Lupus neuropsiquiatria

The 10th International Congress on SLEBuenos Aires, Argentina

Neuro-psychiatric SLE

Leonor A. Barile-Fabris, MD, PhD Professor of Rheumatology

Chair, Rheumatology Department Centro Médico Nacional Siglo XXI

Mexico City, Mexico

Key points

NP manifestations have been increasingly recognized.

Both attribution and diagnosis remain clinical challenges.

Selection of optimum treatment is complex due to scarce and heterogeneous clinical data.

Key issues in SLE patients with neuropsychiatric manifestations

EULAR Task force on SLE- Evidence and expert-based answers

• Who is at risk to develop NPSLE?

• Is NPSLE common?

• When to suspect NPSLE?

• How can I attribute a NP event to SLE?

• How do I treat NPSLE?

Bertisas GK.Nat Rev Rheumatol.2010:6;1-10

Key points

NP symptoms are present in approximately 20 to 50% of SLE patients, frequently within the first 2 years.

These symptoms are primarily associated with a poor HRQoL and an increase in functional impairment, leading to unemployment in some cases.

Mild manifestations are common and include headache, anxiety, depression, and cognitive deficit. These, however, are not normally related to the disease.

Source: Bertisas GK. Nat Rev. Rheumatol. 2010:6;1-10.

Neuropsychiatric SLE – General statements

1. When do they occur?

-May precede, coincide, or follow the diagnosis of SLE but commonly (40-50%) occur within the first year after SLE diagnosis,

-Usually (50-60%) in the presence of generalized disease activity (B).

2. Cumulative incidence of neuropsychiatric manifestations:

- common (10-20%): cerebrovascular disease, seizures

- relatively uncommon (3-10%): severe cognitive dysfunction, major depression, acute confusional state and peripheral nervous disorders

- rare (<3%): psychosis, myelitis, chorea, cranial neuropathies, aseptic meningitis (B)

EULAR Recommendations for the Management of Neuropsychiatric SLE

eular

Bertisas GK. Ann Rheum Dis: 69.2074-82

NP events at the time of diagnosis

Hanly JG. Ann Rheum Dis 2101;3:529-35.

NP Manifestations in 88 SLE patients at the Centro Médico Nacional “La Raza”, Mexico City

Manifestation Number

Seizures 32

Delirium 21

Stroke 15

Pheripheral neuropathy 12

Optic neuritis 10

Transverse myelitis 4

Barile et al. Lupus 1988;7:S 107

Seizures 99 30.9

Headeache 54 16.8

Psychosis 49 15.3

Delirium 47 14.6

Stroke 34 10.6

Sensitive neuropathy 33 10.3

Motor neuropathy 31 9.6

Coma 10 3.13

Aseptic meningitis 7 2.19

Transverse myelitis 7 1.7

Chorea 5 1.5

Ataxia 4 1.2

Pseudo tumor cerebri 2 0.63

Organic brain syndrome 2 0.63

GLADEL

Barile et al. Lupus 1998 (Suppl);7:53

Differing prevalences in LSE

Highly heterogeneous clinical manifestations.Some are not specific or “subclinical”.Manifestations may be present despite the

absence of other disease activity signs.Attribution is difficult to establish.There might be differences between inception

and survival cohorts.

Bertisas GK.Nat Rev Rheumatol.2010:6;1-10

Bertisas GK.Nat Rev Rheumatol.2010:6;1-10

Neuropsychiatric SLE – General statements

4. Diagnostic work-up

a) In SLE patients with new or unexplained symptoms or signs suggestive of neuropsychiatric disease, initial diagnostic work-up should be similar to that in non-SLE patients presenting with the same manifestations (D).

b) Depending upon the manifestation, this may include lumbar puncture and CSF analysis (primarily to exclude CNS infection), EEG, neuropsychological assessment of cognitive function, nerve conduction studies, and neuro-imaging (MRI) to assess brain structure and function (D).

c) The recommended MRI protocol (brain and spinal cord) includes conventional MRI sequences (T1/T2 FLAIR), diffusion-weighted imaging (DWI), and gadolinium-enhanced T1 sequences (B).

EULAR Recommendations for the Management of Neuropsychiatric SLE

eular

Bertisas GK. Ann Rheum Dis: 69.2074-82

MRI white-matter lesions in NPSLE

• ↑ signal in Τ2 / FLAIR

• Localized in subcortical and periventricular white matter and frontal-parietal lobe (70–80%)

• Prevalence 50–60% of all patients with NPSLE …but 18–40% of non-NPSLE

…no correlation with a particular NP syndrome

• Cerebral atrophy, number and size of WML and cerebral infarcts correlate with severity of cognitive dysfunction

In young SLE patients new MRI WMLs (especially if ≥5, ≥6-8mm, and bilateral may suggest active NPSLE

Case 1

2007 SLE: Arthritis, cutaneous involvement, serologic criteria.

ANA 1:280 C4 3 C3 55

2009 Arthritis, skin.

2010 Arthritis, Raynaud, digital vasculitis.

Methilprdnisolone 3grIV Cy single dose

Abril 2010Anxiety, insomnia, mood disorders.CAT and MRI: Normal. CSF:NormalSteroidal psicoisis Ketiapine 200mg, Prednisone 35mg, Sertraline 50mg MMF 2 gr /d.

2011 SLEDAI 0 (low complement levels) slow prednisone tappering and MMF.

Regional hospital : MMF 500mg d.

24/02/13:Seizures.Increased reflexes.DFH Levertiracetam, Metilprednisolone 3 gr.

03/03/13:Seizures.Increased reflexes.DFH Levertiracetam, Metilprednisolone 3 gr.Abnormal movements.Topiramate and lumbar puncture.

06/03/13:Anxiety-depression disorder.

Case 1 (Readmission)

IRM

Identifying differential diagnosis

Embolic infarct.Opportunistic infection.Brain abscess.NP SLE.Brain tumor.

MRI Diagnosis

Radiology: Infarcts (embolus), cortical, in two different territories, restricted diffusion, low ADC.

Neurology: Opportunistic infection (toxoplasmosis) vs. brain abscess (headache, fever, seizures).

Cardioembolic infarct

NP SLE

Abscess

Tumor

CSF:Cels 0, RC 10, C 100%.Prot25.2 mg/dl, Gluc42 mg/dl, Cl 127 mEq/L. ANA (-), C3 y C4 0, Anti DNA 8.9, aCL 2.0

Gramm (-).Cultive (-)

Brain gammagram Taliium 201 and Gallium 67: normal.

.

IV Cy.

Case 1: results

TE echocardiogram: Normal

MRI in NP SLE

Multiple white matter lesions.Cerebral infarction.Cerebral hemorrhage.Venous sinus thrombosis.Atrophic changes.Spinal cord disease.

Lupus 2003;12:891

Saggital T1 image: Clot in the Stright sinus

Take-home messages,case 1

There is not such thing as a typical MRI in neurolupus.

Differential diagnosis comprises a wide range of causes.

Prognosis and treatment

Prognosis

Poor prognosis factors:• Caucasians?• Active disease• aRO, LA, IgG aCl.

Rheumatology 2004; 43:1555-1560.

Prognosis in 2 referral hospitals in Mexico City

71%

29%

improvement no response

Poor prognosis, cont’d.

Male gender.neuroSLICC ≥1 p = 0.0001.↑antiDNA p= 0.21.Low complement levels p= 0.05.↑ESR p= 0.036.

Poor prognosis factors

Consolidation analysis:

Normal ESR and complement: 85.7% improved.Low complement and high ESR : 69.2% worsened.P= 0.001

Treatment

Barile L. Reumatol Clin. 2005;1 Supl 2: S42-5

5. Therapy

a) Corticosteroids and immunosuppressive therapy are indicated for neuropsychiatric manifestations felt to reflect an immune/inflammatory process (acute confusional state, aseptic meningitis, myelitis, cranial and peripheral neuropathies, and psychosis) following exclusion of non-SLE related causes (A, D).

b) Anti-platelet/anti-coagulation therapy is indicated when manifestations are related to anti-phospholipid antibodies, particularly in thrombotic cerebrovascular disease (A, D).

c) The use of symptomatic therapies (e.g. anticonvulsants, antidepressants) and the treatment of aggravating factors (e.g. infection, hypertension and metabolic abnormalities) should also be considered (D).

d) Anti-platelet agents may be considered for primary prevention in SLE patients with persistently positive, moderate or high, anti-phospholipid antibody titers (D).

EULAR Recommendations for the Management of Neuropsychiatric SLE

eular

Neuropsychiatric SLE – General statements

• Induction Metilprednisolone (MP) 1 g/d for 3 d.

• MP 1 g/d por 3 d, monthly for 4 m, then bimonthly for 6 m, and subsequently every 3 m for 1 y.

or

• Ciclophosphamide (Cy) 0.75 g/m2 bs monthly for 1 y, and every 3 m for another y.

Ann Rheum Dis 2005;64:620–625.

Allocation

Median monthly values of visual analogue scale ratings for changes in muscular strenght in NP and TM patients

0= No changes from basal conditions; 10= the best possible improvement

P=0.04

MPDCFM

Seizures

Average prednisone intake/ day

Response to treatment

Response MPD CY

Failure 7 1

Improvement 11 18

p

<0.003

<0.05

Trevisani et al Cochrane 2008

Case: Female, 62 years old.

2001: Optic Neuritis in right eye.2010: Non Hodgkin lymphoma, QxTx RxRx. May 2010: Optic Neuritis in left eye.Hypotiroidism. ANA 1:640 H, lymphopenia,

leukopenia, Neurolupus: Pdn 50mg/d and Mycophenolate.

Oct 3 2010: Hyperstetic sensitive level C5 and T7, medular discharges, hyporeflexia.

Oct 3 2010: Hyperstetic sensitive level C5 and T7, medular discharges, hyporeflexia.

MRI: Hyper intensity with T1 enhancement, suggestive of longitudinal myelopathyFrom C2 to T12 with high activity in neuro-imaging

Selecting treatment

• IV MP• Oral prednisone and high dose MMF• IV Cy• Plasmaphereis• IV MP and IV Cy• Others?

MP 5 gPdn 50 mg/d

Partial improvement in sensitivity. Paraplegia. Acute confusional syndrome. Delirium. IV Cy 700mg.

Currently: 6 pulses Partial recovery Sensitivity fully recovered Motor capacity 30% recovery

Take-home messages: Case 2

Despite published evidence, response to treatment even within the same clinical manifestation may be heterogeneous.

Transverse myelopathy has a better prognosis than longitudinal myelopathy.

Final considerations

There are different clinical subgroups in neurolupus.

Etiopathogenic mechanisms might be different, but they all seem to be related to vascular endothelium.

NP SLE has a profound impact in prognosis, HRQoL and damage.