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DEMYELINATING DISEASES, PART II ADEM, PML, ODS NEUROPATHOLOGY May 15, 2013

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DEMYELINATING DISEASES, PART II

ADEM, PML, ODS

N E U R O P A T H O L O G Y

May 15, 2013

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DEMYELINATING DISEASES, PART II1. Acute disseminated encephalomyelitis (ADEM)

a. Acute hemorrhagic leukoencephalopathy (AHL)

2. Progressive multifocal leukoencephalopathy (PML)a. JC virus (JCV)

3. Osmotic demyelination syndrome (ODS)

•Definition

•Clinical Features

•Radiology

•Pathology

•Treatment

N E U R O P A T H O L O G Y

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DISEASES OF CENTRAL MYELIN

N E U R O P A T H O L O G Y

Neuromyelitis optica

DEMYELINATING DISEASES, PART II

CADASIL

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CASE 1

•2 y/o boy with headache, confusion, behavioural change, and irritability

•antecedent history of viral upper respiratory tract infection 2 weeks prior

•otherwise healthy, no previous episodes

•bilateral weakness on exam, left worse than right

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART II

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ACUTE DISSEMINATED ENCEPHALOMYELITIS•a first, polyfocal, typically monophasic clinical CNS event with presumed inflammatory demyelinating cause, which usually follows within a short time of an inciting event (viral infection, vaccination)

•multiple punctate foci of demyelination that are typically centered on small veins and venules, along with associated perivascular mononuclear cell infiltrates

•disseminated throughout the brain and spinal cord

•AKA perivenous, postinfectious, or postvaccinial encephalomyelitis

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITIS•predilection for children (most cases) and young adults

•encephalopathy: behavioural changes (confusion, irritability), alteration in consciousness

•headache, vomiting, and fever; seizures may occur

•subsequent development of weakness, sensory loss, ataxia, visual impairment, incontinence, and stupor

•symptoms of spinal cord involvement may predominate

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITIS•usually occurs after a nonspecific upper respiratory illness

•up to 93% of patients report an infection in the preceding 21 days versus 5% with previous vaccination within the month

•latent period between the preceding infectious illness (or vaccination) and the development of neurologic symptoms is usually a few days, but may be up to 3-4 weeks

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITIS•specific inciting events/associations include: measles, mumps, varicella, influenza, rubella, or other viral infections (often with waning of the primary infection)

smallpox vaccinationimmunization against rabies, Japanese encephalitis (particularly with an inoculum inadvertently contaminated with CNS tissue in early immunization procedures)

bacterial infections with organisms such as Mycoplasma pneumoniae or Campylobacter jejuni

no identified predisposing cause

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITIS•symptoms and signs usually resolve over several weeks, allowing a good recovery in most patients; treatment hastens improvement

•some patients are left with permanent neurologic deficits; mortality varies according to different sources (<5% to 25%)

•very rarely, ADEM is associated with the development of concurrent Guillain–Barré syndrome

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITISMultiphasic ADEM (5-10% of cases)

•two episodes consistent with ADEM separated by three months but not followed by any further events

•second event can involve either new or a re-emergence of prior neurologic symptoms, signs, and MRI findings

•relapsing disease beyond a second event indicates a chronic disorder, most often leading to the diagnosis of MS or NMO

•a recurrent form of demyelinating perivenous encephalomyelitis has been reported in association with familial erythrophagocytic lymphohistiocytosis

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITIS•diffuse, poorly demarcated, large (>1–2 cm) lesions involving predominantly the cerebral white matter

•basal ganglia and posterior fossa lesions are common

CT

•non-enhanced CT is usually normal

•contrast-enhanced CT may

show multifocal punctate or partial ring-enhancing lesions

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITISMRI

•T1: often normal or may show grayish hypointense foci in white matter

•T2/FLAIR: multifocal hyperintensities, varying from small round/ovoid foci to flocculent “cotton ball” lesions (very hyperintense centres surround by less hyperintense areas with fuzzy margins)

•T1+C: enhancement varies from none to intense; punctate, linear, ring, partial ring patterns

•severe acute lesions may show diffusion restriction

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITIS

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

T2 FLAIR

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITIS

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

T1+C T1+C

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITISPathogenesis

•sensitization to some altered CNS antigen during immunization

•viral infection with cross reactivity (“molecular mimicry”) between a viral antigen and CNS white matter

•ADEM resembles the human equivalent of a form of experimental allergic encephalomyelitis (EAE), produced in rodent models by immunization with myelin or white matter constituents, causing some animals to manifest an encephalitic-like disease process associated with demyelination• demyelination appears to result from a cell-mediated delayed hypersensitivity reaction

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITISGross

•apart from some congestion and swelling, the brain and spinal cord may look macroscopically normal

•in some cases, scattered small foci of yellow or gray discoloration, some obviously centered on a small blood vessel, are evident in the white matter 

•gray matter may also be involved, although usually to a lesser degree

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITIS

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

Macroscopic appearance of brain in ADEM. (a) Congested blood vessels in the white matter are surrounded by ill-defined zones of gray discoloration. These are most prominent in the left cerebral hemisphere. (b) The deep parietal white matter and corpus callosum have a mottled appearance due to the gray perivascular discoloration.

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITISMicroscopic

•many small veins and venules within the brain parenchyma are surrounded by an infiltrate of lymphocytes, macrophages, and occasional plasma cells

•inflammatory infiltrate extends a variable distance into the surrounding tissue and is associated with a corresponding zone of demyelination

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITIS

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

Histology of ADEM. (a) Infiltrate of lymphocytes and macrophages around a vein (v) in the cerebral white matter. Note the paucity of inflammation in relation to the adjacent artery. (b) A zone of demyelination surrounds the affected blood vessels.

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITIS

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

(c)Because the demyelination is so closely related to veins and venules, it tends to form a more irregular pattern than is usually seen in multiple sclerosis

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITIS

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

(d) A combined solochrome cyanin stain for myelin and neurofilament immunostain for axons reveals a perivascular sleeve of (brown) axons that lack a (blue) myelin sheath (arrows). (e) Slightly larger zone of perivenular demyelination

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITISMicroscopic

•there may be small perivascular hemorrhages

•although loss of myelin predominates, there may be some axonal destruction

•arteries are relatively free of inflammation, but there are often inflammatory cells in the leptomeninges

•subpial inflammation and demyelination may occur in the brain stem and spinal cord

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITISStains

•histochemical studies of LFB-PAS (myelin), and Bielschowsky or neurofilament immunohistochemistry (axons) demonstrates the demyelinative nature of the process

•immunostains for CD68 and CD3 typically illustrate the perivascular macrophage and T-cell-dominant cellular prominence in ADEM

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITISDifferential diagnosis

•unlike typical MS, lesions are all of the same age

•vessel walls intact and lack severe destruction, fibrinous exudate, and surrounding RBCs and neutrophils that are seen in acute hemorrhagic leukoencephalitis

•microglial clusters and neuronophagia (indicative of ongoing viral infection and tissue damage) are not typically present

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE DISSEMINATED ENCEPHALOMYELITIS•intravenous corticosteroids

•IVIG

•plasma exchange

•symptoms and signs usually resolve over several weeks, allowing a good recovery in most patients

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE HEMORRHAGIC LEUKOENCEPHALOPATHYClinical

•fulminant, usually fatal disorder, regarded by some as a hyperacute form of ADEM

•abrupt onset of fever, neck stiffness, seizures, and focal signs

•half the patients have an antecedent upper respiratory tract illness or influenza 2 to 12 days before onset, similar to ADEM

•confluent non-enhancing lesions predominantly affecting cerebral white matter (FLAIR); punctate hemorrhages (T2*)

•treatment is similar to ADEM but mortality is high (60-80%)

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE HEMORRHAGIC LEUKOENCEPHALOPATHY

N E U R O P A T H O L O G Y

Macroscopic appearance of brain in AHL. Section through the cerebrum (a) and the cerebellum and pons (b) of a patient with Crohn's disease who developed AHL. Perivascular hemorrhages and foci of gray-brown discoloration are scattered throughout the white matter in the cerebrum, and the brain stem and cerebellum.  

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE HEMORRHAGIC LEUKOENCEPHALOPATHYPathology

•cerebral swelling and variable petechial hemorrhages +/- necrosis

•similar to ADEM with superimposed venous angiitis and perivenous destructive foci

•many small blood vessels undergo fibrinoid necrosis, surrounded by a narrow zone of necrotic tissue containing nuclear debris and, in some cases, a larger zone of hemorrhage • ring- and ball-shaped perivascular hemorrhages

•other blood vessels are still recognizable as veins or venules, but are surrounded by fibrin and a mixed inflammatory infiltrate, including neutrophils and mononuclear cells

•some fibers within the infiltrates are demyelinated, but others show axonal fragmentation

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE HEMORRHAGIC LEUKOENCEPHALOPATHY

N E U R O P A T H O L O G Y

Histology of AHL. (a) Scattered ball-shaped perivascular hemorrhages and areas of demyelination in the white matter. (b)Ring-shaped hemorrhage around a zone of fibrinoid necrosis.

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE HEMORRHAGIC LEUKOENCEPHALOPATHY

N E U R O P A T H O L O G Y

(c) Blood vessel showing fibrinoid necrosis and surrounded by a zone of demyelinated tissue with a predominantly mononuclear cell inflammatory infiltrate. (d) Acute fibrinoid vascular necrosis. The vessel wall is partly infiltrated by neutrophils.

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE HEMORRHAGIC LEUKOENCEPHALOPATHY

N E U R O P A T H O L O G Y

(e) Section through a region of perivenous demyelination. Note the vascular necrosis and inflammatory infiltrate. (f) An adjacent section shows relative axonal preservation.  

DEMYELINATING DISEASES, PART IIADEM PML ODS

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ACUTE HEMORRHAGIC LEUKOENCEPHALOPATHY

N E U R O P A T H O L O G Y

Demyelination and axonal fragmentation in AHL. (a) Loss of myelin staining with a zone of perivascular hemorrhage in AHL. (b) In this lesion, although a few axons appear to be preserved, most are fragmented.

DEMYELINATING DISEASES, PART IIADEM PML ODS

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CASE 2•47 y/o man with 3 month history of progressive cognitive impairment, lethargy, right sided weakness, aphasia

•HIV positive, poorly compliant with HAART

•CSF positive for JC virus

•Dies 4 months later

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART II

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

•PML is a disease of immunosuppressed patients in which infection of oligodendroglia by JC virus (polyomavirus) results in widespread demyelination and occasionally, cavitation of the white matter

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

•JCV infection in humans is generally asymptomatic (80% seropositive)

•latent JC virus is demonstrable in the kidneys and in B cells in the tonsils of most adults and in the brains of some

•PML results from reactivation of latent JC virus within the CNS or in peripheral tissues, usually as a result of impaired cell-mediated immunity

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

•develops in immunocompromised adults with predisposing disorders including:• lymphoproliferative diseases• chronic infections (e.g. AIDS, TB)• inflammatory diseases such as sarcoid and rheumatoid arthritis• iatrogenic immunosuppression• MS patients treated with natalizumab

•today, mainly a disease of the young and middle-aged populations affected by AIDS

•increased numbers have paralleled the rise of the AIDS epidemic• from 1984 to 1994 the percentage of deaths due to PML increased

from 0.2 to 3.3 deaths per million population

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

•present with focal neurologic deficits including dysarthria, limb weakness, visual disturbances, ataxia, personality changes, and occasionally seizures

•usually progresses relentlessly over a few months, resulting in increasing neurologic impairment, dementia, and eventually death

•treatment of the cause of the underlying immunosuppression (e.g. of AIDS, with highly active anti-retroviral therapy) can lead to remission

•paradoxically, reconstitution of the immune system occasionally causes an inflammatory response to the virus in the CNS, with exacerbation of disease

•JC virus may be detected in CSF by PCR (sensitivity 50-90%, specificity 98-100%; new “ultrasensitive” technique >95%)

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

•solitary or multifocal widespread lesions

•any area of the brain can be affected, although the supratentorial lobar white matter is the most commonly affected site

•extent varies from small scattered subcortical foci to large bilateral but asymmetric confluent white matter lesions

CT

•hypodense areas in the subcortical and periventricular white matter on non-enhanced CT

•generally do not enhance

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

MRI

•T1: multifocal, bilateral but asymmetric, irregularly shaped hypointensities 

•T2/FLAIR: heterogeneously hyperintense, frequently extending into the subcortical U-fibers all the way to the undersurface of the cortex

•T1+C: generally does not enhance, although faint peripheral rim-like enhancement occurs in 5% of cases• May enhance in patients with immune reconstitution syndrome

•DWI: restricts strongly in new, active lesions; rim of restriction in subacute lesions; no restriction in chronic lesions

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

FLAIR T1

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

T1+C DWI

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Pathogenesis

•JC virus can be detected in circulating B lymphocytes in a high proportion of patients with PML, suggesting that these cells may play a role in viral entry into the CNS

•impairment of cell-mediated immunity results in reactivation of latent JC virus within the CNS or in peripheral tissues

•demyelination in PML is the result of infection and subsequent degeneration of oligodendroglial cells

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Gross

•cut surface of the fixed brain appears asymmetrically pitted by small foci of gray discoloration mixed with larger confluent areas of abnormal parenchyma, which may be centrally necrotic

•lesions tend to be most numerous in the cerebral white matter, but also involve the cerebral cortex and deep gray matter

•cerebellum, brain stem, and much less commonly the spinal cord, may also be involved

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

PML. (a) Numerous small and larger confluent foci of gray discoloration in the cerebral cortex and white matter. Some of the foci are partly cavitated. (b) In this case there is granularity and focal cavitation of the white matter.

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

(c) Extensive loss of myelin staining in the basal ganglia and hypothalamus. (d) Foci of demyelination in the white matter of the cerebellum.  

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

B. Coalescent, granular, tan demyelinative lesions in the cerebral white matter begin near the cortical gray-white matter junction; note small tan lesions in the upper right (formalin-fixed brain).

C. Whole-mount section of numerous demyelinative lesions shows ovoid foci of myelin loss that coalesce into large confluent lesions over time. Inset illustrates typical violaceous intranuclear viral inclusion within an oligodendrocyte; note that viral particles fill the nucleus (Luxol fast blue/H&E).

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Microscopic

•multiple foci of demyelination - some are small and rounded, others confluent, irregular, and occasionally with central necrosis

•lesions contain moderate numbers of foamy macrophages, but only scanty perivascular lymphocytes

•presence of very large astrocytes with bizarre, pleomorphic, hyperchromatic nuclei (particularly in older lesions)

•large oligodendroglial nuclei with homogeneous amphophilic (“plum-colored”) inclusions

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

Histology of PML. (a) Section stained for myelin with solochrome cyanin. (b) Adjacent section stained for axons. Axons traverse the foci of demyelination. The scattered cells with very large nuclei, seen best in (a), are atypical astrocytes.

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

(c) Foamy macrophages, bizarre astrocytes, and very sparse lymphocytes in a region of demyelination. (d) Oligodendrocytes at the edge of a focus of demyelination have enlarged nuclei containing amphophilic viral inclusions (arrows). Note the large atypical astrocyte (arrowhead).

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Stains/ancillary tests

•EM: Filamentous and spherical viral particles (“stick and ball” or “spaghetti and meatballs”) in oligodendroglial nuclei

•IHC: JC virus can be demonstrated immunohistochemically (e.g. with SV40 antibody, which also labels JC virus)

•ISH: viral nucleic acids can be detected and specifically identified by in situ hybridization

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

Viral particles are seen within an oligodendrocyte nucleus and are both filamentous and spherical in appearance.

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

(f) Many of the enlarged nuclei within oligodendrocytes near the edge of a focus of demyelination appear immunopositive when labeled with antibody to SV40. Note too the very scanty lymphocytic cuffing of small blood vessels.

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Differential diagnosis

•bizarre astrocytes resemble those that can be seen in astrocytic neoplasms but mitoses are rare and there is low cellularity

•presence of macrophages in the background should alert the pathologist to suspect a reactive/inflammatory process

•combination of oligodendroglial and astrocytic changes of PML are essentially pathognomonic

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Differential diagnosis

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

PML diagnostic criteriaConsensus statement from the AAN Neuroinfectious

Disease Section. Neurology 2013;80:1430-8

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

•some patients improve with treatment of underlying immunosuppression, particularly AIDS patients

•majority of patients, particularly non-AIDS patients, progress rapidly to death, typically within 6 to 12 months

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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JC VIRUS

•named after John Cunningham, who died of PML and donated his brain to research

•polyomavirus (formerly papovavirus), similar to BK and SV40

•traditionally thought to exclusively inhabit glia

•can also infect cortical pyramidal neurons and cerebellar granule cell neurons

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

JC VIRUS DISORDERS

Tan CS, Koralnik IJ. Lancet Neurol 2010;9:425-37

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REAL CASE

N E U R O P A T H O L O G Y

74M several week history of: - Falls, gait unsteadiness- Progressive leg

weakness- Wide-based gait, LUE

dysmetria and dysdiadochokinesis- Cutaneous sarcoidosis, psoriasis, SCC of lung

May

2009

Sep 2009

Aug 2009

Jul 2009

Jun 2009

Nov

2009

Oct 2009

Normal MRI

Wheelchair-bound

Paraneoplastic panel -

ve

SCA panel -ve

- LP normal, -ve for JC virus

- Declined biopsy

- Died

DEMYELINATING DISEASES, PART IIADEM PML ODS

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N E U R O P A T H O L O G Y

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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Clockwise: 1) High power of an area of myelin pallor; 2) These regions of myelin pallor contained numerous myelin laden macrophages but no other inflammatory cells were present and the axons were relatively preserved3) enlarged, round, oligodendroglial cells with intra-nuclear viral inclusions4) Scattered astrocytes with bizarre nuclear pleomorphism, with foamy macrophages and preserved axons in background

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JC VIRUS GRANULE CELL NEURONOPATHY

Areas of granule neuron depletion and intense gliosis scattered throughout the cerebellar cortex with relative sparing of the Purkinje cell and molecular layers, often flanked by relatively normal appearing cerebellum

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DEMYELINATING DISEASES, PART IIADEM PML ODS

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JC VIRUS GRANULE CELL NEURONOPATHY

Dual labelling with JCV ISH and GFAP immunohistochemistry showing JCV within cerebellar granule neurons lacking GFAP expression

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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CASE 3•60 y/o woman admitted to hospital with Na+ of 118 mmol/L

•off-service neuropathology resident starts her on 3% saline continuous infusion

•12 hours later, patient is found to have quadriparesis, dysphagia, and dysarthria

•repeat Na+ is 142 mmol/L

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART II

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OSMOTIC DEMYELINATION SYNDROME

•monophasic syndrome producing demyelination, typically involving the basis pontis but in other sites as well, typically resulting from rapid correction of hyponatremia

•central pontine myelinolysis (CPM)

•extrapontine myelinolysis (EPM)

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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OSMOTIC DEMYELINATION SYNDROME

•most predisposing conditions are associated with hyponatremia (e.g. alcoholic liver damage, extensive skin burns, SIADH, psychogenic polydipsia, hyperemesis gravidarum)

•risk of developing ODS is related to the severity, duration, and speed of correction of the hyponatremia

•occasionally complicates chronic malnourishment or debilitation

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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OSMOTIC DEMYELINATION SYNDROME

•usually manifests with rapid onset of confusion, limb weakness (often progressing to quadriparesis), conjugate gaze palsies, dysarthria (or mutism), dysphagia, and hypotension

•movement disorders (dystonia and choreoathetosis) occur in some patients and have been attributed to extrapontine myelinolysis

•in severe cases ODS is fatal within a few weeks, but there are increasing numbers of well-documented cases of partial or complete neurologic recovery over a period of weeks or months

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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OSMOTIC DEMYELINATION SYNDROME

•imaging findings in ODS typically lag one or two weeks behind clinical symptoms

CT

•non-enhanced CT scans can be normal or show hypodensity in the affected areas, particularly the central pons

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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OSMOTIC DEMYELINATION SYNDROME

MRI

•Standard MR sequences may be normal in the first several days

•T1: hypointense

•T2/FLAIR: hyperintense

•T1+C: late acute or subacute ODS lesions may demonstrate moderate confluent enhancement

•DWI: most sensitive sequence for acute ODS and can demonstrate restricted diffusion when other sequences are normal 

•lesions are typically well-demarcated and symmetric

•pontine ODS is round, triangular, or "bat wing"-shaped

•involvement of the basal ganglia and hemispheric WM is seen in at least half of all cases

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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OSMOTIC DEMYELINATION SYNDROME

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

T1 T2

DEMYELINATING DISEASES, PART IIADEM PML ODS

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OSMOTIC DEMYELINATION SYNDROME

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

T1+C DWI

DEMYELINATING DISEASES, PART IIADEM PML ODS

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OSMOTIC DEMYELINATION SYNDROME

Pathogenesis

•in chronic hyponatremia, the brain preserves cell volume by decreasing intracellular osmolarity -- electrolytes, organic osmolytes including amino acids (alanine, glutamine, glutamate, taurine, and glycine) and sugars such as myoinositol

•during rapid correction of hyponatremia, intracellular electrolyte corrections are rapid but the brain is unable to correct the lost organic osmolytes expeditiously, resulting in cell injury and demyelination• brain shrinkage leading to shearing of oligodendrocyte processes

initiating myelin break down• osmotic shrinkage of endothelial cells opens the blood-brain barrier,

allowing the entry of complement and other cytotoxic plasma components

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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OSMOTIC DEMYELINATION SYNDROME

Gross

•basis pontis includes a fusiform region of gray discoloration, which is abnormally soft and appears granular on sectioning

•extent of the lesion is variable

•cross-sectional area is usually greatest in the upper part of the pons, where only a narrow rim of subpial tissue may be spared

•may involve the middle cerebral peduncles, but rarely extends rostro-caudally beyond the confines of the pons and lower midbrain

•lesion may be asymmetric, being largely or completely confined to one side of the pons

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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OSMOTIC DEMYELINATION SYNDROME

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

ODS. Transverse sections through the brain stem in CPM showing gray discoloration and slight granularity of much of the basis pontis

Sections of the pons in CPM. (a) There is extensive loss of myelin. Note the sparing of myelin in a narrow rim of subpial tissue and in small ‘islands’ within the base of the pons. (b) In an adjacent section, axons are seen to be well preserved.

DEMYELINATING DISEASES, PART IIADEM PML ODS

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OSMOTIC DEMYELINATION SYNDROME

Gross

•reported frequency of extrapontine lesions varies, but careful examination will reveal lesions in other parts of the CNS such as the cerebellum, lateral geniculate body, external or extreme capsule, subcortical cerebral white matter, basal ganglia, thalamus, or internal capsule in 25–50% of cases

• up to 25% of patients the lesions may be exclusively extrapontine

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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OSMOTIC DEMYELINATION SYNDROME

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

ODS: extrapontine demyelination. This section shows extrapontine demyelination in the white matter in the cerebellum. (Luxol fast blue/cresyl violet) 

DEMYELINATING DISEASES, PART IIADEM PML ODS

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OSMOTIC DEMYELINATION SYNDROME

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

Subcortical demyelination in ODS. (a) Gray discoloration of the demyelinated subcortical white matter (arrows) in a case of extrapontine myelinolysis associated with ODS. (b) Solochrome cyanin staining confirms the presence of subcortical demyelination involving white matter in the crests of gyri (arrows).  

DEMYELINATING DISEASES, PART IIADEM PML ODS

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OSMOTIC DEMYELINATION SYNDROME

Microscopic

•active demyelination

•lesions contain reactive astrocytes and large numbers of foamy lipid-laden macrophages, but only very scanty lymphocytes

•silver impregnation may reveal some axonal fragmentation, but most neuronal somata and axons are intact

•within the lesions, cranial nerves or central ‘islands’ of transverse pontine fibers or corticospinal tracts may be preserved

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

DEMYELINATING DISEASES, PART IIADEM PML ODS

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Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

Preservation of neuronal somata and axons in ODS. (a) Section of pons stained to show myelin. (b) Section of pons adjacent to (a) stained for axons. There is good preservation of neuronal somata and axons within the zone of demyelination.

DEMYELINATING DISEASES, PART IIADEM PML ODS

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OSMOTIC DEMYELINATION SYNDROME

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

Foamy macrophages in ODS. Higher magnification of the zone of demyelination in ODS reveals large numbers of foamy macrophages

DEMYELINATING DISEASES, PART IIADEM PML ODS

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OSMOTIC DEMYELINATION SYNDROME

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

Stains

•as with other myelinopathies, LFB-PAS, neurofilament (or Bielschowsky), and CD68 stains are most useful

DEMYELINATING DISEASES, PART IIADEM PML ODS

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OSMOTIC DEMYELINATION SYNDROME

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

Differential diagnosis

•the distribution of lesions, their identical age (if multiple), the paucity of lymphocytic inflammation, and clinical circumstances should allow this disorder to be distinguished from multiple sclerosis

•poor myelin staining of the deeper part of the pons due to inadequate fixation may on cursory examination lead to a misdiagnosis of ODS

DEMYELINATING DISEASES, PART IIADEM PML ODS

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OSMOTIC DEMYELINATION SYNDROME

Definition Clinical Features Radiology Pathology Treatment

N E U R O P A T H O L O G Y

•treatment with steroids, intravenous immunoglobulin, and thyrotropin-releasing hormone have been proposed, as well as the use of organic osmolytes during the correction phase and relowering serum sodium

•supportive

•prevention: chronic hyponatremia should be corrected at less than 12 mmol/L per 24 hours 

DEMYELINATING DISEASES, PART IIADEM PML ODS