Chenjie Xia
Neurology AHD
Wednesday, February 2, 2011

Lupus

Lupus
• What are the diagnostic criteria for SLE?

Lupus
• Need 4 / 11 of the following:
– Discoid rash
– Oral ulcers
– Photosensitive rash
– Arthritis
– Malar rash
– Immunologic criteria (anti-dsNDA, anti-Sm, VDRL)
– NEuropsychiatric manifestations
– Renal involvement (proteinuria, cellular casts)
– ANA +ve
– Serositis (pleural or pericardial)
– Hematologic abnormalities (  plt / Hgb / WBC)

Lupus
• Need 4 / 11 of the following:
– D iscoid rash
– O ral ulcers
– P hotosensitive rash
– A rthritis
– M alar rash
– I mmunologic criteria (anti-dsNDA, anti-Sm, VDRL)
– NE uropsychiatric manifestations
– R enal involvement (proteinuria, cellular casts)
– A NA +ve
– S erositis (pleural or pericardial)
– H ematologic abnormalities (
 plt / Hgb / WBC)

Lupus
• Clinical pearls:
– Malar rash spares NLF, whereas rash in dermatomyositis involves NLF
– Oral ulcers are painless

Lupus
• Which of the following is not a neurological manifestation of SLE?
– A) Headache
– B) Acute confusional syndrome
– C) Seizure
– D) Chorea
– E) Myelopathy
– F) AIDP / Guillain-Barre syndrome
– G) Myasthenia gravis
– H) Peripheral neuropathy

Lupus
• They all are!
• American College of Rheumatology:
– Neuropsychiatric SLE  NPSLE

Greenberg, The
Neurologist , 2009

Bertsias and Boumpas,
Nature Reviews , 2010

Lupus
• Some key points:
– Lupus can virtually cause any neurological sign and symptom …
– Neuropsychiatric manifestation can occur anytime
• Preceding, during, or after Dx of SLE
• Both in active and inactive states of SLE

Seizing in SLE…

Lupus and Seizures
• 42F, known SLE, presents to the ER with one episode of GTC seizure lasting 2 mins, and is now back to baseline. What is your next step?
– A) Obtain urgent EEG
– B) Load with IV anti-epileptic
– C) Start steroids
– D) Start steroids and cyclophosphamide
– E) Admit and observe in hospital
– F) Consult rheumatology

Lupus and Seizures
• Seizures
– 7-20% of SLE patients report seizures
– Pathophysiology:
• Direct antibody effect with neuronal binding capability
• More likely APLA-mediated ischemia  small epileptogenic foci
– Management
• Screen for APLA antibodies, treat for thrombosis (if indicated)
• AED (may be withheld if no brain lesions or EEG abnormalities)
• immunosuppressants considered (if seizure 2/2 inflammation)

Lupus and Seizures
• 42F, known SLE, presents to the ER with one episode of GTC seizure lasting 2 mins, and is now back to baseline. What is your next step?
– A) Obtain urgent EEG
– B) Load with IV anti-epileptic
– C) Start steroids
– D) Start steroids and cyclophosphamide
– E) Admit and observe in hospital
– F) Consult rheumatology

Lupus and Seizures
• None of the above!
• First step : r/o other causes
– obtain imaging, as we do for all other patients who present with first episode of seizure! (CT on urgent basis, then MRI)

Bertsias and Boumpas,
Nature Reviews , 2010

Lupus and Seizures
• Important THM:
– Never automatically attribute neurological
S/Sx to SLE
– Always r/o other causes
• E,g hypo/hyperglycemia, uremia, lytes abnormalities, liver/thyroid disease, vitamin deficiencies, medication side-effects
• Avoid framing bias!

Making sense of SLE, APLAs and ischemic stroke…

Lupus and Stroke
• What is antiphospholipid syndrome?
• What are antiphospholipid antibodies?

Lupus and Stroke
• Antiphospholipid syndrome (APS):
– Presence of antiphospholipid antibodies
(confirmed on repeat testing, separated by 6-
12 wks)
AND
– Presence of clinical event (developing thrombosis or miscarriage)

Lupus and Stroke
• Antiphospholipid antibodies
– a) Lupus anticoagulant (LA)
• Recognizes negatively charged phospholipids
– b) Anticardiolipin antibody (aCL)
• Recognizes negatively charged phospholipids
– c) Plasma protein beta-2 glycoprotein I
• Less well known, but may be more clinically relevant

Lupus and Stroke
• Lupus anticoagulant (LA)
– Anticoagulant :

PTT
– A misnomer: prothrombotic
– Non-specific inhibitor:
• 
PTT
– does not correct with adding normal plasma
– 
PTT corrects when phospholipids added
• dRVVT (diluted Russel viper venom time)
–  clotting time des not correct with normal plasma
–  clotting time corrects when phospholipids added

Lupus and Stroke
• Anticardiolipin (aCL) antibodies
– Screened for with ELISA targeting aCL IgM,
IgG and IgA

Lupus and Stroke
• True or false: All patients with SLE have antiphospholipid antibodies and vice versa.

Lupus and Stroke
• False
– Not all patients with SLE have APS
• APS is only 1 of 11 diagnostic criteria for SLE
– Not all patients with APS have SLE
• APS can be a secondary condition related to SLE
• APS can be a primary condition on its own
– Remember, presence of APLAs does NOT automatically mean APS
• Vila et al. 1994: 552 normal donors, 15.9% had aCL antibodies and no thrombotic events within 12 mos of f/u

Lupus and Stroke
• True or false: The risk of ischemic stroke is increased in SLE patients only if they have antiphospholipid antibodies.

Lupus and Stroke
• False
•  risk of ischemic stroke in:
– Patients with APLAs, but no SLE
– SLE patients with APLAs
– SLE patients without APLAs (due to
 whole blood viscosity?)

Lupus and Stroke
• Management of patients ischemic stroke and
APLAs:
– Controversial for both primary and secondary prevention management
– Secondary prevention:
• APLAs and Stroke Study  No difference b/w ASA and coumadin
• NEJM 2003: No difference between INR 2-3 and INR 3-4
– Current guidelines
• +APLA, -stroke: ASA only
• +APLA, +stroke: coumadin INR 1.4-2.8
• +APLA, +++stroke: coumadin INR > 2.8 OR coumadin + ASA

Lupus and Stroke
• Management of ischemic stroke in SLE
– Acute management similar to non-SLE patients with ischemic stroke
– Secondary prevention
• Antiplt, lifestyle, control of vascular RFs, +/- CAE
• +++APLAs: consider oral A/C target INR 2-3
• Recurrent events + APLAs: target INR > 3 or coumadin + antiplt

Bertsias and Boumpas,
Nature Reviews , 2010

Lupus and Stroke
• Types of strokes in SLE:
– Ischemic stroke or TIA (>80%)
– Multifocal disease (7-12%)
– Intracerebra hemorrhage (7-12%)
– SAH (3-5%)
– Sinus thrombosis (2%)

The Story of SLE and
Demyelination…

Lupus and Demyelination
• Can you reliably differentiate multiple sclerosis from SLE with demyelinating disease?
– A) No, patients presenting with a classic demyelinating episode need to be screened for systemic rheumatological conditions
– B) Yes, demyelination is monophasic in SLE and recurrent in MS.
– C) Yes, the McDonald’s criteria can be used to differentiate MS from SLE demylination
– D) Yes, 
IgG index and

OCBs are not seen in SLE
– E) Yes, MS patients do not have positive ANA

Lupus and Demyelination
• Can you reliably differentiate multiple sclerosis from SLE with demyelinating disease?
– A) No, patients presenting with a classic demyelinating episode need to be screened for systemic rheumatological conditions
– B) Yes, demyelination is monophasic in SLE and recurrent in MS.
– C) Yes, the McDonald’s criteria can be used to differentiate MS from SLE demylination
– D) Yes, 
IgG index and

OCBs are not seen in SLE
– E) Yes, MS patients do not have positive ANA

Lupus and Demyelination
• First demyelinating event:
– Screen for rheumatologic condition
• Clinical symptoms
• Serologic evidence
– “lupus sclerosis”
– May need acute aggressive immunosuppression (e.g. pulse steroids, cyclophosphamide)

Greenberg, The
Neurologist , 2009

Lupus and Demyelination
• Lupus and transverse myelitis
– Patients with SLE are at  risk for TM
– Lesions in SLE tend to be larger , more edematous and cause more damage than in MS
– MRI, CSF
– Start antimicrobials empirically if CSF inflammatory
– Initiate immunosuppression early (w/i hours)
– Lesions similar to those in NMO and neurosarcoidosis
(may be part of same spectrum ?)

Lupus and Neurology
Hodgepodge

Lupus and Headache
• Types of headache
– Migraine with/without aura, tension headache
• Prevalence
– Documented in over 50% of SLE patients
• Strength of association
– Convincing evidence for association lacking
• If no red flags, manage as other HA patients

Lupus and Cognition
• Degree
– Range of severity, definitions vague
• Prevalence
– If any cognitive deficit: up to 80%
– If mild deficit discounted: <24%
– Severe deficits uncommon : 2-5%
• Pathophysiology
– Not well understood (?autoimmune)
– Not correlated with CNS events (e.g. stroke, seizure)
– Tend to persist despite control of systemic SLE

Bertsias and Boumpas,
Nature Reviews , 2010

Lupus and Confusion
• Acute Confusional State (ACS)
• Heterogeneous etiology
– Antineuronal abs, CVST, ischemic stroke, seizures, white matter lesions, SiADH
• Diagnosis of exclusion in SLE patients
– Early imaging
– R/o other causes (e.g. infection, metabolic)

Lupus and Confusion
ACS in SLE Psychiatric disorder
Acute onset
Visual hallucinations
Fluctuating LOC,
 attention
Slow onset with intermittent exacerbations
Auditory hallucinations
Deficits in reality testing

Bertsias and Boumpas,
Nature Reviews , 2010

• Types
– Chorea ***
– Others: hemiballism, parkinsonian
• Screen for SLE in young patients presenting with abnormal movements
• Pathophysiology
– Direct antibody-mediated?
– Small vessel ischemia

Lupus and Polyneuropathy
• Most common: symmetric, lengthdependent polyneuropathy
• May be related to glucose intolerance due to prolonged steroid use
• Overall rare, SLE patients make up very small proportion of patients with neuropathy

Final Words on ANA
• Which of the following is false?
– A) Serum ANA is often the most cost-effective way to screen for lupus.
– B) Serum ANA is helpful only when systemic manifestations for SLE are present.
– C) There are a variety of overlap syndromes in which ANA is positive.
– D) Detailed history and physical exam help to screen for SLE.

Final Words on ANA
• Which of the following is false?
– A) Serum ANA is often the most cost-effective way to screen for lupus.
– B) Serum ANA is helpful only when systemic manifestations for SLE are present.
– C) There are a variety of overlap syndromes in which ANA is positive.
– D) Detailed history and physical exam help to screen for SLE.

Lupus and Management
• Immunosuppresive therapy
– Corticosteroids (only FDA-approved Rx for SLE)
– +/- another immunosuppressant ( Imuran,
Cyclophosphamide )
– If refractory to above: PLEX, IVIG, rituximab
• Antiplatelet +/- anticoagulation (when indicated)
• Symptomatic treatment (when indicated)
– E.g. anticonvulsants, antidepressants, antipsychotics

Neurological Manifestations of
HIV/AIDS

HIV / AIDS
• HIV-1
– T-trophic viruses: replicate in T-lymphocytes
– M-trophic viruses: replicate in macrophages
• Period of clinical latency
– Viral replication is still very active
– High rate of mutation, readily become resistant
• Ingress into brain
– Carried into CNS by monocytes through BBB
• Productive CNS infection
– Occurs only when systemic immunosuppression occurs

Neurological manifestations of
HIV/AIDS
Primary HIV neurologic disease (HIV is necessary and sufficient to cause the illness)
Secondary or opportunistic neurologic disease
Treatment-related neurologic disease
HIV dementia
HIV vacuolar myelopathy
HIV neuropathy
PML
Toxoplasmosis encephalitis
Cryptococcus meningitis
CMV
PCNSL
IRIS
NRTI-induced neuropathy

Dementia

HIV / AIDS and Dementia
• AKA
– AIDS dementia complex (ADC)
– HIV-associated dementia
– HIV-associated cognitive motor complex

HIV / AIDS and Dementia
• HAND: HIV-Associated Neurocognitive
Disorder
– ANI: asymptomatic neurocognitive impairment
• Subclinical decline in cognition
– MND: minor neurocognitive disorder
• Mild decline in cognition, with mild daily functioning impairment
– HAD: HIV-associated dementia
• Significant decline in cognitive, with severe functional impairment

HIV / AIDS and Dementia
• What are characteristic findings for HAND in each of the following domains?
– 1) Cognitive
– 2) Behavioural
– 3) Motor

HIV / AIDS and Dementia
• Subcortical dementia
– Cognitive: short-term memory loss, impaired attention and concentration, executive dysfunction
– Behavioural: apathy, irritability, psychomotor retardation, new-onset mania
– Motor: ataxia, incoordination, motor slowing, tremor, impaired saccades, hyperreflexia, release signs

HIV / AIDS and Dementia
• Which of the following is most helpful in making the diagnosis of HAND?
– A) CSF analysis
– B) MRI
– C) MRS
– D) PET
– E) Brain biopsy

HIV / AIDS and Dementia
• Which of the following is most helpful in making the diagnosis of HAND?
– A) CSF analysis
– B) MRI
– C) MRS
– D) PET
– E) Brain biopsy

HIV / AIDS and Dementia
• Investigations
– CSF:
• may be needed to exclude infection (e.g. cryptococcus or tuberculous meningitis)
• usually not needed in afebrile pt with typical history
– MRI:
• r/o opportunistic processes
• Cortical/subcortical atrophy , characteristic confluent signal abnormalities

McArthur et al.
Lancet Neurol , 2005

HIV / AIDS and Dementia
• Investigations (cont’d)
– MRS
•  choline: astrocytosis
• 
NAA: neuronal injury
– PET
• Early: hypermetabolism in basal ganglia; late: hypometabolism in basal ganglia
• Dissimilar to other dementias (e.g. AD)
– Brain biopsy
• Generally not needed

HIV / AIDS and Dementia
• Which of the following statements is false?
– A) HAART is the mainstay of treatment in
HAND
– B) HAND can be reversed with HAART
– C) Different regimens of HAART are equally effective, as long as they are adequately treating the underlying HIV/AIDS.
– D) Ritalin has been shown to improve cognitive slowing in HAND

HIV / AIDS and Dementia
• Which of the following statements is false?
– A) HAART is the mainstay of treatment in
HAND
– B) HAND can be reversed with HAART
– C) Different regimens of HAART are equally effective, as long as they are adequately treating the underlying HIV/AIDS.
– D) Ritalin has been shown to improve cognitive slowing in HAND

HIV / AIDS and Dementia
• Treatment issues
– HAART is begun when CD4<350 or serum
HIV RNA > 100 000 copies/ml
– Most common regimen: 2 NRTIs + NNRTI/PI
– Efficacy of HAART regimen depends on CNS penetration (
 for PI)
– Adjunctive treatment
• Ineffective: memantine, selegiline, nimodipine
• In progress: minocycline, valproic acid
• Effective: methylphenidate

HIV / AIDS and Dementia
• Can you name a few mimickers of
HIV/AIDS dementia?

HIV / AIDS and Dementia
• Can you name a few mimickers of
HIV/AIDS dementia?
– CMV encephalitis
– PML
– Cryptococcal or tuberculous meningitis
– PCNSL
– Depression

HIV / AIDS and Dementia
McArthur et al.
Lancet Neurol , 2005

HIV-associated myelopathy

HIV and myelopathy
• Which segment of the cord is most commonly affected by HIV-associated vacuolar myelopathy?
– A) cervical
– B) thoracic
– C) lumbar
– D) sacral
– E) there is no special predilection for any particular cord segment

HIV and myelopathy
• Which segment of the cord is most commonly affected by HIV-associated vacuolar myelopathy?
– A) cervical
– B) thoracic
– C) lumbar
– D) sacral
– E) there is no special predilection for any particular cord segment

HIV and myelopathy
• Vacuolar myelopathy
– Slowly progressive painless spastic paraparesis, sensory ataxia, neurogenic bladder, paresthesias, ED
– Particularly affects the thoracic cord, and the lateral and posterior columns
– MRI typically normal, or non-specific nonenhancing hyperintensities
– HAART has not been proven to be effective
– Methionine may be beneficial?

HIV and myelopathy
• Other causes of myelopathy in HIV:
– HIV-associated myelitis (TM with enhancing cord lesions)
– HTLV-1 associated myelopathy
– CMV myeloradiculitis
– HZV myelitis
– Enterovirus myelitis
– Tuberculous myelitis
– Syphilitic myelitis
– Vit. B12 deficiency

HIV and neuropathy

HIV and neuropathy
• Which of the following statement best characterizes HIV-associated distal sensory neuropathy:
– A) Pain is present in some, but not all patients
– B) It can readily be differentiated from antiretroviral toxic neuropathy
– C) It is primarily a mitochondrial-mediated process
– D) Both myelinated and unmyelinated nerve fibers are affected, akin to diabetes and amyloidosis.

HIV and neuropathy
• Which of the following statement best characterizes HIV-associated distal sensory neuropathy:
– A) Pain is present in some, but not all patients
– B) It can readily be differentiated from antiretroviral toxic neuropathy
– C) It is primarily a mitochondrial-mediated process
– D) Both myelinated and unmyelinated nerve fibers are affected, akin to diabetes and amyloidosis.

HIV and neuropathy
• HIV-associated DSPN
– Dominated by pain (“aching,” “painful numbness,”
“burning”)
– Rarely have significant weakness
– Ankle jerks typically absent or reduced
– NCS: axonal, length-dependent, sensory polyneuropathy
– QST:  pain and temperature threshold
– Pathophysiology: inflammatory infiltrates of lymphocytes and activated macrophages, gp120 induces apoptosis

HIV and neuropathy
• Antiretroviral toxic neuropathy
– Etiology typically determined by timing with respect to medication exposure (begin w/i 6 months, and peak within 3 months)
– Mostly related to exposure to specific dideoxynucleosides ( d4T/stavudine, ddI/didanosine, ddC/zalcitabine )
– Prominent mitochondrial abnormalities, inhibitor of gamma DNA polymerase, induces neuronal necrosis
– NRTIs not associated with toxic neuropathy: zidovudine, lamivudine, abacavir

HIV and neuropathy
• Treatment
– AEDs (lamotrigene, gabapentin), narcotics, topical capsaicin / lidocaine
– Amitriptyline and acupuncture ineffective
– D/C offending agent in antiretroviral toxic neuropathy  Sx improvement first seen at 3 weeks, some up to 6 wks – 6 months

HIV and opportunistic processes

HIV and PML
• Which of the following statements regarding HIV and PML is true:
– A) PML lesions on MRI are always nonenhancing.
– B) The most sensitive and specific test for
PML is the CSF JCV PCR.
– C) The seroprevalence of JCV is 90% in normal population.
– D) Cidofovir has been shown to decrease
PML mortality in HIV.

HIV and PML
• Which of the following statements regarding HIV and PML is true:
– A) PML lesions on MRI are always nonenhancing.
– B) The most sensitive and specific test for
PML is the CSF JCV PCR.
– C) The seroprevalence of JCV is 90% in normal population.
– D) Cidofovir has been shown to decrease
PML mortality in HIV.

HIV and PML
• 70-90% seroprevalence of JCV in worldwide population
• Most cases occur when CD4 < 100
• Diagnosis
– Definitive: needs biopsy
– Probable: clinical history + imaging and laboratory findings
• MRI: bright T2 and dark T1 lesions, most non-enhancing; those who do enhance  better prognosis
• Positive JCV PCR considered diagnostic in typical clinical context, but suboptimal sensitivity and specificity
• HAART improve survival
• Other agents (topotecan, cytarabine, cidofovir): no proven benefit

HIV and CMV
• Which of the following statements is false:
– A) 60% of the population show evidence of past exposure to CMV
– B) Neurologic manifestations of CMV infection in HIV are limited to encephalitis and myelitis
– C) CSF CMV PCR is the gold standard for identifying CNS CMV infection
– D) CMV infection in HIV can be treated with ganciclovir, foscarnet, or cidofovir.

HIV and CMV
• Which of the following statements is false:
– A) 60% of the population show evidence of past exposure to CMV
– B) Neurologic manifestations of CMV infection in HIV are limited to encephalitis and myelitis
– C) CSF CMV PCR is the gold standard for identifying CNS CMV infection
– D) CMV infection in HIV can be treated with ganciclovir, foscarnet, or cidofovir.

HIV and CMV
• 60% of population show evidence of CMV exposure
(higher in homosexual men)
• Neurological manifestations of CMV infection emerge when CD4 < 50
• Presentations are diverse : encephalitis, ventriculitis, myelitis, radiculoganglionitis, peripheral polyneuropathy, combinations of above
• CSF CMV PCR = gold standard
– Identifying infection
– Follow response to Rx (w quantification)
• Treatment: start with ganciclovir or foscarnet ; cidofovir if above fails

• Who am I?
– I can be eradicated with pyrimethamine, sulfadiazine and leucovorin
– My presence often cause 
ICP
– I am seen on MRI as multiple contrast-enhancing lesions, often surrounded by edema.
– I am an encapsulated yeast, visualized in CSF with
India Ink
– I should be treated immediately with amphotericin, combined with flucytosine

• Who am I?
– I can be eradicated with pyrimethamine, sulfadiazine and leucovorin  Toxo
– My presence often cause 
ICP  Crypto
– I am seen on MRI as multiple contrast-enhancing lesions, often surrounded by edema.  Toxo
– I am an encapsulated yeast, visualized in CSF with
India Ink  Crypto
– I should be treated immediately with amphotericin, combined with flucytosine  Crypto

• Who am I? (cont’d)
– I most commonly present as a subacute meningoencephalitis
– I am a parasite that usually cause a silent primary infection, and then remain latent for years
– I am spread thru dust and bird droppings
– My appearance as T2 hyperintense, enhancing focal lesions is often confused with PCNSL
– Cats are my definitive host, but I can be carried by all mammals

• Who am I? (cont’d)
– I most commonly present as a subacute meningoencephalitis  Crypto
– I am a parasite that usually cause a silent primary infection, and then remain latent for years  Toxo
– I am spread thru dust and bird droppings  Crypto
– My appearance as T2 hyperintense, enhancing focal lesions is often confused with PCNSL  Toxo
– Cats are my definitive host, but I can be carried by all mammals  Toxo

HIV and PCNSL
• Major RF: CD4 < 100
• Almost always a/w EBV (seroprevalence of 90%), can be detected and quantified by PCR in CSF
• Almost always high-grade B-cell lymphomas
• Imaging: multiple, contrast-enhancing lesions, surrounded by edema, mass effect
• Biopsy can be problematic:
– Lesions are multifocal and necrotic, sampling often inadequate
– Use of steroids before biopsy  lysis of most neoplastic lymphocytes
• HAART lowered incidence of PCNSL and improved survival
• Treatment options: RTX, MTX

IRIS…not the flower….nor the philosopher!

IRIS
• I mmune R econstitution I nflammatory S yndrome
• Paradoxical clinical worsening , w/i 4-8 wks after starting
HAART
– Worsening of a known infection
– Unmasking of subclinical infection
– Most common infections involved: HIV encephalitis, toxo, crypto,
PML
• Neuroimaging: contrast enhancing lesions
• Steroids may be needed for 
ICP, although therapeutic benefit controversial
• Most patients survive

References
• Bertsias and Boumpas. Pathogenesis, diagnosis and management of neuropsychiatric SLE manifestations,
Nat. Rev. Rheumatol. 6, 2010, pp. 358-367.
• Greenberg, Benjamin. The neurologic manifestations of systemic lupus erythematosus, The Neurologist , 15 (3),
2009, pp. 115-121.
• Muscal et al. Neurologic manifestations of systemic lupus erythematosus in children and adults, Neurol Clin ,
28 (2010), pp. 61-73.
• McArthur et al. Neurological complications of HIV infection, Lancet Neurol , 2005, 4, pp. 543-555.
• Singer et al. Neurologic presentations of AIDS, Neurol.
Clin. 28, 2010, pp. 253-275.