The Neurology of Immunosuppression
Transcript of The Neurology of Immunosuppression
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The Neurology of Systemic Disease
Monday 13th November 2017
Royal College of Physicians of London
The Neurology of Immunosuppression
Dr Nicholas DaviesConsultant Neurologist
Chelsea & Westminster and Charing Cross Hospitals, London
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Introduction
• What is immunosuppression?
– Congenital; acquired; iatrogenic
– Caveats: adult physician; not an immunologist; will focus on CNS
• What neurological presentations?
– Infectious vs non-infectious
• Case examples
• Immune reconstitution
• Conclusions
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What is Immunosuppression?
• Impaired immune response due to congenital, acquired or iatrogenic causes.
– Impairment of cell-mediated immunity• Inability to fight intracellular organisms e.g. listeria; MTB
– Impairment of humoral immunity• Hypogammglobulinaemic patients: nb enterovirus
– Impairment of innate immunity• Splenectomised patients & encapsulated organisms e.g.
pneumococcus
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What is Immunosuppression?
• Acquired immunosuppression
– Systemic illness• Diabetes mellitus; chronic alcoholism; renal or hepatic failure;
autoimmune disorders (e.g. SLE or sarcoid)
– HIV/AIDS (other infections e.g. measles)
– Malignancy
– Haematological • Bone marrow failure; splenectomy; SSD; myeloma
– Age (old & young)
– Pregnancy
– Iatrogenic
• Congenital e.g. idiopathic CD4 lymphopenia
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Iatrogenic Immunosuppression
• Drugs
– Corticosteroids; steroid-sparing agents; biologics
– Risks greater when on multiple agents
• Ionising Radiation
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Immunosuppressive Drugs
Drug or Drug family Mechanism of Action Infection Risk
Corticosteroids Suppress innate & adaptive immune system
Bacterial; mycobacterial; fungal & viral
Methotrexate Dihydrofolate reductase inhibitor
Increased risk of UTIs &c little evidence of opportunistic infections
Cyclophosphamide &
other alkylating agents
T & B-cell suppressive effects Bacterial; mycobacterial; fungal & viral
TNF alpha inhibitors Inhibit granuloma formulation & maintenance
Granulomatous infection (TB; fungal; toxoplasmosis). Increased risk of extrapulmonary TB
Rituximab Depletion of CD20 cells PML
Natalizumab Alpha-4 integrin inhibitor PML (4.2/1000)
Fingolomod Sphingosine 1-receptor modulator; inhibits lymphocyte egress from LN
HSV/VZVPML; cryptococcus
Dimethyl fumarate Shifts TH1 to TH2; lymphopenia
PML
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Non-Infectious Neurological Presentations of Immunosuppression
• Malignancy– E.g. Primary CNS lymphoma; melanoma
• Graft versus host disease e.g chronic myositis
• Posterior reversible encephalopathy syndrome (usually drug-related – tacrolimus/cyclosporine)
• Post transplant lymphoproliferative disease
• Drug-induced autoimmunity (demyelination triggered by anti TNF alpha drugs; hypophysitis with checkpoint inhibitors).
• Other drug neurotoxicities e.g. toxic neuropathy, cerebellar toxicity, seizures, myelopathy
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From: Pruitt (2017) Neurologic
complications of transplantation 23:
802-821
Posterior reversible
encephalopathy
syndrome (PRES) can have
many MRI variations, as
shown in these fluid-attenuated
inversion recovery (FLAIR)
MRI sequences.
A, The typical pattern seen in
PRES is hyperintensity in the
occipital lobes.
B, More widespread PRES,
with involvement of more
anteriorcerebral areas.
C, Laminar necrosis after
resolution of the acute PRES
episode.
D, An extensive brainstem
abnormality producing
hydrocephalus caused by
PRES and fully reversible.
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What are the differences in infection presentation between an immunocompetent and immunosuppressed
person?
• Symptoms
– Often subacute and lacking prominent inflammatory response.
• Organisms
– Atypical microbes that otherwise might be considered commensals e.g. atypical mycobacteria
– Atypical presentations of commonly pathogenic infections e.g. brain stem presentations of HSV encephalitis in
HIV/AIDS.
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Diagnosis of Acute Neurological Infection
• The neurological formulation:• Anatomy
• Pathogenetic mechanism
• Aetiology
• The ID mantra:• Why did this person?
• From this place?
• At this time, get this disease? Davies & Thwaites. THE BARE ESSENTIALS
Infections of the nervous
System. Practical Neurology 2011;11:121–131
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Solid Organ Transplant
• Think about the organ donor
– West Nile Virus (USA)
– Rabies (USA)
– Halicephalobus (2013)
• Nematode – x2 UK transplant cases*
– CMV & EBV status of donor / organ
* NHSBT Report https://nhsbtdbe.blob.core.windows.net/umbraco-assets-
corp/4602/odonoghue_and_gunning_overview_report.pdf
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Principles of HIV Neurology
• Time Locking
– Relationship to CD4 cell count
• Parallel Tracking
– Involvement of multiple parts of the nervous system
• Layering
– Different pathologies superimposed
• Unmasking
– Second pathology dominated by subacute first pathologies symptoms e.g. HIVE & Cryptococcus
Brew (2001) HIV Neurology OUP
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Neurological Complications of HIV
Davies, N. & Thwaites, G. Infections of the nervous system. Pract Neurol 11, 121-131 (2011).
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Mass Lesion in HIV
From: Bowen et al (2016) HIV-associated opportunistic CNS infections: pathophysiology, diagnosis &
treatment. Nature Reviews Neurology doi: 10.1038/nrneurol.2016.149
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Management of HIV
patients with focal
neurology & CD4 cell
count <200 cells/uL.
Nelson et al (2011) BHIVA & BIA Guidelines for
treatment of opportunistic infection in HIV-
seropositive individuals. HIV Medicine 12 Supp 2.
• G6PDH deficiency & sulphadiazine
• SPECT scans
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Differentiating CNS Toxoplasmosis from PCNSL in HIV
CNS Toxoplasmosis PCNSL
Basal ganglia and corticomedullary junction
Sub ependymal spread
Multifocal Solitary
Nodular or ring enhancing Solid enhancement; may be ring
MRS – increased lactate MRS – increased choline
PCR – low sensitivity; most seropositive
PCR – often high cope load of EBV
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Viral Infections in Immunocompromised
Virus Syndrome Risk Factor Test
HSV-1 Limbic encephalitis Multiple; nbradiation
CSF PCR
VZV Shingles (sine herpete); vasculopathy; segmental motor weakness; cranial neuropathies; retinitis; meningitis; myelitis.
GvHD; calcineurininhibitors; corticosteroids
CSF PCR; CSF antibody studies
CMV Encephalitis; retinitis; myelitis T-cell depletion; solid organ transplants: donotorgan positive
Ependymal enhancement on MRI; CSF PCR
EBV Meningoencephalitis; post transplant lymphoproliferative disorder
Solid organ transplant: donor organ positive
CSF PCR
HHV-6 Limbic encephalitis; myelitis Cord blood cell source; SIADH
CSF PCR
JCV PML; granular cell neuronopathy
Lymphopenia; MS drugs
CSF PCR
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MRI in Progressive Multifocal Leucoencephalopathy
From: Bowen et al (2016) HIV-associated opportunistic CNS infections: pathophysiology, diagnosis &
treatment. Nature Reviews Neurology doi: 10.1038/nrneurol.2016.149
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Pulmonary sarcoid & focal seizures
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Case 1 MRI head scans
Axial MR images: T2 and T1 with gadolinium
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Case 1 Further tests
• Pulmonary and CNS TB
• Pulmonary & CNS Cryptococcal infection
• Invasive aspergillosis
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Long term fungal cultures
• Dematiaceous fungi isolated• Aspergillus PCR test : Negative• Pan fungal PCR test: POSITIVE • PCR sequence identification :
Cladophialophora bantiana
–Amphotericin 1.0 Sensitive –Itraconazole 0.06 Sensitive –Voriconazole 0.06 Sensitive –Posaconazole 0.06 Sensitive –Flucytosine 2 Sensitive
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CNS Fungi• Aspergillus
– Necrotising Vasculitis
• Candida
– Microabsses
– Fundoscopy
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CNS Fungi
• CSF – lymphocytosis, high pressure/protein, low glucose
• Serum beta glucan
– Sensitivity ~70%
• Serum Galactomannan
– Up to 95% sensitivity for Aspergillus
• 18S rRNA
– CSF, serum, sputum
FURTHER READING: Li et al Cerebral phaeohyphomycosis (2009) Lancet
Infectious Diseases 9: 376-83
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Sep 2015GBM
T1 MRI post Gadolinium
Oct 2015Alcoholic TravellerMRI head scan - axial T1 with gadolinium
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Aerobic bottle from 2 sets of cultures
Gram negative rods
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Aerobic bottle from 2 sets of cultures
Gram negative rods
Microbe:Burkholderia pseudomallei
Pulmonaryinvolvementcommonest
CNSmelioid
Rare
Mortalityupto25%1
Riskfactors
Diabetesmellitus,Immunosuppression,Alcoholexcess 2
Wiersinga WJetal.Melioidosis.NEngl JMed2012;367:1035-1044
Melioidosis
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Listeria monocytogenes
• Intracellular pathogen; invasive listeriosis; meningitis rhombencephalitis
• Motile gram positive rods
• Empirical treatment in >60 yrs presenting with meningitis
• Poor response to cephalopsorins
• Blood clutures; CSF cultures and CSF PCR
McGill (2016) The UK joint specialist societies guideline on the diagnosis and management ofacute
meningitis and meningococcal sepsis in immunocompetent adults. J Infection 72:405-38.
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Immune Reconstitution Inflammatory Syndrome (IRIS)
Johnson, T. & Nath, A. Neurological complications of immune reconstitution in HIV-infected
populations. Ann N Y Acad Sci 1184, 106-120 (2010).
• Definition:
“a paradoxical deterioration in clinical status attributable
to the recovery of the immune system during ART.”
• Other examples in neurological practice- Reversal reactions in leprosy
- MS relapse following pregnancy
- Cessation of natalizumab in MS
- Tuberculoma development in treated-TBM
- Stroke in S pneumoniae meningitis
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Johnson, T. & Nath, A. Neurological complications of immune reconstitution in HIV-infected populations. Ann N Y Acad Sci 1184, 106-120
(2010).
IRIS: Classification1
Simultaneous = Unmasked
Delayed = Paradoxical
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14/8/15 04/9/15
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14/8/15 04/9/15 06/10/15
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IRIS Associated with CNS Opportunistic Infections
Adapted from: Martin-Blondel, G., Delobel, P., Blancher, A., et al. Pathogenesis of the immune reconstitution inflammatory syndrome affecting
the central nervous system in patients infected with HIV. Brain 134, 928-946 (2011).
Microbe Frequency Neuro-IRIS Extraneural-IRIS
JCV 17% (2-50) Inflammatory PML None known
MTB 16% (10-25) Meningitis; tuberculoma; radiculomyelitis
Lymphadenitis; pulmonary infiltrates; pleural effusions; cutaneous abscess
Cryptococcus neoformans
20% (7-45) Meningitis; cryptococcoma
Lymphadenitis; cavitating pneumonia; skin
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IRIS Associated with CNS Opportunistic Infections
Adapted from: Martin-Blondel, G., Delobel, P., Blancher, A., et al. Pathogenesis of the immune reconstitution inflammatory syndrome affecting
the central nervous system in patients infected with HIV. Brain 134, 928-946 (2011).
Microbe Frequency Neuro-IRIS Extraneural-IRIS
JCV 17% (2-50) Inflammatory PML None known
MTB 16% (10-25) Meningitis; tuberculoma; radiculomyelitis
Lymphadenitis; pulmonary infiltrates; pleural effusions; cutaneous abscess
Cryptococcus neoformans
20% (7-45) Meningitis; cryptococcoma
Lymphadenitis; cavitating pneumonia; skin
MAC Rare Tuberculoma Lymphadenitis; pulmonary infiltrates; pleural effusions; cutaneous abscess
Toxoplasma Rare Encephalitis Retinitis
HSV Rare Encephalitis; myelitis Genital ulceration
VZV Rare Vasculitis; myelitis Dermatomal zoster
CMV Rare Encephalitis Uveitis; retinitis; colitis
Parvovirus B19
Rare Encephalitis; ventriculitis; brain vasculitis
Pure red cell anaemia
Syphilis Rare Encephalitis Uveitis; ?skin
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IRIS: Clinical Recognition & Management
Johnson, T. & Nath, A. Neurological complications of immune reconstitution in HIV-infected populations. Ann N Y Acad Sci 1184, 106-120
(2010).
Differential Diagnosis:• Drug toxicity / interaction
• Progression of underlying condition due to:
- Resistance of organism
- Poor adherance
- Inadequate drug levels
• Further pathological process e.g. development of PRES
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Conclusions
• Prevent:
– Vaccinations; preparation & prophylaxis
• History:
– How immunosuppressed?
– How long since intervention?
• May be minimal immune response
• Involve ID/microbiologists/radiologists
– Laboratory input critical
• Watch for paradoxical reactions with immune reconstitution
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References• Bowen (2016) HIV-associated opportunistic CNS infections: pathophysiology,
diagnosis & treatment. Nature Reviews Neurology doi: 10.1038/nrneurol.2016.149
• Bradshaw (2017) CNS infection associated with immunosuppressive therapy for rheumatic disease. Rheu Clinic N Am 43: 607-619
• Davies (2011). Infections of the nervous system. Practical Neurology 11: 121-131.
• Johnson (2010) Neurological complications of immune reconstitution in HIV-infected populations. Ann N Y Acad Sci 1184, 106-120.
• Levin (2017) Infectious complications of novel MS therapies Current ID Report 19: 7
• Li et al Cerebral phaeohyphomycosis (2009) Lancet Infectious Diseases 9: 376-83
• McGill (2016) The UK joint specialist societies guideline on the diagnosis and management ofacute meningitis and meningococcal sepsis in immunocompetent adults. J Infection 72:405-38.
• Nelson (2011) BHIVA & BIA Guidelines for treatment of opportunistic infection in HIV-seropositive individuals. HIV Medicine 12 Supp 2.
• Pruitt (2017) Neurologic complications of transplantation Continuum 23: 802-821
• Wiersinga (2012) Melioidosis. N Engl J Med 367:1035-1044