IMAGING OF TOXIC AND METABOLIC ENCEPHALOPATHY SYNDROME

DR .AMOL GULHANE DNB RESIDENT ,

CARE HOSPITALS , HYD

Acute toxic-metabolic encephalopathy is an acute condition of global cerebral dysfunctionencompassing delirium and the acute confusional state in the absence of primary structural brain disease.

Toxic and metabolic encephalopathies are common amongcritically ill patients and usually present with seizures and focal neurological deficits.

In general, toxic and acquired metabolic disorders produce a widespread,symmetric pattern of injury that often involves the deep gray nuclei and cerebral cortex.

Myelin, with its high lipid content is particularly vulnerable to lipophilic toxic substances.

Acute Hyperammonaemic Encephalopathy

can occur in acute fulminant hepatic failure or in patient with chronic liver disease.

Patients present with progressive drowsiness, seizures, and coma due to toxic effects of ammonia on the brain parenchyma with elevated serumammonia levels (normal levels 9-30umol/l).

MRI shows diffusion restriction in symmetrical pattern involving insular and cingulate gyri .

These cortical changes appear to be early imaging findings and potentiallyreversible if aggressive treatment is instituted.

Involvement of brain regions other than the insular or cingulate gyrus is more variablewith bilateral symmetrical diffusion restriction seen in temporo-occipital cortex, caudatehead, lentiform nucleus, thalami, midbrain (sparing cerebral peduncles) and dorsal pons.

In an appropriate clinical setting and correlation with serum ammonia levels it canbe differentiated with posterior reversible encephalopathy syndrome, seizure activity,hepatic encephalopathy, and diffuse hypoxic-ischemic injury.

Hyperammonaemic encephalopathy. Patient with Chronic liver disease andelevated serum ammonia levels(92umol/l). Axial DWI and ADC images showing diffusionrestriction in bilateral symmetrical pattern involving insular, cingulate,temporo-occipitalcortex, caudate head and thalami.

Hepatic encephalopathy (HE), hepatic coma

• Functional, potentially reversible clinical syndromeduring acute or chronic liver disease, characterized bypsychiatric, cognitive and motor components

• NECTo Acute HE: Severe diffuse cerebral edemao Chronic HE: Cerebral atrophy, mild brain edemao No signal abnormality in BG

• CECT: No contrast-enhancement of affected BG

MR Findings• TIWIo Bilateral hyperintensity in BG, particularly GP• Reported in 80-90% of chronic liver failure cases• Probably caused by manganese accumulation• Blood-brain barrier permeability to manganesemay be selectively increased in chronic condition

Increased Signal intensity in pituitary gland, hypothalamus,and mesencephalon surrounding red nuclei

• Occasionally increased signal only in pituitary gland

o Atrophy, especially affecting cerebellum

o Acute HE: Blurring of gray-white matter junction

• T2WIo Acute HE: High signal in most of cerebral cortex,sparing perirolandic and occipital regions

o Hyperintense dentate nucleus, periventricular whitematter (WM)

• FLAIR: 1 Signal alonghemispheric WM in/around corticospinal tract

• DWI: Acute HE: Increased cortical signal

• Tl C+: No contrast-enhancement

• MRSo dec. Myoinositol (ml), 1 glutamine/glutamate (Glx), dec.choline (Cho)

Osmotic or Central Pontine Myelinolysis (Central pontine and extrapontine myelinolyisis)

CPM can be seen in patients with chronic alcoholics,malnourished patients, cirrhotic liver disease, organ transplants, severe burns, addison’ disease, and electrolyte disturbances.

Rapid correction of prolonged hyponatremia is themost important risk factor for the development of CPM.

Acute: Confluent T2 hyperintensity in central ponswith sparing of periphery and corticospinal tracts

The classic imaging appearance is focal symmetric, "trident or mexican hat shaped" high signal in the basal pons on T2-weighted/FLAIR sequences and corresponding diffusionrestriction with sparing of the tegmentum and corticospinal tracts

Associated symmetric signal abnormality may also be present in the extrapontine locations includingthe basal ganglia, midbrain, thalami and cerebellum

Central Pontine Myelinolysis. Axial DWI and ADC images in a hyponatremicpatient with rapid correction of serum sodium showing diffusion restriction in central ponswith triradiate appearance(The Mexican Hat Sign).

Extrapontine Myelinolysis. Same patient as in Fig. showing diffusion restrictionwith FLAIR hyperintensity in bilateral basal ganglia and thalami.

Metronidazole Induced Encephalopathy

Metronidazole can produce neurologic symptoms atdoses exceeding 2 g/d.

On MRI the dentate nuclei in the cerebellum are most commonly involved, followed by the tectum, red nucleus, periaqueductal gray matter, dorsal pons , splenium of corpus callosum and dorsal medulla

Lesions are often bilateral and symmetric in distribution showingincreased signal intensity on T2/FLAIR images, do not show contrast enhancement and are reversible after discontinuation of the drug.

Diffusion restriction can be seendepending on the severity of edema (cytotoxic or vasogenic).

The most important differential diagnosis includes acute wernicke's encephalopathy where the involvement is predominantly of the diencephalon and midbrain.

Acute nonalcoholic wernicke's encephalopathy can present with bilateral symmetric lesions at the dentate nuclei, vestibular nuclei and the tegmentum mimicking MIE.

Although MR imaging findings of bilateral involvement of the dentate nuclei are a very characteristic feature of MIE the differential diagnosis of bilaterally symmetrical T2 hyperintense dentate nuclei includes• Methyl bromide intoxication, maple syrup urine disease and enteroviralencephalomyelitis.

Metroindazole Induced Encephalopathy. Symmetrical areas of diffusion restrictionin corpus calosum and T2/FLAIR hyperintensity involving the dentate nuclei.

• Alcoholic (EtOH) encephalopathy; methanol (MtOH)encephalopathy; Wernicke encephalopathy (WE)

• Primary (direct) effects of EtOH = neurotoxicity(cortical/ cerebellar degeneration, peripheral polyneuropathy)

• Rare treatable complication = WEIMAGINGiFINDINGs

o EtOH: Disproportionate superior vermian atrophyo MtOH: Bilateral hemorrhagic putaminal necrosisoWE: Mamillary body, medial thalamus, hypothalamus, periaqueductal gray abnormalsignal/enhancement

Alcoholic (EtOH) encephalopathy

o MtOH: Putamen, hemispheric white matter

oWE• Mamillary bodies, periaqueductal gray matter,hypothalamus• Thalami adjacent to 3rd ventricle

o EtOH• Cerebral hemispheres, especially frontal lobes,Cerebellum, superior vermis• Corpus callosum (Marchiafava-Bignami disease)+/-lateral extension into adjacent white matter• Basal ganglia (associated liver disease)

CT Findings• NECTo EtOH: Generalized atrophy; superior vermis atrophyo MtOH: Bilateral hemorrhagic putaminal necrosiso WE (acute): Often normal• May see hypodensity in periaqueductal graymatter, mamillary bodies and medial thalamus• CECT:Acute alcohol-induced demyelination mayEnhance

MR Findings• TlWIo EtOH (dose-dependent)• Symmetric enlargement of lateral ventricles, sulciwith chronic EtOH• 1 Size of cerebral sulci, interhemispheric/Sylvianfissures• +/- Hyperintensity in basal ganglia (liverdysfunction)

Wernicke's Encephalopathyis associated with chronic alcohol abuse, gastroplasty for obesity, anorexia nervosa, voluntary food starvation, chronic uremia, and parenteral therapy.

The hallmark of the disease is represented by a clinical triad of alteredconsciousness, ocular dysfunction, and ataxia.

MRI shows symmetric T2 hyperintensity in the mamillary bodies, medial thalami, tectal plate and periaqueductal area with contrast enhancement in the same regions most commonly the mamillary bodies.

The changes in the mamillary bodies are more often seen in alcoholic patients.

Diffusion restriction can be seen in the involved regionssuggestive of cytotoxic edema.

Atypical MRI findings are more common in non-alcoholic patients represented by symmetric signal alterations of the cerebellar vermis, dentate nuclei, cranial nerve nuclei, red nuclei, caudate nuclei, splenium, and cerebral cortex

The differential diagnosis in this scenario includes metronidazole-induced encephalopathy.

The conversion of metronidazole to a thiamine analog and its vitamin B1 antagonism acting via metabolic pathways similar to those operating in wernicke‘s encephalopathy has been described.

Therefore, the differential diagnosis between WEand metronidazole-induced encephalopathy may be difficult in malnourished patients treated with metronidazole.

Wernicke's Encephalopathy. Chronic alcoholic with altered sensorium. Axial T2/FLAIR . Symmetric hyperintensity seen in the mammillarybodies.

Wernicke's Encephalopathy. Axial and Coronal Postcontrast images showingintense homogeneous contrast enhancement in the mammillary bodies.

Atypical Wernicke's Encephalopathy. Symmetrical diffusion restriction in thebilateral dentate nuclei,dorsal midbrain involving the superior colliculli and bilateralthalami. The mammillary bodies are normal in signal intensity.

Postpartum Hypernatremic Encephalopathy

Neurological manifestations due to hypernatremia during postpartum period producing encephalopathy and osmotic demyelination.

Diffusion restriction with T2/FLAIR hyperintensity involving the corpus callosum especially the splenium is seen in most of thepatients with symmetrical hyperintensities also seen in cerebellar peduncles, cerebellar white matter, thalami, internal capsules and corona radiata

On coronal T2 weighted images symmetrical hyperintensities of the internal capsule, crus cerebri, and pons similar to the 'wine-glass' pattern of hyperintensities found in amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and leukodystrophies has been described.

The 'wine glass' pattern depicts the involvement of corticospinal tract inthese different conditions.

The differential diagnosis of T2 hyperintense lesions in the spleniumof the corpus callosum besides hypernatremia includes Marchiafava-Bignami disease, acute toxic encephalopaties, encephalitis(demyelinating, viral), osmotic myelinolysis and anti-epileptic drugs

Postpartum Hypernatremic Encephalopathy. Symmetrical diffusion restrictionin splenium of corpus callosum, middle cerebellar peduncles, cerebellar white matter,external capsules ,posterior limb of internal capsules and medial thalami

Posterior reversible encephalopathy syndrome/Hypertensive encephalopathy

PRES is most commonly seenin patients with eclampsia, organ transplantation related to cyclosporine ortacrolimus, wegener granulomatosis, systemic lupus erythematosus, hypertension and post chemotherapy.

Patients typically experience headache, altered sensorium, visualdisturbances, severe hypertension and generalized seizures

The most characteristic imaging pattern in PRES demonstrates vasogenic edema seen as T2/FLAIR hyperintensity without diffusion restriction involving the white matter of theparieto-occipital regions in a relatively symmetric pattern that spares the calcarine and paramedian parts of the occipital lobes

Imaging Patterns in PRESThree primary variations of the traditional PRES imaging pattern can be seen

Dominant Parietal-Occipital PatternThe typical "posterior" pattern invovling the parietal and occipital cortex and white matter with variable involvement of the temporal lobes.

Partial expression of PRES (defined as the absence of signal intensity abnormality in either the parietal lobes bilaterally or the occipital lobes bilaterally) can be seen.

Asymmetric expression of PRES (defined as unilateral absence of signal intensity abnormality in either the parietal or occipital lobe) can be seen

Holohemispheric Watershed PatternVasogenic edema in a linear pattern spanning the frontal, parietal, and occipital lobes withlesser involvement of the temporal lobes at the junction between the medial hemispheric (ACA and PCA) and lateral hemisphericbranches (MCA) consistent with the watershed or anastomotic border zone

Superior Frontal Sulcus PatternDistinct involvement of the frontal lobe associated with varying degrees of parietal and occipital abnormality

Atypical" Lesions in PRES

Involvement of the basal ganglia, brain stem, cerebellum, splenium and deep white matter can be seen less commonly.

This can be confidently recognized as part of the PRESparticularly when associated with the hemispheric features

Posterior reversible encephalopathy syndrome (PRES) - Dominant Parietal-Occipital Pattern. Symmetric FLAIR hyperintensity representing vasogenic edemainvolving the cortical-subcortical white matter of bilateral parieto-occipital regions.

Posterior reversible encephalopathy syndrome (PRES). Holohemisphericwatershed pattern. FLAIR sequences showing bilateral vasogenic edema involving thewhite matter of the bilateral occipital, parietal, frontal, and temporal lobes,basal gangliaand external capsule.

Posterior reversible encephalopathy syndrome (PRES). Superior frontal sulcus

pattern. FLAIR sequences showing bilateral vasogenic edema involving the frontal sulcus

area and, to a lesser degree, the white matter of the right parieto-occipital lobes.

Chemotherapy Induced PRES. Patient with Burkitt's lymphoma Postchemotherapy status. Confluent hyperintensity on T2/ FLAIR images in bilateralparieto-occipital subcortical white matter. Cortical laminar necrosisis seen as multifocalhemorrhages on T1 weighted and susceptibility weighted images.

Hypoglycaemic encephalopathy

Hypoglycaemia is a sudden decrease in serum glucose level less than 50 mg/dl.

symptoms included altered sensorium or hypoglycemic coma.

On MRI severe hypoglycaemia manifests as bilateral symmetric diffusion restriction involving the temporal, occipital, insular cortex, the hippocampii and the basal ganglia with sparing of the thalami

The deep white matter may be involved in mildercases involving the internal capsule, corona radiata and splenium of corpus callosum.

These findings can be similar to sporadic Creutzfeldt-Jacob disease, although theclinical setting should exclude the neurodegenerative disorder.

Correlation with the blood glucose levels may be useful to differentiate this potentially reversible condition fromhypoxix ischemic encephalopathy (HIE) and acute infarction.

DWI may be useful to predict outcome.

When diffusion restriction is seen in the corpus callosum, internalcapsule or corona radiata which regress on follow up images, the patient will likely to recover without a neurologic deficit.

Hypoglycemic Encephalopathy. Patient with decreased serum glucose 38 mg%) levels. Symmetric areas of restricted diffusion involving the bilateral temporo-occipitalregions, insular cortex and the hippocampi on either side.

Neonatal hypoglycemic brain injury

Imbalance between supplyand utilization of glucose (Gluc); neonatalhypoglycemia - brain injury

Imaging Findings• Best diagnostic clue: Severe occipito-parietal edema orinfarctions in a newborn with seizures

• DWI: Restricted diffusion, low ADC (may be transient)

Top Differential Diagnoses• Venous thrombosis• Metabolic stroke

Hypoxic ischaemic encephalopathy

Hypoxic-ischaemic cerebral injury occurs at any age, although the aetiology is significantly different: drowning and asphyxiation remain common causes in childrenwhile cardiac arrest or cerebrovascular disease with secondary hypoxemia are common in adults.

During the first 24 hours DWI demonstrates increased signal intensity in the basal ganglia, cerebral cortex in particular, the perirolandic and occipital cortices.

The thalami, brainstem, hippocampi or cerebellar hemispheres may also be involved

DWI abnormalities usually pseudonormalize by the end of the 1st week.

In the early subacute period (24 hours-2 weeks) conventional T2-weighted images typically become positive and show hyperintensity of the injured gray matter structures.

The other variant is parasagittal infarction which involves the deep white matter only atborder zones of major arterial territories (water shed).

Hypoxic Encephalopathy. Confluent areas of restricted diffusion involvingbilateral parieto-occipital, perirolandic regions, caudate nucleus, lentiform nucleus,anterior & posterior limbs of internal capsules, bilateral thalami and hippocampal regions

Chemotherapy induced leukoencephalopathy

Several cases of chemotherapy related encephalopathy are noted in the literature with some agents being more problematic than others.

Common agents implicated includecisplastin, methotrexate, bleomycin and tacrolimus.

Acute and delayed chemotherapy induced white matter abnormalities occur in a variety of clinical settings including treatment for lymphoma, leukemia, glioma, lung cancer andmetastatic disease.

Acute disseminated leukoencephalopathy (ADL) has been proposed as a broad clinical-radiological term describing a range of abnormalities from mild reversible clinical symptoms with MRI changes to profound encephalopathy resulting indeath.

DWI/ADC abnormalities are seen in subcortical white matter of the cerebral hemispheres, corpus callosum, and brainstem.

Persistent imaging abnormalities characterized byFLAIR/T2 hyperintensities on MRI can be seen

Chemotherapy Induced Leukoenceohalopathy. Patient on Tacrolimus. Pre(above) and post chemotherapy MRI(below). New confluent areas of abnormally T2 and FLAIR hyperintensity seen in the bilateral centrum semiovale extending along the corticospinal tracts in posterior limb of internal capsules,the cerebral peduncles and the pons.

Chemotheapy Induced Leukoencephalopathy. Patient with carcinoma of leftlung, on chemotherapy. MRI shows new confluent T2/FLAIR hyperintensities (image onleft) involving the centrum semiovale and corona radiata.

Bilirubin or posticteric encephalopathy

• Encephalopathy due to deposition of toxic unconjugated bilirubin

o Chronic: I T2 signal posteromedial border GP anddentate nucleus (DN); Tl normal

CT Findings• Not Useful in suspected cases of Kernicterus

MR Findings• TlWIo Acute: I Tl signal in GP, hippocampi, SN, DN• Deposition unconjugated bilirubin or related toliver dysfunction (I manganese ?)

• T2WI: I T2 signal/volume loss in posteromedial borderGP, hippocampi; occasionally DN

DIFFERENTIAL DIAGNOSISGlobus pallidus lesion look-alike

• Hyperalimentation (manganese): I Tl signal GP/SN• Hepatic failure: I Tl signal GP/SN, history known• Toxic/metabolic: Methyl-malonic acidemia, creatinedeficiency, CO exposure

Profound hypoxic encephalopathy• I Tl, T2 signal posterior putamen, lateral thalamus,peri-Rolandic

• Anoxic-ischemic encephalopathy/CO poisoning

NECTo Symmetric hypodensity in GPo Symmetric diffuse hypodensity in cerebral WM• More advanced in centrum semiovale• CECT:Enhancement in GP has been reported

MR Findings• T1WI: Both T1 hypointensity in GP (probably due tonecrosis) and T1 hyperintensity in GP (probably dueto hemorrhage) have been reported

• T2WI

• Bilateral T2 hyperintensities of GP surrounded byhypointense rim (probably due to hemosiderin)

• Caudate nucleus and putamen may be affected,either alone or in addition to GP abnormality

o Cerebral hemispheric WM: Bilateral confluent T2hyperintense WM (periventricular, centrumsemiovale)

• Reflects diffuse demyelination

• Abnormal signal in cerebral cortex (less frequent)

Wilson disease/ hepatolenticular degeneration

abnormal ceruloplasmin metabolism.

Total body copper is elevated with deposition and resultant damage to a variety of organs, e.g. liver and brain.

The basal ganglia are the most frequently affected site .CTMay demonstrate atrophic changes in the basal ganglia, cortical and cerebellar regions

NECT: copper deposition does not increase density on CT

CECT: lesions do not contrast-enhance

MRHyperintensity in lentiform nuclei and mesencephalic regions on T1 have been described as most common initial MR abnormality

T2 hyperintensity is also seen typically involving basal ganglia

putamenglobus palliduscaudate nucleus

thalamus: ventrolateral aspect

Axial T2 MR at midbrain level can show a face of the giant panda sign , a characteristic finding of Wilson disease.

Diffusion restriction may be seen early in the course of the disease

Wilson disease in an 11-year-old girl with abnormal findings on a liver function test.A, Initial T1-weighted axial MR image shows a subtle increased signal intensity in both globus pallidi (arrows).B, Follow-up T1-weighted axial MR image obtained after 5 years shows increased extent of the lesion (arrows)

Japanese encephalitis (JE)

• Homogeneous T2 hyperintensities in BG and thalami,symmetric or asymmetric

• Most characteristic finding in JE

o Bilateral thalamic hyperintensities ± hemorrhage

• JE is meningoencephalitis ~ meningeal enhancement

Characteristic MRI findings in Japanese encephalitis. A) FLAIR sequence shows bilateral thalamic, globus pallidus and caudate involvement. B) Bilateral midbrain involvement