Grand RoundsVanderbilt Eye Institute

4/27/07

Ryan Tarantola M.D. PGY-2

Initial Evaluation 3/5/07

CC: Headache and acute bilateral vision loss

HPI:

• 43 year-old female

• 24 hour hx of HA, nausea/vomiting

• Awoke with bilateral NLP vision.

PMH: Relapsing B cell lymphoma dx 10/05 S/P multiple courses of chemo and recent BMT

POH: Wears glasses No eye disease No trauma or surgeries

Allergies: Codeine, PCN

FH: No eye disease

SH: Married with 2 children. No tobacco, alcohol, or drug use.

ROS: +HA, N/V

Meds: Levaquin, Mycofungin, Valtrex, Nystatin, Cyclosporin, Prednisone, Zyrtec, Effexor, Prevacid, MVI

VA sc at near:OD: NLP OS: NLP

General: Depressed level of consciousness Developed right gaze preference and seizure-like episode. Intubated and treated with IV Ativan at that time.

Localization?

Pupils: 42mm, no RAPD OU

Visual Fields: unable

Motility: Full OU

Tp: OD:16 OS:13

Pen Light Exam: WNL OU

Dilated Fundus Exam:

Vitreous: Clear OU

Optic Nerves: C/D: 0.3 OU

Macula: WNL OU

Periphery: WNL OU

Labs:

Toxicology Screen: Negative

CSF: clear, cell count wnl, protein: 43, gram stain -, culture -

CBC c differential, CMP: WNL

Imaging:

CT Head s Contrast: No acute intracranial abnormality

Acute onset of HA and N/V followed by bilateral post-geniculate visual loss, and SZ.

Differential Diagnosis?

Differential Diagnosis1. Vascular

a. Granulomatous angiitisb. SLEc. PANd. PRES: Posterior Reversible Encephalopathy Syndrome

2. Ischemic/Thrombotica. Ischemic stroke of posterior circulationb. Cerebral Venous Thrombosis

3. Infectiousa. Progressive Multifocal Leukoencephalopathyb. Infectious Encephalitis

4. Inflammatory/Demylenating

a. Acute Disseminated Encephalomyelitis 5. Mitochondrial Disease

a. MELAS: Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like episodes

6. Non-Organic

Additional Studies?

MRI of the Brain 3/5/07

DWI ADC

DWI ADC

FINDINGS:

• Patchy areas of increased signal on T2 and FLAIR involving the cortical and subcortical white matter of the occipital and parietal lobes bilaterally

• No associated restricted diffusion or enhancement

• Findings consistent with posterior reversible encephalopathy syndrome (PRES). Consider Cyclosporine toxicity

PRES: Posterior Reversible Encephalopathy Syndrome

• Described in 1996 by Hinchey et al in NEJM

• Transient, reversible, posterior cerebral edema

• Headache, nausea, vomiting, altered mental status, seizures, and visual disturbances

• Blurred vision, visual field loss, and complete cortical blindness

• MRI brain reveals characteristic findings

PRES: Posterior Reversible Encephalopathy Syndrome

• Involve the white matter > cortex

• Completely reversible when promptly recognized and treated

• Patients can progress to ischemia, massive infarction, and death

• Multiple systemic associations

PRES: Posterior Reversible Encephalopathy Syndrome

Associations: 1. Toxemia of Pregnancy

2. Drugs:CyclosporinTacrolimus (FK506)Interferon-alphaFlutarabineCisplatinGemcitabineErythropoietinIfosfamide

3. Secondary Hypertension:SLEAcute GlomerulonephritisHTN with CRF

4. Uncontrolled Essential Hypertension

5. Others:Hemolytic Uremic SyndromeHepatorenal SyndromeAcute Intermittent PorphyriaHIVBlood TransfusionPost-CEATTP

PRES: Posterior Reversible Encephalopathy Syndrome

Pathophysiology:

• Posterior cerebral circulation has reduced perivascular sympathetic activity.

• Autoregulation in response to hemodynamic challenge (HTN) is insufficient.

• Local increases in hydrostatic pressure cause extravasation of fluid.

• Regions of vasoconstriction and vasodilatation develop hypoperfusion.

• Focal areas of blood-brain barrier breakdown and further fluid extravasation

PRES: Posterior Reversible Encephalopathy Syndrome

Radiologic Findings:

Vasogenic Edema:

• DWI shows parieto-occipital signal changes caused by fluid entrapment in the edematous region.

• ADC map removes the underlying T2 signal (T2 shine through) allowing distinction between vasogenic and cytotoxic edema.

MRI

• T1: Short TR, Short TE Fat>White Matter>Gray Matter>Vitreous/CSF>Air Demonstrates normal anatomy

• T2: Long TR, Long TE Vitreous/CSF>Gray Matter>White Matter>Fat. Demonstrates inflammation, ischemia, and neoplasia

• FLAIR: Very Long TR, Long TE Fat>Gray Matter>White Matter>Vitreous/CSF>Air Similar to T2 without CSF signal. Demonstrates demylelination

• DWI: Cellular swelling slow diffusion of molecules into cells Demonstrates regions of edema Reflects both diffusion weighting and T2 effects

• ADC: Constructed from diffusion data Removes underlying T2 signal

• CT, T2: Bilateral occipital lesions with a white matter predominance. • DWI: Slight hyperintensity, left more than right. ? cytotoxic edema due to infarction vs. T2 effects• ADC: Shows T2 shine through supporting a vasogenic pattern of edema

PRES

• T2: hyperintensity along the right calcarine cortex• DWI: Marked hyperintensity (lightbulb sign) characteristic of acute infarction• ADC:Hypointensity confirms that this is restricted diffusion related to cytotoxic edema

Acute Occipital Infarction

T2

DWI

ADC

Pande et al, 2006

• Multicenter retrospective study

• 53 patients July 1999-June 2003

• PRES lesions in the subcortical white matter showed significantly higher reversibility (76-91%) than those in the brain stem (44%), deep white matter (47%) and thalamus (60%).

• Complete resolution of radiographic findings occurred in 12/12 with eclampsia, 7/11 with hypertension, 12/21 drug-induced, 2/5 renal failure.

• Conclusions: Location of lesions and etiology are significant factor in reversibility of PRES.

How Reversible is PRES?

Cyclosporin and PRES

• Cyclosporin inhibits gene transcription of IL-2, IL-3, IFN- and directly inhibits activation / differentiation of T cells

• Most common medication associated with PRES

• Likely secondary to its ability to increase bp and cause fluid retention

• Toxic effect on vascular endothelium

• Low magnesium, aluminum overload, and high-dose steroids also potentiate toxicity of cyclosporin

• Frequently causes hypomagnesaemia and lower seizure threshold

Treatment of PRES

• Reduction of bp and removal of causative agent

• IV Nicardipine and Labetalol are 1st line agents

• Avoid: Clonidine CNS depression NTG aggravation of edema due to cerebral vasodilatation

• Identify and treat any systemic disease that may be underlying etiology

• In eclampsia delivery and IV magnesium typically rapid improvement

• Seizure management

• ICU admission for monitoring and supportive care in severe cases

Our Patient

• Cyclosporin discontinued, IV antihypertensives, and seizures treated with IV Ativan

• 3/6/07: A+Ox3, HA and N/V resolved. C/O constant blurry vision, palinopsia (immediate type), and polyopia. Able to read

newspaper print with some difficulty

• 3/7/07: Vision returned to baseline per patient

• 3/8/07: Started on FK-506 to replace Cyclosporin

• 3/13/07: Va 20/20 OD, 20/20-1 OS at near, no field loss

Take Home Points

PRES should be considered in all patients with acute cerebral visual loss

Diffuse white matter hyperintensity on T2/FLAIR, DWI, and ADC are characteristic, and allow differentiation from ischemic cause

Treatment is aimed at controlling bp and determining underlying cause

ReferencesMiller et al. Walsh and Hoyt’s Clinical Neuro-Ophthalmology

Kline et al. Neuro-Ophthalmology Review Manual

Kahana et al. Cortical Blindness: Clinical and Radiologic Findings in Reversible PosteriorLeukoencephalopathy Syndrome. Ophthalmology. 2005;112:e7-e11.

Eckard et al. Cerebral Hemodynamics and Autoregulation in Reversible Posterior Leukoencephalopathy Syndrome. Cerebrovasc Dis. 2006;22:204-208.

Covarrubias et al. Posterior Reversible Encephalopathy Syndrome: Prognostic Utility of Quantitative Diffusion-Weighted MR Images. AJNR. 2002;23:1038-1048.

Pande et al. Clinicoradiological factors influencing the reversibility of posterior reversible Encephalopathy Syndrome: a multicenter study. Radiat Med. 2006;24:659-668.

Hinchey et al. A Reversible Posterior Leukoencephalopathy Syndrome. N Engl J Med. 1996;334:494-500

Ayoub, Mirza. Posterior reversible encephalopathy syndrome: A variant of hypertensive Encephalopathy. J of Clin Neurosci. 2006; 590-596.