the neuro-infectious diseases - ulbmedecine.ulb.ac.be/ftpupload/dec13_syndic_neuro_ucl.pdf ·...

The Neuro -Infectious Diseases

C.J.M. SINDICLaboratory of Neurochemistry53-59 Avenue Mounier1200 Bruxelles

Haematogenous

- Coxsackie, echo, polio,mumps

- in monocytes : HIV

- in lymphocytes : JC virus

- in red blood cells : plasmodium

-Nesseiria meningitidis, Streptococcus pneumoniae, Listeria,Mycobacterium tub.,Nocardia

- Cryptococcus, Candida,Aspergillus

- Larvae

- Olfactory nerve(Herpes simplex)

- by proximity : nose,ears, sinusesBacteria, fungi,mucormycosis

- Trigeminal nerveherpes simplex,herpes zoster

-peripheral nervesrabiesBorreliaherpes zosterherpes simplex

Infectious muscle diseases

1) viral polymyositis with myalgiagroup B coxsackie, influenza, Epstein-Barr

2) Borrelia burgdorferi myositis

3) parasitic myositis� cysticercosis : calcifications in association with

neurocysticercosis� trichinosis : encysted larvae of Trichinella spiralis

weakness mainly in the cranial muscles(tongue, masseters, extra-ocular andpharyngeal muscles)

� eosinophilia, serum antibodies, muscle biopsy if requ ired

Peripheral nerves

� infectious mononeuropathy or multiple neuropathiesleprosy, HIV, hepatitis C virus, Borrelia burgdorferi� EMG, biopsy, CSF

� plexopathypara-infectious or post-vaccinal (Parsonage Turner syndrome)(Epstein-Barr Virus)� EMG, seldom CSF analysis, MRI

� polyneuropathiesacute idiopathic polyradiculoneuritis or Guillain-Barre syndromepost-infectious in 2 cases out 3 (mainly, CMV and Campylobacter jejuni)� EMG, CSF

Leprosy-related neuropathies

� “Mycobacterium leprae” is an obligatory intracellular organism

� no culture possible

� the nasal mucosa is the preferential site of entry an d exit of

the bacillus

� the oral mucosa is the secondary site of transmission

and infection

� worldwide, the detection of new cases is decreasing

from about 515,000 in 2003

to 245,000 in 2007


Leprosy can be classified into three major clinical su btypes based

on the extent of host immune response :

� lepromatous (multibacillar) : predominant humoral resp onse

� tuberculoïd (paucibacillar) : predominant cell-mediat ed

immune response

� borderline (in- between)


� about 4 – 10 % of patients with leprosy could have a pure

neural involvement

� nerve involvement may affect sensory, motor and auton omic

fibers

� granulomatous inflammation may cause palpable enlarge ment

� the posterior tibial nerve is the most commonly affect ed,

causing anesthesia on the soles of the feet, follow ed by the

ulnar, median, lateral popliteal and facial nerves (1 7 %)

� nerve biopsy is often required for the diagnosis

Case report : Leprosy in Belgium !

1993 - skin, brown lesion, right arm : « sarcoidosis » after biopsy

- glucocorticoids, good outcome

1998 - skin lesion in the left leg; fatigue, fever, weigh t loss (10 kgs)- glucocorticoids, good outcome

2001 - fatigue, fever, high CRP levels, recurrent skin le sions- glucocorticoids, good outcome

June 2001- nose involvement, epistaxis, oedema, ulcers, pares thesiae

in the legs, skin nodules, « dermitis »- muscle reflexes OK but pure sensory axonal

polyneuropathy- thermoanalgesia below the knees

� Nerve biopsy : typical globiZiehl/Auramine +PCR +

Trip in Tunisia, Greece, Thaïland ...

Hepatitis C virus-related neuropathies

� the most frequent extrahepatic manifestation of HCV infection

is cryoglobulinemia, present in up to 50 % of patien ts

� in patients with HCV-associated cryoglobulins, perip heral

neuropathy occurs in 26 to 86 % in function of the di agnostic

criteria used

� HCV-related neuropathies may occur in absence of

cryoglobulinemia

� physiopathology is quite heterogeneous: ischaemic in jury,

immune complexes, HCV-induced autoimmune mechanisms

HIV-related neuropathies

� peripheral neuropathy has become the major neurological

complication of HIV infection in the developed world

� distal sensory neuropathies are the most frequent and have two

different causes resulting in similar signs and symp toms:

-a primary HIV-induced neuropathy

-an anti-retroviral toxic neuropathy, especially seconda ry to the

use of reverse transcriptase inhibitors (didanosine, za lcitabine,

stavudine)

HIV-related neuropathies

� in both cases, the main symptom is a neuropathic pai n defined

as burning or aching sensations in the feet, paresthes ia, allodynia,

beginning in the toes and the soles of the feet

� neurological signs consist of absent or reduced ankle deep

tendon reflexes, and loss of pinprick, temperature or vibratory

sensations in the lower limbs

� in a prospective cohort of 2141 patients, the rate of

asymptomatic neuropathy was 32.1 % at 3 years, and of

symptomatic neuropathy, 8.6% (Evans et al, AIDS, 201 1,25:919-928)

Meningo -radiculitis

� usually, meningeal signs and symptoms are slight an dmay be overlooked

� heavy pain with nocturnal increase in a radicular distribution

� cranial nerves may be preferentially involved,especially the facial nerve,

herpes zoster, sometimes “sine herpete”herpes simplex type 2 (caudal neuritis; sciatalgia)HIVBorrelia burgdorferi

� CSF analysis is mandatory

Varicella zoster virus

� it causes chickenpox (varicella), becomes latent in the cranial

nerve and dorsal root ganglia, and may reactivate anywh ere on

the body several decades later

� the lifetime risk of herpes zoster (shingles) is estim ated

to be 10-20 %

� shingles is characterized by unilateral radicular pain and

a vesicular rash limited to one to three contiguous d ermatomes

Figure 1 Characteristic varicella-zoster virus and herpes simplex virus–1 rashVaricella-zoster virus reactivation is manifest by dermatomal skin l esions (left), while herpes simplex virus

reactivation is manifest by mucosal or patchy skin lesions (right).

Nagel M A , and Gilden D Neurol Clin Pract 2013;3:1 09-117

© 2013 American Academy of Neurology

Figure 2 With a decline in varicella-zoster virus–s pecific cell-mediated immunity, virus reactivates from ganglionic neurons and spreads per ipherally or centrally to cause

diseasePeripheral spread to the skin causes herpes zoster.



Neurological complications of shingles

� postherpetic neuralgia : a neuropathic pain syndrome th at

persists more than three months after the dermatomal r ash has

healed

� PNS complications :

• cranial neuropathies (ophthalmic zoster, Ramsay Hun t syndrome)

• motor neuropathies

• bladder and bowel dysfunction

� CNS complications :

• meningitis

• myelitis

• vasculitic encephalitis

THESE COMPLICATIONS MAY OCCUR IN ZOSTER SINE HERPETE

Herpes zoster oticus or Ramsay-Hunt syndrome

Features may include ipsilateral facial palsy, tinnit us, hearing loss,

hyperacusis, vertigo, dysgueusia, decreased tearing an d ear pain

Vesicles may appear before (60%), simultaneously (25 %) or after

(15 %) the facial nerve palsy

The CSF in Herpes zoster oticus

In a series of 9 consecutive cases of Ramsay Hunt

syndrome observed in our Department, the CSF showed

• a pleocytosis in 8 cases

• a positive PCR for VZV DNA in 6 cases

Grégoire et al, JNNP, 2006,77:938-942

Figure 3 Varicella-zoster virus vasculopathy and my elopathy on MRI(A) Varicella-zoster virus (VZV) vasculopathy is characterized by deep-seated lesions, typically at gray–white matter

junctions (arrows).



Zoster sine herpete

� in the absence of rash, disc herniation or other compres sive

causes, a painful sciatica, cruralgia or any other radi cular pain

requires an analysis of the CSF including VZV PCR an d detection

of intrathecal synthesis of anti-VZV antibodies

� in case of suspected CNS vasculitis, CSF analysis s hould also

include VZV PCR and anti-VZV antibodies

Neurosyphilis and Neuroborreliosis

Neurosyphilis and neuroborreliosis:

• Both are spirochetal infectious diseases

• Both induce an aseptic meningitis after the primary infection, which heals

spontaneously in most cases; a meningoradiculitis s yndrome with nocturnal

heavy pain predominates in neuroborreliosis

• Both may cause a meningovascular disease with acute stroke

• Both may be responsible for a chronic CNS infection with focal signs,

dementia, seizure…

• The CSF is always abnormal, with a predominant intr athecal IgM antibody

response, pleocytosis, and specific oligoclonal IgG bands

Neurosyphilis

Clinical presentations:

• Neuropsychiatric disorders: psychosis, delirium, de mentia (50%)

• Acute stroke with focal neurological deficit (15%)

• Ocular: uveitis, visual loss, optic nerve dysfuncti on (12%)

• Myelopathy (9%)

• Seizure (9%)

• Brain stem/cranial nerves (5%)

Neurosyphilis

Diagnosis:

• Positive CSF VDRL (Venereal Disease Research Labora tory) test

OR

• Positive anti-FTA antibody index and

•Abnormal CSF count

•Intrathecal IgM synthesis

•CSF specific oligoclonal IgG bands

Neuroborreliosis

Lyme neuroborreliosis:

• Sindic CJM et al, JNNP, 1987,50:1565-1571 (18 MR ca ses)

• Depré A et al, Rev Neurol,1988,144:416-420 (2 ME cas es)

• Montaigne P. et al, Rev Neurol,1994,150:75-77 (névr ite du grand dentelé)

• Van Snick S. et al, Acta neurol Belg, 2008,108:103- 106 (pontine stroke)

• Charles V. et al, JNNP, 2007 (polio-like)

• Sindic C. Infectious neuropathies Curr. Opin Neuro l, 2013,26:510-515

Neuroborreliosis

In Lyme neuroborreliosis with CNS involvement,

• a mononuclear pleocytosis is constant

• an impairment of the blood-CSF barrier is the rule

• an intrathecal immune response occurs after few day s (> 10 days),

characterized by :

�a predominant IgM response (in percentage of the in trathecal fraction)

�the presence of oligoclonal IgG bands with anti-Bo rrelia activity

�an associated, minor, polyspecific immune response

� the 41 kDa flagellar antigen is the most important epitope.

� this immune response may persist for years (up to 2 0) as an immune

scar, even in seronegative patients

Borrelia induced facial palsy (Lyme disease)

• Summer months (May - October)

• more frequently in children, with general signs (fe ver, pain)

• frequently bilateral

• CSF almost always abnormal in our hands (pleocytosis, local IgM synthesis, oligoclonal IgG bands)

Borrelia burgdorferi myelitis

Gadolinium +

Meningitis

� severe headache, stiff neck, nausea and vomiting,photophobia, phonophobia, feverdrowsiness and confusion make difficult to distingui sha pure meningitis from meningoencephalitis

� viral infections : enteroviruses (echo, coxsackie, pol io), mumps,herpes simplex type 2, Epstein-Barr, herpes zoster, aden ovirus,HIV, lymphocytic choriomeningitis

� bacterial infections : streptococcus pneumoniae, Nes seriameningitidis, Haemophilus influenzae, Listeria mono cytogenes,other Gram -bacilli, Streptococcus suis (Hantson et al, ANB, 1 991)…Mycobacterium tuberculosis

� spirochetal infections : syphilitic meningitis, neuro borreliosis,leptospirosis

� fungal infections : Cryptococcus, Candida, Aspergil lus, Mucor

Meningococcal meningitis with cortical involvement

PCR of infectious DNA in CSF is a very

important tool for diagnosis of many,

but not all, CNS infections

Sensitivity and specificity of PCRfor selected CNS infections

Pathogen Sensi tivity (%) Pathogen Sensi tivity (%) Specificity (%)Specificity (%)

HSV type 1HSV type 1 > 95> 95 100100CMVCMV 80 80 -- 100100 75 75 -- 100100VZVVZV unknownunknown 100100EBVEBV 9797 100100JC virusJC virus 74 74 -- 9292 92 92 -- 9696EnterovirusEnterovirus 9797 100100

Borrelia burgdorferiBorrelia burgdorferi 40 40 -- 5050 95 95 -- 100100(Ab : > 95%)(Ab : > 95%)

Mycobacterium tuberculosisMycobacterium tuberculosis 60 60 -- 9090 94 94 -- 100100

THE QUANTIFICATION OF AN INTRATHECAL SYNTHESISOF ANTIBODIES IS BASED ON :

� the calculation of a CSF/serum antibody quotient (Qab) after ELISA determination on a continuousscale (arbitrary units)

� the use of an antibody index : Q ab/QIgG

� the use of a correction factor , Q Limit ,if Q IgG > QLimit (Reiber and Lange, Clin. Chem., 1991, 37 : 1153-1160)

Méningite à Herp ès simplex type 2

� tout patient qui présente des signes et des symptôm esméningés dans le décours d’un herpès génital estsuspect de m éningite à herpes simplex type 2

� à l’inverse, tout patient présentant une m éningite viraledoit être examiné pour la présence d’un herpès génit al

� cependant, une m éningite à herpes simplex type 2 peutsurvenir en l ’absence d’une anamnèse d’herpèsgénital, et sans lésion herpétique concomitante

Méningites lymphocytaires récidivantes

� Herpes simplex type 2 est la cause la plus fréquent edu syndrome de m éningite lymphocytaire bénignerécidivante, appelée aussi m éningite de Mollaret

� la PCR pour l’ADN de herpes simplex type 2 estpositive dans le LCR, dans 75 à 85 % des cas

� une synthèse intra-thécale d’anticorps anti-herpèssimplex est quasi constante.

Le diagnostic des m éningites tuberculeuses

1. Suspicion clinique

Signes m éningés, fièvre et altération du niveau de conscience(confusion, somnolence)

AVEC un CT scan ou une IRM anormaux

- prise de contrastes méningé dans les scissures de Sy lvius et les

citernes de la base

- une hydrocéphalie

ET/OU des radiographies du thorax suggestives de tubercul ose

ET/OU un LCR avec pléocytose lymphocytaire, hyperprotéino rachie,hypoglycorachie

Le diagnostic des m éningites tuberculeuses

2. Confirmation microbiologique

� culture positive du LCR

� examen direct positif (Ziehl)

� détection par PCR du génome de Mycobacteriumtuberculosis dans le LCR

� synthèse intrathécale d ’anticorps anti-mycobactéries

Monteyne and Sindic, Acta Neurol. belg. 1995, 95 : 80-87

Tuberculomas in cerebellum and brainstem

lanes 1,2,3 : same patient; samples before, 2 weeks and 3 months after treatment

lane 4 : another case of TB meningitis

lanes 5,6 : controls

Fungal infections of the CNS

1. Cryptococcus neoformans

meningitis, encephalitis

2. Candida albicans

meningitis, encephalitis

3. Aspergillus fumigatus

meningitis (biopsy !) (van de Wyngaert et al, J.Neu rol, 1986)

4. Mucormycosis

meningitis, vasculitis (biopsy !) Dusart et al, ANB, 2013)

lymphocytic or neutrophilic chronic meningitis !

CSF-specific oligoclonal bands are frequently observ ed!

Cryptococcal meningitis and brain involvement

Candida albicans encephalitis

Clinical history

• G.N. , 64 year-old, retired, civil engineer

• Medical past history :

– 1985 : somatotropic pituitary macroadenoma

treated by transsphenoidal surgery and

radiotherapy � anterior pituitary deficiency.

– Pulmonary tuberculosis (recurrence in 2001,

during a travel in Congo)

Dusart A. et al, ANB, 2013, 113:179-184

Timeline

Right hemifacial pain

Right nasal

obstruction

Right hemifacial pain

Right nasal

obstruction

Diplopia

Right VIth nerve

partial palsy

Diplopia

Right VIth nerve

partial palsy

11.2006 01.2007 05.200703.2007 06.2007 08.2007

Appearance of

archaïc reflexes

Appearance of

archaïc reflexes

Cognitive

decline

Cognitive

decline

Meningeal signsMeningeal signs

Fluctuating

consciousness

Fluctuating

consciousness

Bradypsychia

Incontinence

Bradypsychia

Incontinence

Sphenoïd

sinusitis

Sphenoïd

sinusitisCarotid

Pseudoaneurysm

Carotid

Pseudoaneurysm Carotid and

aneurysmal

thrombosis

Carotid and

aneurysmal

thrombosis

Radiologic

statu quo

Radiologic

statu quoHydrocephalus

Pachymeningitis

Thalamic ischemia

Pansinusopathy

Hydrocephalus

Pachymeningitis

Thalamic ischemia

Pansinusopathy

CSF : 16c/µl, (ly),

P : 76mg/dl,

G : 44mg/dl, BO (-)

CSF : 16c/µl, (ly),

P : 76mg/dl,

G : 44mg/dl, BO (-)

CSF : 62c/µl (ne),

P : 131mg/dl

BO (+)

CSF : 62c/µl (ne),

P : 131mg/dl

BO (+)

CSF: 22c/µl (ne),

P : 186mg/dl,

BO (++)

CSF: 22c/µl (ne),

P : 186mg/dl,

BO (++)

VIth nerve

complete palsy

VIth nerve

complete palsyRight trigeminal

hypoesthesia

Right trigeminal

hypoesthesia

Evolutive sphenoid sinusitis

T2-weighted images (coronal sections) : evolution of the sphenoid sinusopathy between December 2006 and

February 2007. Hyperintense mucous thickening evolving to a submucous oedema of sphenoid sinus. Ethmoid

and frontal sinuses seem initially normal but are only partially seen. Hemifacial pain can be explained by the

sphenoid sinusopathy as well as by a trigeminal nerve invasion/inflammation or compression in the cavernous

sinus.

T1-weighted images (coronal

sections) : occurrence of a

large and irregular

pseudoaneurysmal dilatation

of the right intracavernous

internal carotid.

Right internal carotid pseudoaneurysm

Brain CT angiography (transversal and coronal sections) : voluminous right internal carotid pseudoaneurysm

MRI angiography and FLAIR-weighted images : mucormycotic thrombosis of the right internal carotid

pseudoaneurysm. Preservation of middle cerebral artery flow via the posterior communicant cerebral

artery. No acute ischemic lesion was seen in diffusion-weighted images..

May 2007May 2007

Spontaneous occlusion of the carotid

pseudoaneurysm

T1 and T2-weighted images (coronal sections) : enhancing of the pituitary mass

involving cavernous sinus. Thrombosis of the large carotid aneurysm

May 2007May 2007

T1, post-gadolinium

T1 and FLAIR

weighted images

(transversal

sections) :

progression of

hyperintense lesions

of the skull base

with meningeal

enhancing

FLAIR post-gadolinium,

Diffusion and T1+gado-

weighted images : right

paramedian thalamic

ischemia and extensive

enhancing cavernous

mass. Ventricular

dilatation with trans-

ependymal resorption.

Autopsy

• Microscopic findings :

– Purulent invasion of pituitary area:

• Cellular debris

• Polymorphonuclear neutrophilic infiltrate

• Inflammatory infiltrate of vessel wall

– Presence of wide and irregular hyphae with some right-angle branchings

– Hyphae are found in vessel wall and in intravascular thrombi

– Meningeal inflammation

Histopathology

PAS : intravascular mucorthrombus and

necrotic debris in the vessel wall

Periodic acid schiff stain : right-

branching, irregular, thin-walled hyphae

Histopathology

H&E stain : hyphal invasion of the vessel

wall and polymorphonuclear infiltrate

Hematoxylin and eosin stain : aseptate

fungal hyphae

Histopathology

Grocott-GMS stain : fungal

hyphae

Myelitis

� poliomyelitis : injury of anterior horn cellspolio, some arboviruses

�myelitis with long tracts involvement

Viral : herpes simplex, herpes zoster, HIV, HTLV-I

Spirochetal : Borrelia, Treponema pallidum

Parasitic : schistosomiasisToxocara

Para-infectious : EBV, Mycoplasma pneumoniae

� spinal MRI, CSF

Duprez et al, Neuroradiology, 1996, 38 : 792-795

Goffette et al, Eur. J. Neurology, 2000, 7 : 703-70 6

Schistosomiasis

GADO +

FLAIR

CEREBRAL SCHISTOSOMIASIS

Rommel et al, Acta Neurol. Belg.

2005, 105, 89-93

GADO +

CEREBRAL SCHISTOSOMIASIS

POST-TREATMENT

HTLV-I spastic paraparesis (Ossemann et al, ANB, 19 96,96:117-125)

HTLV-I infection

A-B : September 89 C-D : September 93

Acute Viral Encephalitis

a febrile illness expressed by meningitis, to which areadded in various combinations :

confusion, stupor, comaseizuresmutism, aphasia, hemiparesis, ataxiacranial nerve palsies

except for herpes simplex encephalitis, viral encep halitis are seasonal and occur in epidemic form (arboviruse s, such as Eastern, Western, and Venezuelan equine, St Louis, West Nile…)

� MRI, CSF, serology

Virus responsables d ’enc éphalites primaires

� Rage : • mortalité > 99 %� Herpes simplex : • mortalité > 70 % en absence de

virus traitement� Arbovirus : • mortalité de 1 à 50 % (dépend du virus et

de l ’âge de l ’hôte)� Oreillons : • encéphalites peu sévères� EBV, CMV, : • encéphalites rares et peu sévères,

HHV-6 lors de la primo-infection� Adénovirus : • encéphalites très rares; sévères chez

l ’enfant et l ’immunodéprim é� Coxsackie : • encéphalites rares, parfois fatales che z le

nouveau-né

Subacute or chronic encephalitis

� Viral : HIVencephalitis related to immunodeficiency states : CM V,

Herpes zoster, papovavirus (PML)

�Tuberculoma, brain abscesses

� Parasitic : neurocysticercosistrypanosomiasiscerebral malariatoxoplasmosisechinococcosis

� Fungal : cryptococcosis, candidiasis

� Spirochetal : tertiary Lyme disease, late neurosyphilis

NEURO-AIDS

� Primary infection: stade A

� Headache (50%) and aseptic meningitis (20-25%)

� Meningo-radiculitis (with facial palsy)

� Acute polyradiculoneuritis (Guillain-Barrésyndrome)

� Acute encephalitis with psychosis (rare)

NEURO-AIDS

� Latent infection: stade B

� Recurrent shingles

� Chronic aseptic meningitis

� Intrathecal synthesis of anti-HIV antibodies (Bukasa et al, ANB, 1988,51:1063-1068)

NEURO-AIDS

� Stade C

� C1: opportunistic CNS infections: toxoplasmosis, PML, cryptococcal meningitis, tuberculous meningitis, CMV encephalitis

� C2: CNS lymphoma

� C3: HIV-related chronic encephalitis, HIV-related neuropathies, vacuolar myelopathy

CMV encephalitis in a AIDS patient

Toxoplasma gondii abscess

Putative Toxoplasma abscesses in a HIV-positive pat ient

Progressive multifocal leukoencephalopathy (PML)

or

JC virus encephalitis

Guillaume et al, Eur. J. Neurol, 2000, 7 : 101-106

Progressive multifocal leukoencephalopathy

Progressive Multifocal Leukoencephalopathy (1)(PML)

�described in 1958 by Astrom, Mancall andRichardson in 2 CLL and 1 Hodgkin ’s diseasepatients

� papova virus-like particles in oligodendrocytesnuclei

� isolation of the virus in 1971 from the brain of a patient with Hodgkin’s disease (JC)

�The brain biopsy : the gold standard for diagnosis ofPML challenged by JCV DNA detection in the CSF(PCR)1°) JCV-infected oligodendrocytes with enlarged nucl ei

confirmed by immunochemistry for polyomavirus proteins or in situ by hibridization for JCV DNA

2°) reactive gliosis with enlarged astrocytes, some harboringa non-lytic JCV infection

3°) lipid-laden macrophages phagocyting myelin

Progressive Multifocal Leukoencephalopathy (3) (PML)

Associated diseases :N = 61 between 1996 to 2003 :

80 % with AIDS and highly active antiretroviraltherapy (HAART)

13 % with haematological malignancies

5 % with transplantation

2 % with chronic inflammatory diseases

Koralnick et al, NEJM, 2004,350:1882-1893

Before HAART : AIDS was the underlying disease in 87 % of PML cases


Associated diseases in HIV-negative patients:N = 58 between 1957 and 2005 (Mayo Clinics) :

55 % with haematological malignancies15 % with chronic inflammatory diseases9 % with sarcoidosis

7 % with transplantation

7 % with other conditions (cirrhosis, pulmonaryfibrosis)

7 % without predisposing illness except for agebetween 66-80 y.

Aksamit, The Neurologist, 2006


Classical signs and symptoms :subacute neurological deficits� hemiparesis or monoparesis� altered mental status� appendicular or gait ataxia� hemianopsia� diplopia� other symptoms mimicking a cortical disorder

aphasiacortical blindness

seizures (18%)

sparing of the optic nerves and the spinal cord


Classical disease course :

� progressive and death within a few months� few patients experience disease stabilization and

prolonged survival� before HAART, only 10 % of HIV-positive patients wit h

PML lived for more than a year� with HAART, 1-year survival has increased to 50 %

but in case of survival, there is no remyelination neurological sequelae are severe


Classical MRI lesions :� hypodense areas on CT scans� hypointense on T1-weighted images� hyperintense on T2 and FLAIR images� well demarcated, not contrast-enhancing, not

surrounded by oedema, without substantial masseffect

Lesions are usually bilateral, asymmetric, localized i n the subcortical hemispheric white matter

The posterior fossa and the deep gray structures (basa l ganglia and thalamus) are affected in up to 55% of cases

PML can also rarely present initially as a single les ion


Diagnosis

�brain biopsy : sensitivity of 64 to 96 %specificity of 100 %

�CSF PCR : sensitivity close to 100 %specificity of 100 %


About the JC virus

� a small DNA virus (5100 bp), in a capsid constituted by 3 proteins (VP1, VP2, VP3)

� asymptomatic seroconversion of JCV occurs usually inchildhood, but seroprevalence continues to increase untilthe seventh decade of life

� JCV can be found in the urine samples of approximatel y30 % of people, regardless of their immune status

� the primary infection could occur through urine-oralcontamination


About the JC virus

� after primary infection, the virus remains latent in th ekidneys and in lymphoid organs (tonsils, bone marrow)latency in the brain ? In normal digestive system ?

� profound cellular immunosuppression leads toreactivation with JC viremia :

- rare in healthy individuals

- in 20-40 % of HIV-positive patients

- in 60-80 % of PML patients

B cells are the main blood cells carrying JCV


Treatment� there is no specific treatment

� optimization of HAART in AIDS-related PML

� removal or decrease of any potential sources ofimmunosuppression, steroids included

� cytosine arabinoside :

- active on JCV replication in vitro

- positive in some case reports

- negative in a multicenter prospective study with a combinedIV and intrathecal administration

(Hall et al, NEJM, 1998, 338 : 1345-1351)


� 54 year-old left-handed female� Admitted 07.1998� 1983 polyarthritis

– Prednisolone 7.5 mg/d since 1983– Methotrexate 15mg/w 1990-1995– Cladribine 36mg/2w 06.95-05.97– Azathioprine 100 mg since 1997

Case report : history 1

Case report : current disease

� Admitted July 1998� Complains for two months about

– Problems to dress– Problems to use left hand– « visual problems », expecially for distances,

with unability to read,to drive� Neurological examination

Neuropsychological examination

Magnetic Resonance Imaging

Hypo T1, cortex spared, Gado (-), hyper T2, hyper F LAIR, no mass effect

Pathology

Macrophages

Astrocytes

Multifocal demyelination, withmacrophages and giant astrocytes (Trichrome de Masson)

Pathology

Enlarged Oligodendrocyte nucleuswith viral inclusion

Enlarged bizarre atrocytes

Magnetic Resonance Imaging

3 months : slight gado(+)1 year : gado(-), necrosis2 - 5 years : regression, dilatation

Natalizumab -related PML

• About 400 cases worldwide

• 20 % died

• Increased prevalence in long duration (>2 years) treat ment and in case of previous immunosuppressive treatments

• Virtually never observed in JC-seronegative patients

Estimates of PML Incidence Overall and By Duration*

2,80

0,55

0,981,18

1,91

2,68

3,21

0,20 0,230,41

0,70 0,70

0,11

1,00

0,37

0,65 0,75

1,19

1,46

0,89

0,44

0,0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

Clinic

al T

rial s

Post M

arketin

g>=1

2 Inf

u sions

>= 18

Infus

ions

>=24

Infu sio

ns>=3

0 Inf

u sions

>=36

Infu

sions

Estimated PML Incidence by Treatment Duration

Inci

denc

e pe

r 10

00pa

tient

s

*In Europe, we assume one infusion per month

Neuro -cysticercosis

�The most frequent parasitic disease of the CNS in the world

�Seizure as the main neurological symptom

�Subacute encephalitis, focal deficits, hydrocephalus…t

Neurocysticercosis

PINS : general characteristics

� arise within 4-6 weeks of a systemic infection/vacci nation

� 8 % are postvaccination syndromes and may present all the

syndromic phenotypes

� mean age : 60 years (18-80)

� excluding PNS involvement only, PINS are :

• central in 64% (E, EM, M) and

• mixed (EMRN, MRN) in 36 % (Marchioni et al, Neurology, 2013, 80 :

882-889)

Postinfectious neurologic syndromes (PINS) : syndromic phenotypes

� involving the peripheral nervous system only

• Guillain-Barré syndrome (2/3)

• brachial plexitis (Parsonage-Turner)

� involving the central nervous system only (“ADEM ” : acute

disseminated encephalomyelitis)

• encephalitis

• myelitis

• cerebellitis

• rhombencephalitis

Postinfectious neurologic syndromes (PINS) : syndromic phenotypes

� involving both peripheral and central nervous system s

• encephalomyeloradiculoneuritis

• myeloradiculoneuritis

PINS : clinical characteristics

In the series of 179 patients in Marchioni et al :

� maximum clinical dysfunction 6 days after onset (med ian)

� polysymptomatic in 94 % : paraparesis, urinary dysfunc tion,

consciousness impairment are the most frequent sympto ms

PINS : CSF abnormalities

� 12 % had normal CSF profile

� blood-CSF barrier damage (albumin quotient > 8) in 83 %

� pleocytosis, except in 6 cases with albumin-cytolog ical

dissociation

� CSF IgG pattern:

• polyclonal : 58.5 %

• mirror : 13.6 %

• mixed (mirror + specific bands) : 2 %

• specific bands : only 1 = 19 %

> 1 = 6 %

in 7 out 11 cases, IgG bands were transient

PINS : relapses

� in 24.6 % of patients with central PINS, in 41.6 % w ith mixed

syndromes

� the relapse consisted in isolated myelitis in 98 % ( 51 of 52

patients), even when the first episode had involved the brain

alone

� relapses occurred more frequently within the 12 months of onset,

never after 24 months

� relapses are located at the same spinal level in 71% of cases

at a different spinal level in 29 % of cases

� in all cases, lesions observed during the first episod e had

disappeared

� the only independent predictor of relapse was PNS in volvement

Myélite post-Mycoplasma pneumoniae

CONCLUSIONS

� An anatomic diagnosis is required to focus imagingtechniques on the relevant areas

� Imaging techniques are rarely specific enough foretiologic diagnosis especially at the spinal cord l evel

� Blood and CSF analysis are important tools foretiologic diagnosis but must be correlated with eac hother

� « Tropical diseases » may be encountered worldwide

the neuro-infectious diseases - ulbmedecine.ulb.ac.be/ftpupload/dec13_syndic_neuro_ucl.pdf ·...

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