Case 35-2008 - Amnestic Syndrome

7/28/2019 Case 35-2008 - Amnestic Syndrome

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Clinicopathological ConferenceClinicopathological Conference

Neurology Grand RoundsNeurology Grand Rounds

Kirk R. Daffner, M.D.Division of Cognitive and Behavioral Neurology

Brigham and Womens Hospital

R. Gilberto Gonzalez, M.D., Ph.D.

Neuroradiology

Robert P. Hasserjian, M.D.Pathology


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A 65-year-old man with rapid loss ofA 65-year-old man with rapid loss of

memorymemory

Presentation of case

Roy N. Alcalay, M.D.

Neurology


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Case PresentationCase Presentation

- 65 yo RHM with no significant medicalhistory presented with 4 weeks of lowenergy and depressed mood

- Reported living in a fog, losing his wayhome

- Brought for evaluation because he could not

tell where he was- Mental status exam: disorientation and short

term memory loss. General andneurological exam intact


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Initial impressionsInitial impressions

Dr. Kirk Daffner


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Initial PresentationKey FeaturesInitial PresentationKey Features

65 year old, right-handed man

Subacute changes in cognitive function andmood

Unremarkable general exam


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Initial PresentationOutstanding QsInitial PresentationOutstanding Qs

Characterization of the most salient changesin mental state (e.g., impairments ofattention, memory, language, executive fxs)

Baseline cognitive status and reserve Past medical/psychiatric hxrisk factors

Altered Mental StatusBroad Dif DxBenign, remediable process

Life-threatening process


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Sources of an Altered Mental StateSources of an Altered Mental State

Extra-Cerebral Toxic

Medications (e.g., anticholinergic, sedative, narcotic)Drugs (e.g., alcohol intoxication)

Metabolic (Lytes, Bun, Cr, LFTs, NH3,Ca, Mg, O2,TFTs, etc.) Nutritional (e.g., B1, B12, Dehydration)

Infection (e.g., UTI, Pneumonia, Sepsis)

Other (e.g., sleep deprivation/ disturbance,pain)


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Sources of an Altered Mental StateSources of an Altered Mental State

Cerebral Stroke Mass (e.g., tumor, SDH)

Seizure (e.g., postictal, non-convulsive status)

Infection (e.g., meningitis, encephalitis, prion disease)

Immune-mediated (e.g., limbic encephalitis, SLE,

steroid responsive encephalopathy)

Traumatic Brain Injury

Migraine

Psychiatric (e.g., depression, anxiety)


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Case Presentation, continuedCase Presentation, continued

Roy N. Alcalay, M.D.


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Case Presentation- cont.Case Presentation- cont.

- Basic labs, CBC, TSH were within normal

limits. Lyme negative, vitamin B12: 222

- MRI: symmetric T2 hyperintensities in medial

temporal lobes

- EEG: unremarkable

- LP: lymphocytic meningitis


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Case Presentation- cont.Case Presentation- cont.

- Exam on transfer: alert, attentive,disoriented to time and place. Registers 3/3,

recalls 0/3- Enlarged right scrotum on general exam

- Acyclovir continued, EEG, MRI, spinal tap

and abdominal-pelvic and chest CTrepeated

- Chest CT: 4cm x 2cm mediastinal mass

- Scrotal US: hydrocele


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ReferenceRange,Adults

Firstspinal tap

Secondspinal tap

Color Colorless Colorless Colorless

Turbidity Clear Clear Clear

Xanthochromia None None None

Red cells (per mm3) None 0 1

White cells (per mm3) 0-5 6 16

Neutrophils % 0 0 0

Lymphocytes % 0 0 100

Monocytes % 0 100 0

Protein mg/dl 5-55 74 50

Glucose mg/dl 50-75 71 71HSV I+II PCR Negative Negative

VZV PCR Negative

Borrelia burgdorferiPCR Negative

VDRL Negative


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Neuropsychological TestingNeuropsychological Testing

Janet Cohen Sherman, Ph.D.MGH Psychology Assessment Center


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Goals of Neuropsychological AssessmentGoals of Neuropsychological Assessment

Determine which aspects of cognitive status

have been altered and to what extent Relate findings to integrity of neural

systems function

Distinguish different underlyingneurological conditions


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Neuropsychological MethodologyNeuropsychological Methodology

Administer norm-referenced, standardizedtests

Tests measure a broad range of cognitive

functions Intelligence

Attention

Executive Functions

Memory

Language

Visuospatial Functions


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Determination of ImpairmentDetermination of Impairment

Compare patients performance to normative

data

Mean for someone of his age and education Compare patients performance to an estimate

of premorbid level of functioning

Occupational and educational history

Performance on a test of reading ability, generally

resistant to effects of neurological disease


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Intellectual FunctioningIntellectual Functioning

Test Percentile

Wechsler Test of AdultReading

55

WAIS-III Subtests

Similarities

Information

Letter-Number Sequencing

63

25

50

WAIS-III: Wechsler Adult Intelligence Scale-3rd Edition

Average range: 25th 74th Percentile


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Attention FunctioningAttention Functioning

Test Percentile

RBANS Attention

IndexDigit Span

Coding

66

81

47

RBANS: Repeatable Battery for the Assessment of

Neuropsychological Status


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Test Results: Trails ATest Results: Trails A

Raw: 33 sec

Mean: 39.14 sec

SD: 11.84

Score: 69%


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Test Results: Trails BTest Results: Trails B

Raw: 59 sec

Mean: 91.32 sec

SD: 28.89

Score: 86%


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LanguageLanguage

Test Percentile

Letter Fluency 9

RBANS

Language Index

Animal Fluency (1st )

Naming

16

2

73

Animal Fluency (2nd) 90


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Visuospatial FunctioningVisuospatial Functioning

Test Percentile

RBANS

Visuospatial IndexLine Orientation

Figure Copy

1442

11

Mattis Dementia

Rating ScaleConstruction Subtest

41-59


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Intact Visual ConstructionIntact Visual Construction


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Immediate MemoryImmediate Memory

Test Raw Score Percentile

List Learning

(10 items)

Trial 1: 4

Trial 2: 3

Trial 3: 4Trial 4: 6

1

Story

(12 details)

Trial 1: 7

Trial 2: 5

4

RBANS ImmediateMemory Index

10


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Delayed MemoryDelayed Memory

Test Raw Score Percentile

List Recall 0


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Neuropsychological ImpairmentsNeuropsychological Impairments

Profound and circumscribed memory loss

Severe anterograde amnesia

Limited encoding

Severely impaired consolidation

Memory impairment did not involve working

memory, implicit memory, or retrieval ofremote information


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Declarative Memory Processes:Declarative Memory Processes:

Neuroanatomical CorrelatesNeuroanatomical Correlates

Process NeuroanatomicalCorrelate

Patient Performance

Working Memory Prefrontal Cortex Intact

Retrieval ofAutobiographical Memories

Anterior Temporal/

Neocortex

Intact

Retrieval of semanticknowledge

Temporal Neocortex Relative preservation

Encoding Prefrontal Cortex/Medial Temporal

Structures

Impaired

Consolidation Medial Temporal Impaired

Recall/Retrieval Prefrontal Cortex/Medial Temporal

Impaired


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Key Factors in DifferentialKey Factors in Differential

DiagnosisDiagnosis

Preservation of cognitive and intellectual

functioning with impairment only in memory

Memory impairment specific to formation of

new lasting memories

Onset of difficulties relatively acute


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Possible EtiologiesPossible Etiologies

Posterior Cerebral Artery (PCA) stroke

Anoxic encephalopathy

CNS lymphoma

Limbic encephalitis

Autoimmune responses

Infectious processes

Metabolic disturbances


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Radiology StudiesRadiology Studies

R. Gilberto Gonzalez, M.D., Ph.DR. Gilberto Gonzalez, M.D., Ph.D..

NeuroradiologyNeuroradiology


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A CT of the chest at the level of the aorta reveals a smoothly marginated

anterior mediastinal mass (arrow)


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A coronal FLAIR (fluid-attenuated inversion recovery) image of the brain shows abnormally

high signal intensity involving the medial temporal lobes bilaterally (arrows).


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Differential DiagnosisDifferential Diagnosis

Kirk Daffner, M.D.

Case Key FeaturesCase Key Features


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CaseKey FeaturesCaseKey Features Benign PMH (No meds, no alcohol or tobacco abuse); Neg.

FH

Benign vital signs, general exam, sensory-motor neuroexam

Profound Anterograde Amnesia ~Preserved attention, executive fxs, processing speed,

semantic knowledge, naming

EEG: unremarkable Labs: B12 mildly diminished; otherwise benign CSF

Mild pleocytosis, elevated protein, normal glu

Neg PCR for HSV, HZV, CMV. Neg Lyme, VDRL MRI: T2/FLAIR abnormalities--bilateral limbic system

(medial temporal, basal forebrain, insula). Noenhancement

Chest CT: Anterior Mediastinal Mass

U/S scrotum: normal testes; hydrocele

Amnestic SyndromeAmnestic Syndrome


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Amnestic SyndromeAmnestic Syndrome

Anterograde Memory Loss

Retrograde Memory Loss (Ribots

Law)

Preserved Attention

Strongly implicates dysfunction of

components of the limbic system

Eti l i f A ti S dEtiologies of an Amnestic Syndrome


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Etiologies of an Amnestic SyndromeEtiologies of an Amnestic Syndrome

Wernicke-Korsokoff Syndrome

Traumatic brain Injury Hypoxia/Ischemia injury

Posterior Cerebral Artery Stroke(s)/Ischemia

Anterior Cerebral Artery Aneurysm Rupture Degenerative Dementia (Alzheimers disease)

Limbic Encephalitis

Infectious Herpes Simplex Encephalitis

Other Infectious Encephalitis

Paraneoplastic Limbic Encephalitis

Ab l T2/FLAIR i M di l T l L bAb l T2/FLAIR i M di l T l L b


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Abnormal T2/FLAIR in Medial Temporal LobesAbnormal T2/FLAIR in Medial Temporal Lobes

NOT CONSISTENT WITH

Wernicke-Korsokoff Syndrome

Traumatic Brain Injury

Hypoxic-Ischemic Injury

PCA Distribution Infarction

ACA Aneurysm Rupture

Degenerative Dementia (e.g., AD)

Ab l T2/FLAIR i M di l T l L bAb l T2/FLAIR i M di l T l L b


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UNLIKELY

Tumor Infiltrates (e.g., Primary CNS Lymphoma;Gliomatosis Cerebri)

Inflammatory Process (e.g., sarcoid)

Steroid-responsive Encephalopathy

Toxic Aluminum Encephalopathy

Seizure-relatedTemporal Lobe Edema


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MOST LIKELY

Limbic Encephalitis Infectious

Herpes Simplex Encephalitis (HSE)

Other

HHV6 VZV

Neurosyphilis

Other Infection (e.g., Japanese Encephalitis)

Non-Infectious Paraneoplastic Non-paraneoplasticImmune Mediated

No tumor identified (5 yr rule); Antibodies to neuropil,(e.g., VGKC)

SLE


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MOST LIKELY

Limbic Encephalitis

Infectious

Herpes Simplex Encephalitis (HSE)

Other HHV6

HZV

Neurosyphilis

Non-Infectious

Paraneoplastic Limbic Encephalitis Non-paraneoplastic

Antibodies to neuronal markers, no tumor identified

SLE


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Herpes Simplex EncephalitisHerpes Simplex EncephalitisClinicalClinical

Acute/subacute onset (


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Herpes Simplex EncephalitisHerpes Simplex EncephalitisEvaluationEvaluation

CSF

Lymphocytic pleocytosis (usually ~mild) Increased RBCs (~40%)

Increased protein

Normal glucose

MRI (abnormal in ~90%) T2/Flair/DWI signal abnormalities in temporal lobes

Unilateral

Bilateral

Extra-temporal signal abnormalities (insula, inferior frontal)

EEG (abnormal in ~85%) Focal findings: high amplitude theta or delta slow waves

Periodic lateralized epileptiform discharges from affected region

H Si l E h liti D d TH Si l E h liti D d T


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Herpes Simplex EncephalitisDx and TxHerpes Simplex EncephalitisDx and Tx

PCR

>95% sensitive

~100% specific

False negatives can be seen

Very early stages of the illness

Late stages of the illness

Usually remains positive during the first week of therapy

CURRENT CASE: PCR NEG X 2

Pathophysiology

CNS invasion thru reactivation of latent HSV or after primary HSVepisode in oropharynx via trigeminal N or olfactory tract

Predilection for limbic structures Probably direct virus-mediated injury and immune-mediated response

Treatment

Acyclovir (10mg/kg IV q 8 hrs x 14-21 days)

Even with Tx, relatively high risk of mortality (20-30%) and morbidity

Risk of poor outcome associated with delay in initiating Tx

Paraneoplastic Neurological SyndromesParaneoplastic Neurological Syndromes


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Paraneoplastic Neurological SyndromesParaneoplastic Neurological Syndromes

Neurological disorders associated with a remote effect ofcancer, not due to metastatic disease, metabolic abnormalities,

nutritional deficits, coagulopathy, or infection

Immune response directed at shared antigens expressed by thetumor and by the nervous system

Evidence of both humoral (ab) and cell-mediated immunity

Although the pathogenic role of antibodies remains to beproven, their identification strongly suggests a paraneoplasticdisorder and the need to search for a potential tumor

Many different syndromes (e.g., limbic encephalitis,encephalomyelitis, sensory neuropathy, Lambert-Eaton,opsoclonus-myoclonus, stiff-man syndrome, etc.)

P l i Li bi E h li i Cli i l


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Paraneoplastic Limbic EncephalitisParaneoplastic Limbic EncephalitisClinicalClinical

Subacute Onset (>80%)

Altered Mental Status Short-term memory loss (>80%) Confusion (>40%) Other cognitive impairments (~15%)

Psychiatric symptoms (>40%) Changes in mood (~15%) Changes in behavior/personality (~5%)

Hallucinations (~10%)

Seizures (~50%) (Temporolimbic ~40%)

Possible Hypothalamic dysfunction (>20%)(hyperthermia, somnolence, endocrine abnormalities)

May be part of a broader neurologic syndrome(brainstem, cerebellum)

PLE prior to dx of the underlying cancer (>60%)

P l ti Li bi E h liti W/UParaneoplastic Limbic Encephalitis W/U


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Paraneoplastic Limbic EncephalitisW/UParaneoplastic Limbic EncephalitisW/U

CSF (abnormal in >80%)

Mild pleocytosis (>50%)

Mild elevation in protein (>80%)

Normal glucose

Oligoclonal bands or elevated IgG index

Cytology negative for malignant cells

EEG Focal or generalized slowing

Possible epileptiform activity, especially involving temporalregions

MRI (abnormal ~65%)

Increased T2/FLAIR signal in temporal lobes (unilateral orbilateral)

Abnormal signal in other limbic structures (insula, inferior frontalcortex)

R/O metastatic disease, leptomeningeal enhancement c/w carcinomatous meningitis

PLEPLE AntibodiesAntibodies


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PLE Antibodiest bod es

Thymoma, Mediastinal Germ Cell

Tumor, Thyroid Cancer

Novel Antibodies to neuropil

Thymoma, SCLC,

Often NO CANCER (idiopathic)

Anti-VGKC

SCLCPCA-2

SCLCANNA-3

SCLC, BreastAnti-amphiphysin

Testicular, Lung

Breast

Anti-Ma proteins (Ma1, Ma2)

SCLC,Thymoma

Testicular Germ Cell tumor

Anti-CV2/CRMP5

SCLC, otherAnti-Hu (ANNA-1)

ASSOCIATED CANCERSANTIBODY

P l ti LE Di ti C it iP l ti LE Di ti C it i


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Paraneoplastic LEDiagnostic CriteriaParaneoplastic LEDiagnostic Criteria

Definite

Classic syndrome (like limbic encephalitis) andcancer that developed within 5 years of the dx ofthe neurological disorder

Non-classical syndrome that resolves or

significantly improves after cancer treatment(without concomitant immunotherapy)

Non-classical syndrome with onconeural(paraneoplastic) ab (well-characterized or not) and

cancer than develops within 5 years of the neurodx

Neurologic syndrome (classical or not) with well-characterized onconeural ab and no cancer

Graus et al, 2004

Tumors Associated with ParaneoplasticTumors Associated with Paraneoplastic


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Tumors Associated with ParaneoplasticTumors Associated with Paraneoplastic

Limbic EncephalitisLimbic Encephalitis

Small Cell Lung Cancer

Other Lung Cancers (adenocarcinoma, squamous cell)

Testicular Carinoma/Seminoma

Thymoma Lymphoma (Hodgkins/non-Hodgkins)

Germ Cell Tumors (Ovarian, Testicular, Mediastinal) Teratoma (ovarian) Esophageal Carcinoma

Colon Cancer

Bladder Cancer

Carcinoid

Breast Cancer

Neuroblastoma

Renal Cell Carcinoma

Pancreatic

Ovarian Cancer

Prostate Cancer


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Anterior Mediastinal MassAnterior Mediastinal Mass

Thymoma

Lymphoma

Germ Cell Tumor

Metastatic Disease

Aberrant Thyroid Tissue/ Goiter

Parathyroid Tumor

Lipoma

Sarcoma

Pericardial Cyst

Summary


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MRI Data

Anterior Mediastinal

Mass

Thymoma

Lymphoma Germ Cell Tumor Metastatic Disease Lipoma Sarcoma

Clinical Amnestic Syndrome

Wernicke-Korsakoff

Traumatic brain injury Hypoxia / Ischemia PCA stroke / ACA aneurysm

rupture

Limbic

Encephalitis

HSV

Other infections

PLE

Summary

CSF Results


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DiagnosisDiagnosis

Neurological condition reflects a paraneoplastic limbicencephalitis

Most likely due to a tumor in the anterior mediastinum Thymoma would be high in the differential dx

Lymphoma (or germ cell tumor) also possible

Further workup Biopsy of anterior mediastinal mass for tissue dx (the likely

procedure that was performed)

Send serum and CSF for identification of paraneoplastic-relatedantibodies

Dr. Daffners Diagnosis

P l ti LE M tParaneoplastic LE Management


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Paraneoplastic LEManagementParaneoplastic LEManagement

Find and treat the primary tumor

Immunotherapy

IVIG

Plasmapheresis

Corticosteroids


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PathologyPathology

Robert P. Hasserjian, M.D.


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Tumor

Pericardium


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A gross photograph shows that the tumor is well circumscribed and

thinly encapsulated, with a tanred fleshy cut surface


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The tumor consists of nests of epithelial cells with moderately abundant eosinophilic granular

cytoplasm ( hematoxylin and eosin). Some tumor cells are enlarged and cytologically atypical

( inset, circles).

Cytokeratin Chromogranin


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Neuron-specific enolase Synaptophysin


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Immunohistochemical analysis reveals scattered clusters of weakly cytokeratin-positive

thymic epithelial cells (, arrows) within residual thymic tissue surrounding the strongly

cytokeratin-positive tumor.

D


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Dense core

granules

Intermediate

filaments

Cell-cell

junctions

A transmission electron micrograph shows that the tumor cells contain

dense core neurosecretory granules ( circled).


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Diagnosis: Neuroendocrine carcinomaDiagnosis: Neuroendocrine carcinoma

Typical carcinoid (well differentiated)No necrosis and


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Adjacent normal thymic tissue


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Is the tumor located withinIs the tumor located within

thymus?thymus?

Cytokeratin Chromogranin


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Classification of thymic epithelialClassification of thymic epithelial

tumors (WHO 2004)tumors (WHO 2004) Co-occurrence of thymic

carcinoids together with

thymomas and thymic

carcinomas Distinctive features of

thymic carcinoids

Carcinoid syndrome

exceedingly rare Ectopic ACTH production

relatively common

Association with MEN-1

Common

thymic

epithelial

precursor cell

ThymomasThymic

neuroendocrine

tumors


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Paraneoplastic phenomena inParaneoplastic phenomena in

thymomasthymomas Relatively common (14-56% of cases)

Neuromuscular diseases

Myasthenia gravis (common)

Neuromyotonia, encephalitis, intestinal pseudo-

obstruction (rare)

Pure red cell aplasia and other cytopenias Hypogammaglobulinemia (Good syndrome)

Other autoimmune diseases


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Paraneoplastic phenomena inParaneoplastic phenomena in

thymic carcinoid tumorsthymic carcinoid tumors Ectopic ACTH syndrome (17-30% of adult tumors)

Cutaneous hyperpigmentation and Cushings syndrome

Ectopic production of other hormones GHRH, ADH, ANP, PTHrP

Autoimmune phenomena are very rare

Paraneoplastic autoimmune conditions (including

encephalitis) can occur in small cell lung carcinoma

One case report of limbic encephalitis with anti-Ri

antibodies in a patient with pulmonary carcinoid tumor

Harloff A et al. J Neurol 2005; 252:1404-1405


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Final pathologic diagnosisFinal pathologic diagnosis

Atypical carcinoid tumor (well-

differentiated neuroendocrine

carcinoma) of the thymus

No invasion of pericardium

All resection margins free of tumor


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Management and Follow-upManagement and Follow-up

Roy N. Alcalay, MD


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TreatmentTreatment

- Median sternotomy, radical excision of

thymic lesion, thymectomy and partial

pericardiectomy (Dr. Wright)- Course of IV solumedrol

- IV Ig 2g/kg


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Follow-upFollow-up

Re-admitted for up beating nystagmus

in primary gaze

Repeat MRI showed medial temporal

lobe atrophy

Neuropsychological Follow-upNeuropsychological Follow-up


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Neuropsychological Follow upp y g p

Domain Visit 1

Percentile

Visit 2

PercentileMemory

Immediate

Delayed

10


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Follow-upFollow-up

Treated with another course of

solumedrol and cyclophosphamide

with little response Restaging scans were negative

Patient died 5 months later


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Case 35-2008 - Amnestic Syndrome

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