Leonor A. Barile-Fabris, MD, PhD Professor of Rheumatologo Chair, Rheumatology Department Centro Médico Nacional Siglo XXI Mexico City, Mexico

1. The 10th International Congress on SLE
Buenos 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

2. 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.

3. 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

4. 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.

5. EULAR Recommendations for the
Management of Neuropsychiatric SLE
eular
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)
Bertisas GK. Ann Rheum Dis: 69.2074-82

6. NP events at the time of diagnosis
Hanly JG. Ann Rheum Dis
2101;3:529-35.

7. 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

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

9. 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.

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

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

12. EULAR Recommendations for the Management of Neuropsychiatric
SLE
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).
Bertisas GK. Ann Rheum Dis: 69.2074-82
eular

13. 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

14. Case 1
2007
SLE: Arthritis, cutaneous involvement, serologic
criteria.
2009
Arthritis, skin.
2010
ANA 1:280
C4 3 C3 55
Arthritis, Raynaud, digital vasculitis.
Abril 2010
2011
Methilprdnisolone 3gr
IV Cy single dose
Anxiety, insomnia, mood disorders.
CAT and MRI: Normal. CSF:Normal
Steroidal psicoisis
Ketiapine 200mg, Prednisone 35mg, Sertraline 50mg MMF
2 gr /d.
SLEDAI 0 (low complement levels) slow prednisone tappering and
MMF.
Regional hospital : MMF 500mg d.

15. Case 1 (Readmission)
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.

16. IRM

17. Identifying differential diagnosis
Embolic infarct.
Opportunistic infection.
Brain abscess.
NP SLE.
Brain tumor.

18. MRI Diagnosis
Radiology: Infarcts (embolus), cortical,
in two different territories, restricted
diffusion, low ADC.
Neurology: Opportunistic infection
(toxoplasmosis) vs. brain abscess
(headache, fever, seizures).

19. Case 1: results
.
TE echocardiogram: Normal
Tumor
IV Cy.
Cardioembolic
infarct
NP SLE
Brain gammagram Taliium
201 and Gallium 67: normal.
Abscess
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 (-)

20. MRI in NP SLE
Multiple white matter lesions.
Cerebral infarction.
Cerebral hemorrhage.
Venous sinus thrombosis.
Atrophic changes.
Spinal cord disease.
Lupus 2003;12:891

24. Saggital T1 image: Clot in the Stright sinus

26. Take-home messages,case 1
There is not such thing as a typical
MRI in neurolupus.
Differential diagnosis comprises a
wide range of causes.

29. Prognosis and treatment

30. Prognosis
Poor prognosis factors:
• Caucasians?
• Active disease
• aRO, LA, IgG aCl.
Rheumatology 2004; 43:1555-1560.

31. Prognosis in 2 referral hospitals in
Mexico City
29%
71%
improvement
no response

32. 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.

33. Poor prognosis factors
Consolidation analysis:
Normal ESR and complement: 85.7%
improved.
Low complement and high ESR : 69.2%
worsened.
P= 0.001

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

35. eular
EULAR Recommendations for the Management of Neuropsychiatric
SLE
Neuropsychiatric SLE – General statements
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 antiphospholipid 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).

36. •
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.

38. Allocation

39. Median monthly values of visual analogue scale ratings for changes in
muscular strenght in NP and TM patients
P=0.04
0= No changes from basal conditions; 10= the best possible
improvement

40. Seizures
CFM
MPD

41. Average prednisone intake/ day

42. Response to treatment
MPD
CY
p
Failure
7
1
<0.003
Improvement
11
18
<0.05
Response

43. Trevisani et al Cochrane 2008

44. 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.

45. Oct 3 2010: Hyperstetic sensitive level C5 and
T7, medular discharges, hyporeflexia.
MRI: Hyper intensity with T1
enhancement, suggestive of
longitudinal myelopathy
From C2 to T12 with high activity in
neuro-imaging

48. Selecting treatment
•
•
•
•
•
•
IV MP
Oral prednisone and high dose MMF
IV Cy
Plasmaphereis
IV MP and IV Cy
Others?

49. MP 5 g
Pdn 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

50. 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.

51. 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.