Neurological Manifestations of Selected Medical Conditions 1. Lupus 2. HIV/AIDS Chenjie Xia Neurology AHD Wednesday, February 2, 2011
Jan 14, 2016
Neurological Manifestations of Selected Medical Conditions
1. Lupus2. HIV/AIDS
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:
– 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
• 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 Slow onset with intermittent exacerbations
Visual hallucinations Auditory hallucinations
Fluctuating LOC, attention
Deficits in reality testing
Bertsias and Boumpas, Nature Reviews, 2010
Lupus and Abnormal Movements
• 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, length-dependent 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 dementiaHIV vacuolar myelopathy
HIV neuropathy
PMLToxoplasmosis encephalitis
Cryptococcus meningitisCMV
PCNSL
IRISNRTI-induced neuropathy
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
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
• 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
HIV / AIDS and Dementia
McArthur et al. Lancet Neurol, 2005
• 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
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 non-enhancing 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 non-
enhancing.– 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 non-
enhancing.– 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
HIV and other opportunistic infections
• 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
HIV and other opportunistic infections
• 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
HIV and other opportunistic infections
• 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
HIV and other opportunistic infections
• 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
• Immune Reconstitution Inflammatory Syndrome• 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.