests including electrolytes, glucose, calcium, cell blood count, inflammatory proteins, blood urea and creatinine are essential 1
• Asterixis is strongly suggestive of metabolic encephalopathy but can occur in uraemia, hypercapnia, hypoglycaemia, and urea cycle defects 1

Toxic-Metabolic Encephalopathy

• Accounts for 21% of cases when PRES is not confirmed radiologically 3
• Includes uraemic encephalopathy, recurrent hypoglycaemia, hypo/hyperthyroidism, and inherited metabolic disorders 1
• Correction of electrolyte imbalances is essential, particularly hyponatremia, hypokalaemia, and hypomagnesaemia 1, 4

Drug-Induced Encephalopathy

• Ifosfamide-induced encephalopathy presents with altered consciousness, confusion, and seizures, requiring immediate discontinuation and thiamine administration 4
• Antiepileptic drugs, levodopa, opiates, anticholinergics, benzodiazepines, lithium, and clozapine can all cause asterixis and encephalopathy 1
• Immunosuppressants (tacrolimus, cyclosporine) are well-known causes of PRES itself but can also cause other forms of neurotoxicity including leukoencephalopathy and progressive multifocal leukoencephalopathy (PML) 5, 6, 5

Vascular Pathology

Cerebrovascular Disease

• Accounts for 12% of cases when PRES is not confirmed 3
• Subacute infarcts can mimic PRES on imaging, particularly in posterior circulation 1
• Cerebral microangiopathy (vascular leukoencephalopathy) must be considered, especially in patients with metabolic syndrome and NAFLD 1
• Hypertensive encephalopathy with cerebellar involvement shows increased T2/FLAIR signal but typically has different distribution patterns 7

Hemorrhagic Conditions

Subarachnoid Hemorrhage

• Can present with sulcal FLAIR hyperintensity similar to ARIA-E (a PRES variant) 1
• CT is useful to exclude intracranial hemorrhage when MRI is not immediately available 8, 7

Hypertensive Microhemorrhages and Cerebral Amyloid Angiopathy

• These are differential considerations for ARIA-H (hemorrhagic form of PRES-related changes) 1
• Diffuse axonal injury should also be considered in the appropriate clinical context 1

Neurodegenerative and Demyelinating Disorders

Progressive Multifocal Leukoencephalopathy (PML)

• Presents with hemiparesis, apathy, confusion, cognitive deficiencies, and ataxia in immunosuppressed patients 6
• Risk factors include immunosuppressant therapies (cyclosporine, tacrolimus) and impaired immune function 6, 5
• Neurological consultation should be considered when PML is suspected 6

Posterior Multifocal Leukoencephalopathy

• Included in the differential diagnosis for ARIA-E 1

Neurodegenerative Diseases

• Must be considered when cognitive impairment is accompanied by progressive evolution or absence of fluctuations 1
• Significant temporospatial disorientation, anterograde episodic memory impairment, and visuoconstructive impairments suggest alternative diagnoses 1

Other Considerations

Primary or Secondary Headaches

• Account for 26% of cases when PRES is not confirmed radiologically 3
• Headache alone was not a useful predictor of PRES in clinical studies 3

Psychiatric Disorders

• Anxiety disorders, major depressive disorder, and psychotic disorders can present with altered mental status 1
• These should be considered after excluding organic causes 1

Meningitis and Vasculitis

• Both can present with FLAIR hyperintensities and altered mental status 1
• CSF analysis and contrast enhancement patterns help distinguish these from PRES 1

Key Diagnostic Approach

Essential initial workup includes:

• Brain MRI (preferred over CT) with DWI, T2 FLAIR, and T2* GRE or SWI sequences 1, 8
• Blood tests: electrolytes, glucose, calcium, complete blood count, inflammatory markers, renal function 1, 8
• Blood pressure monitoring and history of hypertension 8, 7
• Medication history, particularly immunosuppressants, chemotherapy, and recent drug changes 1, 8
• Clinical context: eclampsia, renal failure, autoimmune disorders, transplantation 1, 8

Common pitfall: PRES need not necessarily be always associated with high blood pressure, and imaging findings may be variable 2. Atypical imaging presentation should not reject the diagnosis of PRES in a compatible clinical situation 9.