Imaging of Toxic-Metabolic Disorders

1/8/2016

Clinical Neuroimaging: Toxic‐Metabolic Disorders Toxins & brain areas of high‐oxygen demand • Areas of increased cellular respiratory Dara G. Jamieson, M.D. metabolism Associate Professor of Clinical Neurology – basal ganglia, cerebellum, hippocampus Headache Center Stroke Center • Basal ganglia lesions – carbon monoxide, methanol, cyanide – liver dysfunction – hypoxic‐ischemic brain damage – severe glucose abnormalities – mitochondrial disorders

Toxic Metabolic Disorders Bilateral Basal Ganglia Lesions Affecting the CNS • Hypoxic/ischemic injury, • Normal: dilated perivascular spaces • Hypoglycemia • Vascular: hypoxic/ischemic encephalopathy, infarcts • Hypertensive disorders (PRES/RCVS) (arterial, venous) • Toxicity: CO, methanol, cyanide, hydrogen sulfide, Mg, • Osmotic demylination toluene, disulfram • Organ failure: Liver, Renal • Metabolic: hypo/hyperglycemia, osmotic demylination, • Poisoning: ethanol, methanol, alcohol, CO, hemolytic‐uremia syndrome, hepatic disease ethylene glycol • Inherited disorders: Leigh’s, Wilson’s, Huntington’s, • Illicit drugs methylmalonic acidemia, Alexander’s, Canavan, MLD • Infection: toxoplasmosis, cryptococcosis, post‐infectious • Toxic effects of therapies/medications acute striatal necrosis, CJD

Characteristic areas of involvement Acute unknown toxicity – basal ganglia lesions in toxic metabolic disorders 43 year‐old healthy woman blamed acute GI • Areas of increased cellular respiratory metabolism complaints, along with headache and generalized – Basal ganglia aching, on shrimp from a street cart. A week into – Hippocampus her symptoms, she developed hand tremors and – Cerebellum unsteady walking. On examination she had • Cerebral white matter (leukoencephalopathy), sustention/intention tremor and cogwheel rigidity. corpus callosum She recently stopped smoking and urine was • Midbrain, pons positive for cannabinoids. Blood testing and CSF analysis was negative. She recovered with supportive care, without neurological abnormality.

1 1/8/2016

Acute unknown toxicity – basal ganglia lesions Acute unknown toxicity ‐ leukoencephalopathy

DWI FLAIR 26 year old man with depression, anxiety and insomnia was found unconscious by his room-mate after presumably taking medications (including an antidepressant, sleep aid, opioids) and smoking marijuana. His T1C T2 recreational drug use was unknown by his family who brought him to the hospital. He had multiple seizures and was intubated for 6 weeks, with fevers and autonomic instability. He recovered with bilateral foot drop, thought to be peripheral nerve related.

Leukoencephalopathy Midbrain Lesions • Symmetric midbrain lesions: +/‐ diencephalon, basal ganglia. • Hypertension • Ethylene glycol, methanol, chronic alcohol • Environmental toxins abuse (Wernicke’s encephalopathy) – Organic solvents • Kearn‐Sayers syndrome, • Substances of abuse – Cocaine, heroin, toluene, alcohol, methadone • Adult onset X‐linked adrenoleukodystrophy • CNS irradiation • Hepatic disease, Wilson’s disease • Chemotherapeutic/immunosuppressive agents – Methotrexate (IT), BCNU, Ara‐C, cisplatin, thiotepa, fludarabine – Cyclosporine, tacrolimus (PRES)

Known Causes Targets of Toxins in Cerebral White Matter of a Toxic‐Metabolic Disorder

• A woman with new onset renal disease and a headache

• Seizing child with leukemia

• A confused woman with terminal cancer

Filley & Kleinschmidt-DeMasters. N Engl J Med2001; 345:425-431

2 1/8/2016

Nephrotic syndrome & blurred vision 9 year old girl with headaches, and elevated BP. FLAIR DWI 69 year old woman with post‐infectious glomerulonephritis, treated A 9 year old girl with autoimmune hemolytic anemia s/p splenectomy with high dose steroids, was admitted with a headache, blurred vision, developed fever, severe anemia confusion and difficulty walking. Her BP was 186/95. She had LE and low back pain. She was treated edema. On examination paraphasic errors and dysnomia, with a RHH, with ceftriaxone, valgancyclovir, were noted. A HCT was obtained. After aggressive BP control and methylprednisolone and diuresis, her neurological examination normalized. cyclosporine. Her blood pressure, 100/60 on admission, gradually elevated to the 140/90’s over the next week and she developed headaches. She had two generalized seizures about 10 days after admission. An initial MRI scan showed both abnormal FLAIR signal and bright signal on DWI.

Seizures & encephalopathy in a girl Nephrotic syndrome & blurred vision On nicardipine, her BPs decreased to the levels present on FLAIR GRE DWI admission. A follow‐up MRI scan 2 days later showed almost Initial normalization in the DWI signal, but persistent FLAIR signal abnormality.

10 days later

Posterior Reversible Encephalopathy Syndrome (PRES) Nephrotic syndrome & blurred vision • Nomenclature – Not exclusively posterior ; not always reversible What is the cause of this woman’s blurred vision? – “Reversible Posterior Leukoencephalopathy (RPLE)” 1. Lymphoma – Hypertensive encephalopathy 2. Posterior Reversible Encephalopathy Syndrome – Pre‐eclampsia; eclampsia (PRES) • Vasogenic cerebral edema (cortical, subcortical, spinal cord) – Vasoconstriction 3. Acute Disseminated Encephalomyelitis (ADEM) – Hyperperfusion 4. Osmotic Demyelination Syndrome (ODS) • Diverse clinical & radiographic presentations 5. Renal Cell Carcinoma – Headache, seizures, visual symptoms, mental status changes – Parietal‐occipital white matter; holohemispheric pattern; superior frontal region; brainstem; spinal cord – Untreated: intracerebral hemorrhage, coma, death

3 1/8/2016

PRES Deterioration in a woman with metastatic cervical cancer 57 year-old female with cervical cancer, metastatic to bladder & • Theory 1: Hypertension/Hyperperfusion liver, had status epilepticus. She had a history of progressive – Severe HTN exceeds autoregulatory capacity of cognitive decline, with inability to walk. She was intubated in the brain, failed auto‐regulation, hyperperfusion, ICU and seizures were successfully treated. Klebsiella endothelial injury, vasogenic edema pneumoniae sepsis was treated with multiple antibiotics. She had episodes of ileus with vomiting. She was maintained on • Theory 2: Vasoconstriction/Hypoperfusion anti-epileptics with fluctuations in mental status from – Evolving HTN leads to vasoconstriction, decreased perfusion, ischemia, edema unresponsive to minimally conversant. Responsiveness decreased; she became hypotensive; and she died 36 days after admission.

Diseases underlying PRES Confusion in woman with metastatic cancer • Acute hypertension • Preeclampsia/eclampsia, HELLP • TTP, hemolytic uremic syndrome, porphyria, DKA • Liver disease; renal disease • Chemotherapy (tacrolimus, cyclosporine, CHOP) • Organ/marrow transplantation • IVIG, steroids • Severe electrolyte imbalance • Elevated Ca++; hyperparathyroidism • Sepsis T2-FLAIR

Typical appearance of PRES on MRI Woman with metastatic cervical cancer

Appearance on MRI FLAIR – Multifocal T2‐FLAIR hyperintensities (c/w vasogenic edema) – Favors parietal and occipital white matter but can involve other areas: cortex, thalamus, basal ganglia, cerebellum, brainstem and spinal cord. – Usually not apparent on DWI. DWI • DWI changes maybe related to accompanying seizures . • Ischemic changes on DWI/ADC are associated with worse prognosis. – Can hemorrhage with GRE lesions – Can exhibit subcortical “gyral” enhancement secondary to breakdown of the blood‐brain barrier. – Can show mass effect associated with vasogenic evolving to cytotoxic edema.

4 1/8/2016

Deterioration in a woman with metastatic cervical cancer Osmotic myelinolysis (or demyelination) syndrome 57 year-old female with cervical cancer, metastatic to bladder & liver, had status epilepticus. She had a history of progressive Associated with: – Hyponatremia cognitive decline, with inability to walk. She was intubated in the – Hypernatremia ICU and seizures were successfully treated. Klebsiella – Rapid correction pneumoniae sepsis was treated with multiple antibiotics. She – Slow correction had episodes of ileus with vomiting. She was maintained on – No correction – Severe hyperglycemia anti-epileptics with fluctuations in mental status from Hypernatremia from a hunger strike as a cause of osmotic myelinolysis.van der unresponsive to minimally conversant. Responsiveness Helm-van Mil AH, van Vugt JP, Lammers GJ, Harinck HI.Neurology. 2005 Feb 8;64(3):574- 5. decreased; she became hypotensive; and she died 36 days after Extrapontine myelinolysis with involvement of the hippocampus in three children with severe hypernatremia.Brown WD, Caruso JM.J Child Neurol. 1999 Jul;14(7):428-33 admission.

What is the pathological diagnosis in this woman with metastatic cervical cancer? CNS Toxicity of Alcohol 1. Posterior Reversible Encephalopathy Syndrome (PRES) 2. Acute Disseminated Encephalomyelitis (ADEM) 3. Osmotic Demyelination Syndrome (ODS) 4. Paraneoplastic encephalitis 5. Viral encephalitis

Pathological Findings ACUTE CNS EFFECTS OF ALCOHOL Myelin loss, Gliosis, Edema, Vacuolization • Pons BAL Effect • Occipital cortex, parietal lobe, frontal lobe • Cerebellum < 0.04% Mild euphoria • Spinal cord 0.05 ‐ 0.09% Disinhibition, increased self confidence, alteration of judgment 0.10 ‐ 0.14% Confusion, loss of critical judgment, memory impairment, sleepiness Differential Dx: • Osmotic demyelination syndrome 0.15 ‐ 0.29% Ataxia, analgesia, disorientation, exaggeration of emotions – Cerebellum, thalamus, basal ganglia, subcortical white matter 0.30 ‐ 0.39% Stupor, marked incordination • Inflammatory demyelinating disorders (ADEM, MS) >0.4% Anesthesia, deep coma, death – Lesions not inflammatory • B12 deficiency (subacute combined degeneration) – Not pontine BAL – Blood Alcohol Level

5 1/8/2016

Alcohol & Trauma Alcohol‐related brain injury

Atrophy out of proportion to age – Enlarged ventricles/sulci, anterior superior vermis – May reverse with abstinence – Not well correlated with cognitive loss

Marchiafava‐Bignami Syndrome – Demyelination/necrosis of corpus callosum, A 50 year old man with a history periventricular white matter of alcohol abuse fell down the stairs while drunk. On – Malnourishment (alcoholics, non‐alcoholics) examination he was inattentive – Dementia, spasticity, dysarthria, gait disorder but without motor deficits.

Chronic CNS Effects of Alcohol Alcohol/Nutrition‐related brain injury • Wernicke’s encephalopathy • Atrophy – cortical, cerebellar – Ataxia, ophthalmoplegia, nystagmus, encephalopathy • Wernicke – Korsakoff Syndrome – Thiamine deficiency – MRI: can be normal, but generally mamillary body lesions • Marchiafava – Bignami disease / Morel's Laminar Sclerosis – Dorsomedial thalamus, locus ceruleus, periaqeductal grey, • Pellagra ocular/vestibular nuclei – Petechial hemorrhage • Fetal Alcohol Syndrome • Osmotic Demyelination Syndrome / Central Pontine Myelinolysis

Figure. (A) Gadolinium-enhanced T1-weighted axial MRI shows symmetric enhancement of the mamillary bodies (paired arrowheads). (B) Enlarged axial view of the region of the hypothalamus Alcohol & Atrophy showing mamillary body enhancement (paired arrowheads). (C) Enlarged coronal view of the mamillary body enhancement (paired arrowheads). (D) FLAIR hyperintensity of the hypothalamus is seen in an axial view (arrows). (E) FLAIR hyperintensity of the periaqueductal gray (arrows). (F) Surgeon (not FLAIR hyperintensity of the dorsomedian thalamus (arrows). (G) FLAIR hyperintensity of the floor of practicing) the fourth ventricle (arrows). (H) FLAIR hyperintensity is seen throughout the low medulla (arrows). with alcoholism since age 30 years, currently drinking 2 pints of vodka a day. HCTs at age 63 years and age 67 years. Flint A C et al. Neurology 2006;67:2015-2015

6 1/8/2016

Alcohol abuse & nutritional deficiency Alcohol withdrawal 32 yr. old woman was admitted to the psychiatry 67 year male with HIV (last CD4 201, VL undetectable), HTN, and service with a history of alcohol abuse (admitting to decades of 12 oz of vodka a day was evaluated for a seizure, presumed to be due to alcohol withdrawal, in the setting of hospitalization for a 6 pack a day) and binging and purging. Her urine diarrhea. No specific laboratory abnormality was noted. On was + benzodiazepines. She was a thin women, who neurological examination, he was sedated on benzodiazepines but his was confabulatory and incoherent, with difficulty neurological examination was without focality. A CT scan of the head and MRI were obtained. following directions. She had nystagmus. She did not cooperate with strength testing (moving all extremities) but she was unable to walk. Reflexes were decreased distally. An MRI was obtained. With high dose intravenous thiamine, cognition improved. She had a residual foot drop.

Alcohol abuse & nutritional deficiency Wernicke‐Korsakoff encephalopathy in a 32 year old woman Alcohol withdrawal

March 11 On admission

DWI BRAVO

FLAIR April 4 FLAIR After high dose T2 thiamine

Alcohol withdrawal in a 44 year old man CNS Toxicity of Substances of Abuse

He stopped drinking a bottle of vodka a day 4 days before presenting to the ED for agitation and tremulousness. His BP was 221/200 with a HR of 122. While receiving IV diazepam, he seized and was intubated for airway protection. With high doses of benzodiazepines and thiamine his vital signs and agitation were managed but he hallucinated when extubated.

7 1/8/2016

Chasing the Dragon (Heroin Leukoencephalopathy) Alcohol and cocaine toxicity • Toxic spongiform leukoencephalopathy with mortality rate of 25%. • inhaled vapors from heroin that has been heated on a piece of foil aka "chasing the dragon." • Cerebellar ataxia, agitation, focal neurologic symptoms, coma • Often a latent period between exposure and clinical presentation. • MRI: cerebellar white matter, cerebellar peduncles, brainstem, posterior cerebral white matter, posterior limbs of the internal capsules; reduced NAA and increased lactate peaks • DDx: PRES

AJNR 2011;36

Heroin Associated Leukoencephalopathy Acute cranial nerve abnormality in a depressed man. MRI, T2 hyperintensity of centrum semiovale A 50 year old man was depressed about losing a

Biopsy showing delayed job. He was found unconscious and taken to demyelination, luxol fast blue OSH, where he was intubated and hemodialysis was initiated for acute renal failure. After gradual improvement, he was transferred to a psychiatric hospital two weeks later. Two days after admission a stroke code was called when he was noted to have mild left facial weakness (NIHSS 1). HCT was normal. An MRI was obtained.

Alcohol and cocaine toxicity Acute cranial nerve abnormality in a depressed man. 50 year old man was admitted with slurred speech, diplopia and difficulty walking. Chronic alcohol use had recently increased to 24 drinks a week and he used cocaine every other day. He had a 30 pack year smoking history. He abused benzodiazepines. On examination he was alert and oriented with slurred speech. He had bilateral abduction deficits but no nystagmus. He had no motor deficit but reflexes were brisk. Gait was markedly ataxic.

8 1/8/2016

Acute cranial nerve abnormality in a depressed man. Ethylene Glycol C2H4(OH)2

Odorless, colorless liquid with bittersweet taste Metabolites – glycoaldehyde, glycolic acid, oxalic acid Ingestion – metabolic acidosis, ARF, delayed neurological damage. 1‐12 hrs: inebriation, ataxia, coma, seizures 12‐24 hrs: cardiac, pulmonary complications 24‐72 hrs: metabolic acidosis, ARF, crystal oxaluria 5‐20 days: lower motor dysfunction of lower cranial nerves (facial weakness, bulbar dysfunction), basal ganglia disease Etiology of delayed CN disease: Inflammatory response to local oxalate microcrystal deposition?

Reddy et al. Clinical Toxicology 2010;48:967‐973

Ethylene Glycol Brain Toxicity Acute cranial nerve abnormality in a depressed man.

Perivascular Why does this man have cranial nerve Birefringent Calcium abnormalities on MRI? Oxalate Crystals

1. Hypoglycemia 2. Toluene poisoning 3. Cyanide poisoning 4. Ethylene glycol ingestion

—25-year-old man with decreased level of consciousness after suicide attempt by ingesting Acute cranial nerve abnormality in a depressed man. ethylene glycol.

Enhancement of CN V, VII Possible enhancement of IX, X, XI Restricted diffusion of bilateral CN V Sharma P et al. AJR 2009;193:879-886

9 1/8/2016

—25-year-old man with decreased level of consciousness after suicide attempt by ingesting ethylene glycol. Weakness and swallowing difficulties

Sharma P et al. AJR 2009;193:879-886

Methanol (CH₃OH) Toxicity • Bilateral necrosis of Weakness and swallowing difficulties the basal ganglia (putamen) • Cerebral edema/necrosis • Cerebellar lesions • SAH • Bilateral ICH • Bilateral tegmental necrosis Gadodia A, Singhal B, Sharma R. Methanol intoxication causing putaminal necrosis. J Emerg Trauma Shock 2011;4:300-1

Weakness and swallowing difficulties Weakness and swallowing difficulties • 49 year old man awoke with R arm and leg weakness and diplopia, a few days prior to admission. He had transient diplopia • Clival cultures grew methicillin‐resistant 3 months prior to admission. His weakness worsened, with Staphylococcus aureus slurred speech, and he was brought to hospital. • PMH/PSH – denied toxic habits but his sister said he used drugs • Intravenous antibiotics were given for 6 • ROS – sore throat weeks, prior to switching to oral antibiotics. • Tongue with black plaque • Pulmonary congestion • Decreased speech volume and difficulty with secretions. • Mental status: intact but evasive • CN: bilateral VI paresis; cough with water • Motor/sensory: spastic R hemiparesis, decreased sensation in R leg

10 1/8/2016

—32-year-old male drug abuser with loss of consciousness after cocaine overdose. CNS Effects of Metabolic Perturbations

Hypoxia Hypoglycemia Electrolyte imbalance Dysmyelination Disorders of oxygenation Disorders of cerebral autoregulation Organ failure (liver, renal)

Sharma P et al. AJR 2009;193:879-886

—32-year-old male drug abuser with loss of consciousness after cocaine overdose. Hypoxic – Ischemic Injury ‐ Imaging

1‐2 days after event

CT: • Diffuse swelling: effacement of the basal cisterns, ventricles and sulci, attenuation of the grey–white matter interface

• Hypodensity of the cortex, basal ganglia (cytotoxic edema)

• Hypodensity of the white matter (distension of the deep medullary veins, obstruction of the cerebral venous drainage)

• Focal areas of infarction (basal ganglia. cortical boundary zone territories)

Sharma P et al. AJR 2009;193:879-886 Howard et al. Practical Neurology 2011;11:4‐18

Early Profound HIE CNS Effects of Metabolic Perturbations A 43 year old woman suffered an out of hospital cardiopulmonary arrest with CPR started within minutes, with EMS arriving in about 15 minutes. Coarse v-fib was converted to sinus rhythm. In the ED she was unresponsive, with sluggishly responsive pupils, absent corneals, weak gag. Her arms flexed to painful stimulation and she was without movement in her legs. A HCT was obtained.

Cerebral edema .bilateral cerebral hemisphere sulcal effacement .loss of gray-white differentiation .probable decreased size of ventricles and cisterns

11 1/8/2016

Polysubstance abuse & hypoxia Acute hypoxic‐ ischemic injury 32 year old woman with poly‐substance abuse, HCV, HTN was admitted for 2nd and 3rd degree burns over her scapula. After taking A 52 year old woman with vascular risk factors had an in- clonezapam, trazodone, and intravenous heroin, patient fell asleep hospital asthma attack. She was quickly intubated, then went leaning on a heating pipe. A week into the admission for excision and into a PEA arrest. Resuscitation was successful within 2-3 grafting of her burns, she developed hypoxia, lethargy, tachypnea, and mins; but, she had only brainstem reflexes. A CT scan hours pinpoint pupils, so was intubated for airway protection. During Foley later was negative. An MRI scan 2 days later showed extensive insertion, a bottle of clonezapam was found in her vagina/perineum. A restricted diffusion in the cortical grey matter, periventricular head CT scan showed bilateral basal ganglia infarcts. white matter and central pons.

Polysubstance abuse & hypoxia Hypoxic–ischemic brain injury –MRI On examination a week later, when extubated, she was alert, oriented MRI and inappropriately cheerful. STM was poor (1/3). Language was • Acute: – Logistically difficult early after cardiopulmonary event normal. Motor/sensory/coordination/reflex testing was unremarkable. – DWI/FLAIR: hyperintensity in basal ganglia, caudate, striatum, thalamus An MRI scan showed subacute basal ganglia infarcts. – Cortex, subcortical white matter, cerebellum, hippocampus • Subacute: – resolution of DWI signal abnormality with decreased edema – FLAIR/T2: changes in basal ganglia, cortex, subcortical white matter, hippocampus • Chronic: – Diffuse atrophy – Cortical laminar necrosis (cell death in layers III, IV of cortical mantle – Infarction in boundary zone territories between ACA, MCA, PCA – Cerebellar infarcts – Delayed leukoencephalopathy Howard et al. Practical Neurology 2011;11:4‐18 DWI FLAIR T2

Cerebral air embolization Hypoxic–ischemic brain injury –MRI • Arterial: trauma, surgery (especially MRI cardiothoracic/neurosurgery), procedures (e.g. • Acute: ERCP, arterial line, lung biopsy) – Logistically difficult early after cardiopulmonary event • Venous (paradoxical embolization through R‐L – DWI/FLAIR: hyperintensity in basal ganglia, caudate, striatum, thalamus shunt): central venous – Cortex, subcortical white matter, cerebellum, hippocampus catheter placement/removal; IV contrast • Subacute: – resolution of DWI signal abnormality with decreased edema injection into peripheral line – FLAIR/T2: changes in basal ganglia, cortex, subcortical white matter, hippocampus • Confusion, motor weakness, decreased • Chronic: consciousness, seizure and vision loss. – Diffuse atrophy – Cortical laminar necrosis (cell death in layers III, IV of cortical mantle • Ischemic stroke; cerebral edema – Infarction in boundary zone territories between ACA, MCA, PCA – Cerebellar infarcts – Delayed leukoencephalopathy • CT: acute gas that is absorbed rapidly • Supportive treatment; Howard et al. Practical Neurology 2011;11:4‐18 hyperbaric oxygen therapy.

12 1/8/2016

—43-year-old man with hypoglycemic coma who was found to have serum glucose level of Hypoglycemic Brain Injury 1.2 mmol/L (normal reference range, 4–6 mmol/L). • Insulin, medications, systemic diseases, • Lesions • Cerebral cortex, hippocampus, insula, dentate nucleus • Subcortical white matter • Basal ganglia, substantia nigra • Non‐hemorrhage, may enhance • Rare: splenium of corpus callosum, corona radiata, internal capsule • Sparing: cerebellar hemispheres, brain stem, thalamus Sharma P et al. AJR 2009;193:879-886

—43-year-old man with hypoglycemic coma who was found to have serum glucose level of Young diabetic man with hypoglycemia 1.2 mmol/L (normal reference range, 4–6 mmol/L). A 21 year old man with type 1 DM on an insulin pump had two days of memory loss and confusion. His fasting glucose was reported to be 44 and a history was given of intermittent hypoglycemia. He was amnestic for events of the past week. An MRI was obtained. He was given glucose and his pump was discontinued. Memory improved over several weeks. He was brought in by his mother two years later because of anger, anxiety and poor grades in graduate school. A follow‐up MRI was obtained. Sharma P et al. AJR 2009;193:879-886

Acute hypoglycemia Acute on chronic confusion in a middle‐aged woman • 45 year old woman was found by her husband in her pajamas, sleepy and confused at 5 pm. She vomited and complained of a 2 headache. Her husband noted that she seemed more forgetful 0 recently. 0 9 • PSH: – getting MA in history – just finished her examination – living in temporary shelter as home burned down a year ago • PMH: 2 – chronic depression with postpartum acetaminophen OD suicide attempt 0 • Exam: not oriented to date or day, 1/3 with repeated trials, unable 1 to recall events of the day. 1 • At hospital: HCT negative, CSF – bland; EEG – L temporal slowing • An MRI scan was obtained.

13 1/8/2016

Acute on chronic confusion in a middle‐aged woman MRI 4‐08 Leg weakness and confusion

FLAIR 35 year old man was LKN a week prior to transfer from OSH for stroke. Three days prior he was found by the landlord on his bathroom, lying in his waste, foaming at mouth, and lethargic. At OSH CK >20,000, BUN 77, Cr 3.2, and his right leg was weak. With hydration rhabdomyolysis improved. Unremarkable studies included CT of brain and spine, urine toxicology screen and EEG. PMH/SH: no illnesses/toxic habits, pilot, was unpacking in new DWI T2 apartment at time of incident. Exam: oriented; knows address; mildly impaired naming, nl repetition/reading; 1/3 objects; unable to do serial 7’s; RLE: weak, sensory loss, absent reflexes, normal temperature, intact distal pulses MRI scan of the brain was obtained.

Acute on chronic confusion in a middle‐aged woman Leg weakness and confusion 4‐08 DWI FLAIR T2 T1C

T2 C

26 year old man with altered mental status, 13 days after extubation for inhalational injury after a kerosene truck explosion Carbon Monoxide (CO) Poisoning • Mechanisms – CO binds to hemoglobin with more than 200x affinity of O2, forming carboxyhemoglobin – Carboxyhemoglobin causing hypoxemia FLAIR – Decreased release of oxygen to tissues – Direct mitochondrial toxicity of CO • MRI Lesions – Bilateral anterior globus pallidus – Lobar white matter, watershed cortex, hippocampus – Thalamus, caudate, putamen, cerebellum – Hemorrhage, necrosis – Cortex, hippocampus, cerebellum (less common) • Pathologic Lesions – Necrosis –bilateral globus pallidus – Acute demyelination – Chronic atrophy

DWI T1 GRE

14 1/8/2016

CNS Toxicity of Medications Acute onset of R weakness in man with ALL

Acute: DWI lesions

1 week later: DWI resolved; subtle FLAIR lesions

CNS Toxicity of Medications Methotrexate Toxicity

Diffuse leukoencephalopathy • CNS (cerebral, spinal white matter) toxicity associated with intrathecal administration Cyclosporine / FK506 • Symptoms - Acute: headache, confusion, focal Methotrexate neurological deficit, seizures; Delayed: subacute Cytarabine (Ara‐C) encephalopathy, myelopathy, optic atrophy Cisplatin • Focal lesions on DWI with restricted diffusion (cytotoxic edema) BCNU • Focal lesions on T2, FLAIR imaging lesion common Thiotepa • White matter lesions Fludarabine • Non-vascular distribution of lesions Cerebellar lesions/atrophy Lithium Dilantin Metronidazole Sharma P et al. AJR 2009;193:879-886

Acute onset of R weakness in 19 year old man Metronidazole Toxicity A week after the third injection in series of injections of IT MTX, a man with T‐cell ALL • Neurologic symptoms at >2 g/d developed rapidly progressive R hemiparesis and • Dysarthria, gait disturbance, weakness of the extremities, and mental confusion dysarthria. A stroke code was called with NIHSS 6. • MRI: Bilateral, symmetric, T2 lesions, reversible CT/CTA was normal. Treatment with tPA was • Dentate nuclei, the tectum, red nucleus, periaqueductal gray considered but it not given. An MRI was obtained. matter,dorsal pons • Dorsal medulla, corpus callosum (splenium) less often affected

Sharma P et al. AJR 2009;193:879-886

15 1/8/2016

—54-year-old man who was taking metronidazole prophylactically and presented with acute onset gait ataxia and dysarthria. Toxic Metabolic Disorders

• Hypoxic/ischemic injury, hypoglycemia • Hypertensive disorders (PRES/RCVS) • Osmotic demylination • Liver failure • Poisoning: ethanol, methanol, alcohol, CO, ethylene glycol • Illicit drugs • Toxic effects of therapies/medications • Leukoencephalopathies • Mitochondrial disorders • Metabolic diseases

Sharma P et al. AJR 2009;193:879-886

—54-year-old man who was taking metronidazole prophylactically and presented with acute onset gait ataxia and dysarthria. THREE MONTHS LATER

Sharma P et al. AJR 2009;193:879-886

51-year-old woman who developed headaches, tremors, and visual changes 4 weeks after liver transplantation and initiation of cyclosporine therapy. ACUTE & ONE WEEK LATER

Sharma P et al. AJR 2009;193:879-886