2015 台灣神經學學會住院醫師教育課程

Metabolic and Toxic

林靜嫻 臺大醫院神經部 臺大醫院巴金森氏症暨動作障礙中心

1 Learning Objectives

• 1. To describe the clinical presentations and possible pathophysiology of common metabolic/toxic encephalopathy.

• 2. To assess a patient with clinical symptoms and signs, as well as imaging findings, indicative of a specific metabolic/toxic encephalopathy and make appropriate treatments and suggestions.

2 Outlines

3 What is encephalopathy?

• Encephalopathy is described as a brain function manifesting as an attentional disorder anywhere in the continuum between a hyper-alert agitated state and coma.

• The “Consciousness Spectrum of Encephalopathy”

Normal Delirium Stupor Coma

4 Highly metabolic activity brain regions- Deep Gray Matter Nuclei

• The putamen, globus pallidus, caudate, are rich in mitochondria, vascular supply and have high metabolic activity and increased utilization of Lenticular nucleus glucose and oxygen.

Hegde, AN et al., RadioGraphics 2011;31:5-30.5 • Patients usually present with altered sensorium associated with , focal neurological deficits, brainstem signs and extra-pyramidal movement

6 disorders. Krack, P et al., Trends Neurosci. 2010 Oct;33(10):474-84. I. Hypoxic ischemic encephalopathy • Hypoxic ischemic encephalopathy (HIE) is secondary to circulatory or respiratory (cardiac arrest, , drowning, or asphyxiation).

• The severity is determined by the duration of insult, degree of blood flow, temperature, and serum glucose levels.

• Severe HIE characteristically affects the grey matter structures, including the cerebral cortex, , thalamus, and hippocampi.

7 ≦24 hours after onset (brain CT)

• A loss of distinction between grey and white matter is often observed (white cerebellum sign)

8 Bathla G & hedge AN, Clinical Radiology 68 (2013) 545-554 ≦24 hours after onset (brain CT) • Bilaterally symmetric hypoattenuating areas in the thalamus, caudate nuclei, and globus pallidus.

Hegde, AN et al., RadioGraphics 2011;31:5-30.9 Brain MRI findings • <1 hr: DWI: increased signal intensity of the affected areas. • ≧24hrs: T2WI: increased signal intensity and swelling of the affected areas.

T2WI DWI

10 Hegde, AN et al., RadioGraphics 2011;31:5-30. Delayed post-hypoxic encephalopathy (after 14-21 day)

54 Y/O man, DM, HTN, HLP, CAD Cardiac arrest s/p CPR with ROSC within 1 minute.

Progressive slow movement was noted 5 months after discharge.

11 T2WI MRI 5 months after cardiac arrest

12 II.

• Acute hepatic failure: can be a neuropsychiatric presentation caused by hepatocellular dysfunction and .

• Chronic hepatic failure: is more insidious and is due to porto-systemic shunting; causes commonly include alcoholic cirrhosis; nonalcoholic cirrhosis (eg, Wilson disease, viral hepatitis), transjugular intrahepatic portosystemic shunt (TIPS), and urea acid cycle impairment.

13 Clinical grading of hepatic encephalopathy

14 Angel MJ, Young GB. Neurol Clin. 2011 Nov;29(4):837-82. Pathophysiology: Ammonia plays a major role

• 1. ammonia enhanced GABAA receptor activation. • 2. GABA availability in synaptic cleft. • 3. Activation of astrocytic peripheral-type benzodiazepine receptor (PTBR)> GABA

15 Angel MJ, Young GB. Neurol Clin. 2011 Nov;29(4):837-82. Source of ammonia

1. Small intestine: the degradation of glutamine produces ammonia. 2. Large intestine: breakdown of urea and protein by normal flora. 3. Muscle: proportion to muscle work. 4. Kidney: ammonia production increases when hypokalemia develops and when diuretic therapy is used.

16 Hepatic encephalopathy- chronic hepatocerebral degeneration

60 Y/O man, Chronic HBV related liver cirrhosis.

Ammonia: 194.

Prominent posture/action + myoclonic jerks+ mild feature

17 Bilaterally symmetrical pallidal hyperintensity on T1WI

• Manganese deposition

• There is no clear relationship between MRI characteristics and the clinical severity of HE.

18 D/D Mn deposition induced parkinsonsim • Bilateral, symmetric, high-signal abnormalities on a T1-weighted scan in the globus pallidus and substantia nigra pars reticulata.

19 Berg D et al., Mov Disord 2011;26 (6):979-996 SLC30A10 mutations-Mn Transport Disorder

20 Quadri M et al., Mov Disord 2015;30(7):996-1001 Treatment for hepatic encephalopathy

• Avoid and remove ammonia-precipitating conditions. • Dietary protein intake of 1 to 2 g/kg per day. • Lactulose • Flumazenil (antagonist of benzodiazepine recognition site located on the GABAA receptor) • Neomycin and rifaximin: antibiotics target urease- producing bacteria.

21 III. Uremic encephalopathy

• Acute uremic encephalopathy: range from subtle executive dysfunction to coma.  Early signs include reduced attention, impaired construction and writing, executive dysfunction, behavioral changes, and sleep disturbances, which can lead to an agitated delirium and coma.  Combined with , tetany or seizures.

• Chronic uremic encephalopathy : is characterized by slowness of thought, , apathy, flattening of affect, inattention, and constructional impairment.  Sleep disturbances and restless leg syndrome are also common.

22 Angel MJ, Young GB. Neurol Clin. 2011 Nov;29(4):837-82. Pathophysiology

• No single substance is believed to be the sole cause of the clinical state of uremic encephalopathy. • Putative toxins include guanidino compounds, parathyroid hormone, urea, and middle molecules.

23 Encephalopathy related to treatment of uremia a) Dialysis disequilibrium syndrome. b) Wernicke encephalopathy. c) Osmotic demyelination syndrome.

24 IIIa. Dialysis disequilibrium syndrome

• This encephalopathic state is caused by shifts of water and cerebral edema, and affects patients during or shortly after hemodialysis.

• Symptoms include headache, nausea, vomiting, restlessness, myoclonus, disorientation, and somnolence are the classic features, but in severe cases organic psychosis, generalized seizures, stupor, or coma may occur.

25 IIIb. Wernicke encephalopathy

• Clinical triad: 1. Altered consciousness 2. Ophthalmoplegia 3. Ataxia • It is caused by thiamine (vitamin B1) deficiency • Risk groups: alcoholics, cachexia, nausea, vomiting, GI malignancy or s/p surgery aggravate the risk of poor thiamine intake.

26 Thiamine (B1): coenzyme in carbohydrate metabolism • It is indirectly responsible for membrane activity. • It presumably leads to disequilibrium of osmotic gradients, resulting in swelling of both intra- and extracellular spaces.

Bae SJ et al., AJNR Am J Neuroradiol 2001;22:1480-2.27 Imaging findings of Wernicke encephalopathy (I) • Symmetrically signals in medial thalami, mamillary bodies, periaqueductal region, tectal plate, and floor of the fourth ventricle (esp. in alcoholics)

28 Angel MJ, Young GB. Neurol Clin. 2011 Nov;29(4):837-82. Imaging findings of Wernicke encephalopathy (II)

• Sagittal DWI: typical small corpora mammillaria (corpus albicantia) • FLAIR: abnormal hyperintensity of the periaqueductal grey matter.

29 IIIc. Osmotic demyelination syndrome

• Biphasic clinical manifestations: 1. Altered consciousness and electrolyte dysfunction, which transiently improve after treatment. 2. Between 2-7 days after electrolyte correction patients usually develop neurologic abnormalities with tetra- spasticity, pseudo-bulbar palsy, and locked-in syndrome being the more frequent manifestations.

• The pathogenesis likely relates to rapid correction of hyponatremia or over-correction to hypernatremia

30 MRI findings- central pontine myelinolysis (CPM) • signal the central pons with sparing of the pontine tegmentum, ventrolateral pons, and corticospinal tracts, giving rise to the classic “trident shape” appearance.

31 Extrapontine myelinolysis (ECPM) • Isolated extrapontine demyelination may occur in ∼10% of patients (ie, basal ganglia, thalami, lateral geniculate body, cerebellum and cerebral cortex), or may occur together with CPM T1WI FLAIR T1WI with contrast

32 Gianluca Floris et al. 2013;81:1722-1723 How to correct hyponatremia?

33 Angel MJ, Young GB. Neurol Clin. 2011 Nov;29(4):837-82. IV. Hypoglycemia

• Defined as serum glucose concentration < 40 mg/dL. • Regions with higher energy demand and higher efficiency of glucose usage are vulnerable: the medial subiculum, the crest of the dentate gyrus, dentate granule cells of the hippocampus, the neocortex and the basal ganglia.

34 Angel MJ, Young GB. Neurol Clin. 2011 Nov;29(4):837-82. Clinical symptoms • Neuro-glycopenic symptoms are related to activation of the counter-regulatory hormones, especially the catecholamine response. • Severe symptomatic hypoglycemia occurs when counterregulatory mechanisms are overwhelmed. • S/S: 1. Cold perspiration, tachycardia, lightheadedness, headache, and mild agitation. 2. Confusion, lethargy, and stupor. D/D with 3. Seizures brainstem ! 4. Focal neurological sings, mimic stroks 35 Imaging findings of hypoglycemia • DWI/T2WI: signal in the posterior limb of the internal capsules, hippocampi, the basal ganglia and cortical areas. The splenium of the corpus callosum may also show signal changes.(neuronal death and cytotoxic edema) Don’t follow a vessel territory

T2WI DWI

36 V. Hyperglycemia

• Is defined as serum glucose > 140 mg/dL. • Impairment of consciousness typically occurs when serum glucose values are > 300 mg/dL in DKA, and > 600 mg/dL) in NKH. (More frequently in NKH than in DKA).

• Neurological manifestations: Impairment of consciousness (confusion, lethargy, stupor, and coma), and focal neurologic findings including hemiplegia, aphasia, focal motor seizures, and involuntary hyperkinetic movement disorders.

37 Angel MJ, Young GB. Neurol Clin. 2011 Nov;29(4):837-82. Hyperglycemic hemi-ballism

80 Y/O man, Chronic kidney disease (Cre=10.0). DM for 20 years, poor OHA control

One-touch sugar : 348 HbA1c : 13.4%

38 Brain MRI of this patient

T1WI DWI T2WI

39 Hyperglycemic hemi-ballism or hemi-

• Usually unilateral • Elderly : average onset age : 71 y/o • Female : male = 1.8 : 1 (65%) • Eastern Asian ; genetic factors may play a role

J Neurol Sci. 2002;200:57-62 Characteristic image signs

• CT : contralateral striatal hyperdensity • MRI T1WI : high-signal intensity changes – Contralateral putamen, caudate, GP T2WI : Variable findings No gadolinium enhancement VI. Hashimoto encephalopathy

• A brain disorder in a patient with antithyroid antibodies in the autoimmune condition of Hashimoto thyroiditis. • Patients fulfilling the criteria for Hashimot encephalopathy have been reported to have elevated CSF levels of antithyroglobulin antibodies, antithyroi peroxidase (antimicrosomal) antibodies, and circulating immune complexes. • However, these autoantibodies may exist in 20% of asymptomatic people, especially elderly women.

th Merritt’s Neurology, 13 edition42 Clinical features of Hashimoto’s encephalopathy • There are two main presentations : (1) a “vasculitic type” with multiple -like episodes, and (2) a diffuse progressive type with neuropsychiatric symptoms and .

43 Merritt’s Neurology, 13th edition Pathophysiology

• The proposed pathophysiologies of Hashimoto encephalopathy include autoimmune cerebral vasculitis, global hypoperfusion, brainstem vasculitis, and primary demyelination.

• No confirmed mechanism has been proved.

44 Angel MJ, Young GB. Neurol Clin. 2011 Nov;29(4):837-82. Imaging findings

• Usually normal or non-specific.

45 Outlines

46 Carbon monoxide (CO)/Methanol/Cyanide • CO inhibits electron transport, methanol is metabolized to toxic formate, and cyanide blocks trivalent iron in the cellular respiratory chain. > all impair mitochondrial respiratory chain function.

47 CO intoxication-Parkinsonism

44 Y/O man, Depression for years. Suicide 2 years ago (燒煤炭)

Progressive shuffling gait with easy falling was noted 3-4 months after the event.

48 Brain MRI of this patient

• CO in particular has a propensity to affect the globus pallidus.

T2WI T1WI DWI

49 Toxins causing cerebellar syndrome

1. Methyl mercury (Minamata disease) It causes damage to the granule cell layer in the cerebellum, and microscopically diffuse loss of the granule cell layer in the cerebellar cortex. S/S: cerebellar dysfunction and visual/hearing/ olfactory/ gustatory disturbance and cerebral cortex-related somatosensory disturbances. 2. Methyl bromide 3. Organic tin

50 Toxins causing Parkinsonism

1. Manganese 2. CO 3. Methanol 4. Carbon disulfide 5. Paraquat 6. Rotenone 7. Cyanide

Kim Y et al., Saf Health Work 2012;3:243-5651 Take Home Message

1. In addition to affect consciousness level, metabolic abnormalities often involve the basal ganglia or thalamus on both sides.

2. Careful history taking and application of neuroimage can help the differential diagnosis and provide useful information in optimization of the diagnostic algorithm.

52 Thank you for your attention! [email protected]