ENCEPHALOPATHY

encephalopathy types

1. ENCEPHALOPATHY: TYPES, SYMPTOMS, CAUSES, STAGES & TREATMENT Derived from Greek word “ enkephalos ” - meaning brain. “Pathos” meaning is disease. The term “encephalopathy” is defined as altered mental status as a result of a diffuse disturbance of brain function. It represents a brain state in which normal functioning of the brain is disturbed temporarily or permanently. Any clinical condition that causes impairment in consciousness usually accompanied by diffuse EEG abnormalities DR.PRAMOD MEENA SR NEUROLOGY GMC,KOTA

2. Types & Causes of encephalopathy Reversible metabolic encephalopathy, Hashimoto’s encephalopathy, hepatic encephalopathy, infectious of the brain, brain tumours , toxic encephalopathy, nonconvulsive status epilepticus Irreversible chronic traumatic encephalopathy Hypoxic-ischemic encephalopathy

3. Causes of encephalopathy Encephalopathy results main from, Metabolic derangements (Na, K, Ca ) Toxins (exposure to toxic substances, e.g lithium paints, industrial chemicals) infectious (bacteria (TB) viruses, parasites, or prions), Hepatic (liver failure or liver cancer) Inflammations (Systemic Lupus Erythropetosis , sarcoidosis (soft tissues diseases) Drug Induced (Over dozage of the drug) Demyelinating ( e.g MS) Degenerative processes (Alzheimer disease, Parkinson's disease) Anoxic encephalopathy (lack of oxygen to the brain, including traumatic causes) Hereditary encephalopathies ( leucodystrophy white matter)

4. SYMPTOMS Common symptoms confusion memory loss personality changes troubling in thinking or focusing Less common symptoms trouble in speaking muscle weakness or twitches tremors seizures sleepiness

5. Hepatic encephalopathy D efinition: Hepatic encephalopathy is a reversible neuropsychiatric state that complicates severe liver disease. Encephalopathy associated with Cirrhosis and portal hypertension Encephalopathy associated with portal systemic Bypass without hepatocellular disease Encephalopathy associated with Acute liver failure

6. Clinical features Disturbed consciousness: Sleep disturbance (change of sleep pattern to hypersomnia , or drowsiness ) Confusion including delirium Unconscious 2 . Abnormal behavior 3 . Intellectual deterioration (cognition) 4 . Abnormal nerve reflexes Flapping tremor ( asterixis )

7. Clinical grading Stage 1: Abnormal sleep, Abnormal behavior (mood change e.g. euphoria/depression, strange behavior ) Altered cognition ( decreased attention and calculation ability) Flapping tremor (+/-) EEG (+/-) Stage 2: Lethargic, Inappropriate behavior Disorientation and memory decreased Flapping tremor (+), abnormal nerve reflexes(ataxia) EEG (+) Clinical grading Stage 3: Somnolence but can be aroused, marked confusion (delirium) Flapping tremor (+), abnormal nerve reflexes EEG (+) Stage 4: unconsciousness (can not be aroused) abnormal to loss of reflexes

8. Investigation 1. Blood ammonia 2.Electroencephalogram 3 . Evoked potentials 4 . Psychometric tests

9. Treatment . Identification & correction of the precipitating cause: Precipitating factors Drugs ! Electrolyte imbalance – hypokalemia/metabolic alkalosis (diuretics, vomiting, diarrhea, infusion) GI Bleeding Infection Constipation Large protein meal

10. Cont. Intervention to reduce the production & absorption of gut-derived ammonia & other toxins: 1) Diet: reduce and modify dietary protein and maintain Calorie intake 2) Enemas (mild acid) and/or purgation 3) Lactulose or lactitol 4) Inhibition of gut bacteria: Antibiotics: neomycin(oral), metronidazone ? 5) Modification of colonic flora: probiotics? Modify colonic flora, resulting in displacement of urease-containing bacteria with lactobacillus Cathartic effect Lower the colonic pH, resulting in the formation of non-absorbable NH4 from NH3 in the colon

11. Metabolic encephalopathy Pathophysiology: Mainly it depends on the cause However regardless the etiology the main mechanism is due to disruption of arousal and attention centers in the brain (ARAS ). • Another mechanism including compression or injury for areas critical for memory ,attention and executive functions . • Abnormalities in neurotransmitters such as ( (Ach , serotonin, GABA ,dopamine, tryptophan ,cytokines ) also affect these connections.

12. Uremic encephalopathy Pathology : Decrease clearance of osmotically active toxins Proinflammatory state lead to BBB breakage Electrolytes abnormailites Seziures and myoclonus Dysequilibrium syndrome Dialysis dementia Cerebral atrophy

13. symptoms: Seizures and myoclonus Permanent memory loss Dysarthria Facial grimacing Myoclonus Mood and personality changes Confusion Headache Nausea and vomiting Tremors

14. Prognosis: Metabolic encephalopathy is common in the ICU setting • the brain dysfunction that occurs with metabolic encephalopathy was thought to be completely reversible • critically ill patients with metabolic encephalopathy are often left with long-term neurocognitive deficits. • Persistent neurologic and psychiatric deficits occur in up to 32% of medical ICU survivors

15. Management: Any of abnormal movement presented in renal patient should be evaluated by EEG confirm diagnosis of myoclonus • Phenytoin used as AEDs in uremic patient to control sezuires but it worse myoclonus • Best choice for myoclonus is tiratam & valporic acid

16. HASHIMOTO ENCEPHALOPATHY Defined by the detection of thyroid peroxidase (TPO) antibodies in patients with acute or subacute encephalitis that responds to steroids. “Encephalopathy associated with autoimmune thyroid disease” is considered more accurate- due to normal thyroid function. Very vague symptoms- unclear course

17. Clinical features: non specific Stroke-like symptoms Tremor , myoclonus Transient aphasia Sleep and behaviour abnormalities Hallucinations, seizures and ataxia.

18. Diagnosis: clinical triad of neuropsychiatric symptoms, detection of antimicrosomal or antithyroglobulin antibodies, and exclusion of other causes. antithyroid peroxidase, antithyroglobulin , lesser extent thyroid-stimulating hormone receptor blocking antibodies. α- enolase CSF show moderately elevated protein, may be positive for anti thyroid Ab , OCB seen EEG: slowing, triphasic waves, epileptiform discharges. MRI usually normal, occasionally non-specific sub cortical white matter T2 signal changes. Thyroid status may be normal.

19. Treatment: Initial treatment is usually with oral prednisone (50– 150 mg/day) or high-dose IV methylprednisolone (1 g/day) for 3–7 days. Thyroid hormone treatment is also included if required. Failure of some patients to respond to this first line treatment has produced a variety of alternative treatments including azathioprine, cyclophosphamide, chloroquine , methotrexate , periodic intravenous immunoglobulin and plasma exchange. Seizures , if present, are controlled with typical antiepileptic agents . Recurrence – continued steroids, IVIG, other immunomodulatory drugs.

20. NMDA ENCEPHALOPATHY Leading cause of autoimmune encephalitis in children and adolescents. Age- frequently 2– 40 years, 80% Female Stages : Stage1 – prodromal phase Stage 2 – psychiatric and behavioral problems Stage 3 – Decreased level of consciousness Behavioral changes included new-onset temper tantrums, agitation, aggression, and changes in mood or personality

21. Clinical features: Behavioural disturbance,Psychosis  Catatonia Seizures Movement disorders including orolingual dyskinesias and stereotypic movement . Dysautonomia . Ovarian teratoma is associated in up to 50% of the cases

22. Diagnosis CSF : -lymphocytic pleocytosis , - elevated protein levels - oligoclonal bands EEG – extreme delta brush MRI demonstrate medial temporal lobe attenuated inversion recovery high signal or focal areas of hyperintensity in the frontal or parietal cortex fluorodeoxyglucose positron emission tomography (FDG-PET) scan show cortical hypermetabolism in acute stages, and hypometabolism in more subacute stages of the illness.

23. Treatment first line of immunotherapies including corticosteroids, intravenous immunoglobulin, or plasma exchange Rituximab and cyclophosphamide, alone or combined, are often effective in adults Approximately 80% of patients have substantial or full recovery.

24. Septic encephalopathy The term "septic encephalopathy" : acute confusional episodes or other significant cognitive abnormalities that develop during sepsis as an entity that cannot be explained by hepatic or renal dysfunction, hypotension, or hypoxia Occur in a range of 8–70% of septic patients May as an early sign of sepsis Imply poor prognosis , higher mortality

25. Etiology and pathopysiology Most likely multifactorial Underlying mechanisms only been defined in parts Disseminated cerebral microabscesses  -infecting organisms and/or their toxins do not directly cause encephalopathy. Systemic inflammation resulting from infection or other causes action of inflammatory mediators on the brain , cytotoxic response of brain cells

26. Cont. Free radicals damage RBC and limit O2 delivery to brain Inflammatory mediators impair mitochondrial function and O2 extraction by the brain  destroy BBB perimicrovessel edema disruption of astrocyte endfeet aromatic a.a enter brain parenchyma and disturb NT Ultimately, extensive neuronal injury

27. Diagnosis No specific test available Electroencephalopathy Most sensitive diagnostic tool Normal, diffuse slowing,excessive theta,predominantly delta,triphasic waves, and suppression or burst suppression. Evaluating depressed consciousness in critically ill p`ts ( 1) Receiving sedative and narcotic drugs (2) Head injury , intracranial event e.g. cerebrovascular causes ( 3) Metabolic derangements : Sugar , electrolytes (Na , Ca ) , acid-base balance ( acidemia , hypercapnia ), oxygenation (hypoxia , hypotention ) , hepatic encephalopathy ,uremic encephalopathy , septic encephalopathy , alcohol or drug TREATMENT: According to cause of septicemia If hypotension start inotropic supports

28. Question. A 21-year-old primigravida with gestation age of 33weeks whose first and second trimester gestation was uneventful with no history of hypertension and epilepsy before and during pregnancy. She developed sudden onset of headache, giddiness, vomiting, and convulsions. Her blood pressure was 142/94 mmHg. Next day, the patient was taken into C section for fetal distress. On 2nd day of postcaesarean section she developed loss of vision, headache, and vomiting. Her blood pressure was 140/114 mmHg.

29. PRES Posterior Reversible Encephalopathy Syndrome . Variety of symptoms – headache, altered mental status, visual disturbances, and seizures. Hypertension, Pre- eclampsia / eclampsia , immunosuppression, sepsis, chemotherapy, collagen vascular disease, and renal failure.

30. Question. A 36-year-old real estate agent was in the first trimester of her first pregnancy when she awoke with diplopia. She had not been well for several days, feeling lethargic, off-balance and slightly disoriented; symptoms that she attributed to severe morning sickness during the previous eight weeks. She was not taking any medications and had been previously healthy. Exam revealed bilateral ptosis, limitation of gaze in all directions, slow upward saccades, upbeat nystagmus and mild ataxia.

31. Wernicke’s encephalopathy – triad of ophthalmoplegia , ataxia, and confusion. O Triad – minority of cases. O Ocular findings – earliest and most constant. O About 30% have isolated or predominant mental status changes ranging from confusion to frank coma. O Sometimes – sudden onset.

32. Mangement Low serum erythrocyte transketolase – days to obtain . Treat on suspicion . MRI – specific (93%) but sensitivity is low .

33. CNS infections/Para-infection

34. Clinical features: Fever , headache Meningism Focal neurological deficits Seizures Primary source of infection Pneumonia (bacteria, mycoplasma, TB), purpuric rash (meningococcemia), mucosal herpetic lesions, cyanotic heart dis. (brain abscess)

35. Investigations: CBC, CRP, ESR Blood culture Viral study (blood, throat, urine, stool) TB work-up CSF: ME, sugar, protein, C&S, virology, TB, fungus

36. Tumour /CNS Malignancy Suggestive features Signs & symptoms of raised ICP Focal neurological deficit Seizures Extra-cranial primary malignancy Neuro -imaging : 1 st line investigation

37. Toxic encephalopathy Toxic encephalopathy, also known as toxic metabolic encephalopathy, is a degenerative neurologic disorder caused by exposure to toxic substances. It can be an acute or a chronic disorder . Toxic encephalopathy can be caused by various chemicals, some of which are commonly used in everyday life (paints, industrial chemicals, and certain metals).

38. EEG in encephalopathy In general, the most prominent feature of the EEG record in encephalopathies is slowing of the normal background frequency. Reactivity to photic or other type of external stimulation may be altered. Some conditions are associated with an increase in seizure frequency, and in such cases, epileptic activity may be recorded.

39. EEG findings Triphasic has been associated with a wide range of toxic, metabolic, and structural abnormalities . Triphasic waves are associated with an altered level of consciousness that may range from mild confusion to deep coma. The background may be slower in hepatic failure A classic etiology of triphasic wave is hepatic/metabolic encephalopathy. Triphasic’s are high-amplitude (>70 µV). Having three phase + ive , - ive and then + ive . Initial sharp component .

40. Clinical and electrographical features There is good correlation b/w the severity of the EEG changes , the severity of the encephalopathy and the clinical state of the patient. * Degree of impairment is clinically categorized as— * Coma * Stupourous . * Lethargy/ hyper- somnia *Confusion * Delirium * Degree of impairment is Electrographically categorized as, 1.Background slowing without theta delta slow waves. 2.Diffuse theta delta activity associated with normal background activity . 3.Slow background activity with diffuse theta delta activity.

41. Clinical and electrographical features & possible pathologies Background slowing--- cortical (gray matter) dysfunction Delta theta slow waves – (Brain) white matter disease Delta theta slow waves , along with slow background activity--- both cortical and white matter disease Serial EEGs needed to evaluate the course of disease process

42. Grading of EEG abnormalities in diffuse encephalopathy 1 a --slow background 7-8 Hz without theta delta waves 1b —4-6 Hz background without theta delta waves 2a —dominant theta delta with normal background activity. 2b —dominant theta delta with slow background activity 3a- -dominant delta with normal background activity 3b—dominant delta with slow background activity 4a —moderate to high amplitude delta >50 microvolt with no background reactivity 4b —low amplitude < 5sec 5a —burst suppression with suppression period < 5sec 5b —burst suppression with suppression period >5 sec. 6a —near electro cerebral silence. 6b --ECS

43. Burst suppression pattern Recurrent , periodic or pseudo periodic bursts with EEG suppression period of variable duration Burst can be a mixture of sharp, spike, alpha. theta, delta activities The suppression period can last from 2s to 20 mint. Seen in Anoxic brain damage, CNS supressant drugs and severe hypothermia Paradoxical arousal response A stimulus brings out slower activity with generalized high voltage delta bursts, that is called as paradoxical arousal response

44. Triphasic waves Typical and atypical--- * Typical –initial small negative sharp discharges of 2-4 Hz, followed by large positive sharp discharge and subsequent negative wave. *Frontal dominant, Continuous, stereotyped ,forms a phase lag from anterior to posterior region, seen in hepatic encephalopathy. * Atypical—less continuous, less stereotyped ,present in uremic, hyperthyroid, toxic encephalopathies * In dementia (AD) posterior dominant triphasics are present. TW are also seen in encephalopathies associated with renal failure or electrolyte imbalance, as well as anoxia and intoxications (such as lithium, metrizamide , and levodopa)

45. ECS *No EEG activity over 2 micro volts when recorded from scalp electrode pairs 10 cm interelectrodes distance. * Filter settings should not b below 30 Hz and low filter should not be higher than 1 Hz. * Recording should be at-least one hour, with artifacts free 30 min recording on 2uv. * Electrodes impedance should be 100ohm to 10Kohm.

46. References Practical Guide for Clinical Neurophysiologic Testing: EEG: Thoru Yamada MD. * Basic Principles, Clinical Applications, and Related Fields * By Ernst Niedermeyer nelson text book of paediatrics 19 th edition

47. Hashimoto’s Encephalopathy Steroid responsive acute or subacute encephalopathy associated with anti-thyroid antibodies . Presenting features vary widely . Psychiatric symptoms around 60%. TPO and Thyroglobulin. TSH should be high but patients may be euthyroid or hypothyroid. Myxedema coma – acute or subacute and precipitated by stress. Hypothermic, Hypo ventilate, and “suspended animation.”

48. Hyper-Hypoglycemia Hyperosmolality Diabetic ketoacidosis – pH doesn’t correlate well with level of consciousness. Diabetic lactic acidosis . Sudden lowering of serum osmolality – cerebral edema – can be fatal. Head trauma and Stroke patients – Glucose control .

49. H ypoglycemia Stroke like illness . Delirium . Coma. Seizure . H yperglycemia Seizures Hemianopia Hemichorea / Hemiballismus

50. Hypoglycemic Brain Injury Range from reversible focal deficits and transient encephalopathy to irreversible coma. Mean blood glucose was around 30mg/dl. White matter – more sensitive to ischemia than previously thought. The duration of hypoglycemia may be difficult to determine in many cases.

51. Hypoxic ischemic encephalopathy Abnormal neurological behaviour in the neonatal period arising as a result of a hypoxic-ischemic event. Occurs in1-6 per 1000 term live births in developed countries 25% die or have multiple disabilities 4% have mild to moderate forms of cerebral palsy Essential criteria for diagnosis of HIE: - metabolic acidosis -early onset of encephalopathy -Multisystem organ failure

52. Diagnosis Mri is the preferred imaging modality in neonates with HIE CT scan : identifies focal hemorrhagic lesions, diffuse cortical injury and damage to the basal ganglia. aEEG : determine which infant are at high risk for long term brain injury. Treatment 1. hypothermia 2.Drug therapy : phenobarbital,phenytoin 3. Supportive care

53. WERNICKE ENCEPHALOPATHY WE is an acute, potentially reversible, neuropsychiatric disorder caused by thiamine deficiency. The incidence can be as high as 12.5% The altered cognition of WE can progress to KS, a chronic and usually permanent . Approximately 80% of patients with acute WE will develop KS. Mechanism:- Chronic alcoholism – Malnutrition – reduced thiamine uptake and utilization

54. Physical examination The classical triad of symptoms – only 1/3rd of cases Ocular abnormalities – nystagmus , bilateral lateral rectus palsies, conjugate gaze palsies, sluggish pupils, ptosis, and anisocoria Encephalopathy – global confusionalstate , disinterest, inattentiveness, or agitation; Coma is rare. Gait ataxia – cerebellar damage, and vestibular paresis Peripheral neuropathy – foot drop, and decreased proprioception

55. Management Erythrocyte transketolase activity assay, Thiamine assay – very specific tests – not widely available – reserved for diagnostic dilemmas EEG and CSF analysis may exclude other explanatory or concomitant conditions. Emergency department care – Parenteral thiamine –Requirement in chronic alcoholics may be as high as 500mg single dose or multiple daily doses . Never start on Dextrose Treatment with thiamine repletion, currently recommended at 1 gram of IV thiamine per 24 hours for alcoholics with suspected Wernicke encephalopathy , should not be delayed. Death occurs in nearly 20 % of patients with delayed treatment. In-Patient care –Watch for complications – Korsakoff psychosis –Alcohol withdrawal –Congestive heart failure – Lactic acidosis Out-Patient Care – Thiamine 100 mg PO daily, start alcohol cessation program, Advise on importance of balanced diet.

56. Refrences Practical Guide for Clinical Neurophysiologic Testing: EEG: Thoru Yamada MD.  Basic Principles, Clinical Applications, and Related Fields  By Ernst Niedermeyer  nelson text book of paediatrics 19 th edition

57. Thank you