Neurological Manifestations of Selected Medical Conditions 1. Lupus 2. HIV/AIDS

Neurological Manifestations of Selected Medical Conditions

1. Lupus2. HIV/AIDS

Chenjie Xia

Neurology AHD

Wednesday, February 2, 2011

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

• 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)

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

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


• 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 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

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

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.

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



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


• 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


• 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

• 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


• 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


• 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



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


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


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

• 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

• 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

• 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

• 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


• 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

• 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.

Neurological Manifestations of Selected Medical Conditions 1. Lupus 2. HIV/AIDS

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