J Neurol (1992) 239 : 460-464

Journal of

Neurology © Springer-Verlag 1992

Gadolinium-enhanced magnetic resonance imaging of the central nervous system in systemic lupus erythematosus D. H. Miller 1, N. Buchanan 2, G. Barker l, S. P. Morrissey 1, B. E. Kendall i, P. Rudge 1, M. Khamashta 2, G. R. V. Hughes 2, and W. I. McDonald 1 i Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK 2Lupus Research Unit, The Rayne Institute, St. Thomas' Hospital, London SE1, UK Received November 28, 1991 / Received in revised form January 30, 1992 / Accepted February 3, 1992

Summary. G a d o l i n i u m ( G d ) - D T P A

enhanced magnetic r e s o n a n c e i m a g i n g ( M R I ) was p e r f o r m e d in 15 s y s t e m i c l u p u s . e r y t h e m a t o s u s p a t i e n t s with p a s t (12) o r p r e s e n t (3) f e a t u r e s suggesting c e n t r a l n e r v o u s s y s t e m ( C N S ) inv o l v e m e n t . S y m p t o m a t i c G d - D T P A e n h a n c i n g lesions w e r e s e e n in 2 p a t i e n t s , a n d i m m u n o s u p p r e s s i v e t r e a t m e n t was a s s o c i a t e d w i t h a r a p i d r e v e r s a l of e n h a n c e m e n t . T h e p a t t e r n of e n h a n c e m e n t was d i f f e r e n t f r o m t h a t u s u a l l y s e e n in m u l t i p l e sclerosis. G d - D T P A enh a n c e d M R I m a y s o m e t i m e s b e useful in d e m o n s t r a t i n g t h e activity o f C N S lupus.

Key words: L u p u s - N e u r o l o g i c a l d i s e a s e - G a d o l i n i u m - Magnetic resonance imaging

Introduction This p a p e r r e p o r t s t h e findings o f g a d o l i n i u m ( G d ) D T P A e n h a n c e d m a g n e t i c r e s o n a n c e i m a g i n g ( M R I ) in 15 s y s t e m i c l u p u s e r y t h e m a t o s u s ( S L E ) p a t i e n t s w i t h suspected central nervous system (CNS) involvement. G d - D T P A is a p a r a m a g n e t i c c o n t r a s t a g e n t , w h i c h s h o r t e n s t h e T1 r e l a x a t i o n t i m e o f tissues in w h i c h it accumulates, producing enhancement on Tl-weighted M R I scans. G d - D T P A e n h a n c e m e n t is n o t s e e n in n o r m a l b r a i n b u t will o c c u r in r e g i o n s w i t h an a b n o r m a l b l o o d - b r a i n b a r r i e r ( B B B ) . This s t u d y was p e r f o r m e d in o r d e r to assess t h e v a l u e of G d - D T P A e n h a n c e d M R I in d i a g n o s i s a n d m o n i t o r i n g t h e activity of C N S l u p u s , a n d to i n v e s t i g a t e t h e p o t e n t i a l r o l e o f B B B i m p a i r m e n t in p a t h o g e n e s i s o f t h e disease.

Patients and methods Fifteen patients aged 17-60 years (14 female, 1 male) were studied. SLE was diagnosed using the 1982 American Rheumatism

Correspondence to: D. H. Miller

Association criteria [20]. All had a past or present history of neuropsychiatric symptoms (see Table 1). MRI was performed on a Picker 0.5 Tesla superconducting system, provided by the Multiple Sclerosis Society of Great Britain and Northern Ireland. In all patients, a T2-weighted scan (SE2000/60) of the entire brain was obtained with 5-ram axial contiguous slices. After injection of Gd-DTPA (0.1mmol/kg), Tl-weighted scans (SE500/20) were obtained using the same slice thickness and orientation. In addition, the cervical cord was imaged in 1 patient who presented with a subacute myelopathy. All scans were reviewed by a neuroradiologist (B.E.K.) who noted the presence and location of lesions, and whether or not they showed enhancement. In order to look for evidence of a subliminal BBB abnormality, additional calculated images of T1 were obtained in 9 patients, before and after Gd-DTPA injection. Six contiguous slices were selected to include the frontal white matter, caudate nucleus and putamen. The images were calculated using algorithms provided by Picker from two sequences: SE2000/40, IR2000/40/500. Measurements of T1 were taken from normal-appearing frontal white matter, using a large circular region of interest which fell entirely within the white matter. Measurements from the caudate nucleus and putamen were made by tracing around these structures using a cursor on the computer screen (Fig. 1). We did not take measurements from cortex, since we felt that partial volume effects made such measurements less reliable. The mean and standard deviation of values obtained before and after Gd-DTPA enhancement were compared using a two-sample t-test.

Case reports Case I. A 40-year-old female presented with a progressive cervical cord syndrome. There was a past history of arthralgia and arthritis involving knees, wrists and small joints of the hands at the age of 36 years. At that time, rheumatoid factor was negative, but antinuclear antibodies were present with a titre of 1 : 1600, and antibodies to single stranded DNA were positive. She was treated with non-steroidal anti-inflammatory drugs and gold therapy, and the arthritis resolved over 1 year. Eight months prior to admission she developed weakness, numbness and tingling in the legs. These symptoms gradually became more pronounced and ascended to involve the arms 2 months prior to admission. Urinary retention developed, required catheterisation. On admission, she was chairbound, with moderate weakness of elbow extension, wrist and finger movements, and complete paralysis of the legs. Tendon reflexes were exaggerated apart from triceps which were sluggish. Plantar responses were extensor. There was a sensory level to light touch and pain up to C8 on the right and C6 on the left; joint posi-

461 Table 1. Clinical and MRI features.

PVWM, Periventricular white matter lesions; SCWM, subcortical white matter lesions; ctx, cerebral cortex lesion; CRB, cerebellum; BG, basal ganglia; IC, internal capsule; Cx, cervical; +, clinically active; - , clinically inactive

Patient Age Sex no. (years)

1

2

40

28

F

F

Neuropsychiatric features

Clinical activity at time of MRI

T2 MRI

Gd-DTPA enhanced MRI

Subacute myelopathy

(1st scan) + (2nd scan) -

SCWM Cx cord SCWM Cx cord

Cx cord

(lst scan) +

PVWM SCWM etx CRB PVWM SCWM ctx CRB

Acuteencephalopathy; parietal lobe signs

(2nd scan) -

Nil

ctx/SCWM

Nil

3

17

M

Psychosis

+

PVWM SCWM

Nil

4

36

F

Depression

-

N

Nil

5

24

F

Migraine

-

N

Nil

6

45

F

Epilepsy

-

PVWM SCWM ctx

Nil

7

56

F

Retinal vasculitis

-

PVWM

Nil

8

39

F

Psychosis

-

Mild atrophy

Nil

9

44

F

Optic neuropathy

-

N

Nil

10

60

F

Dementia

-

PVWM SCWM BG, CRB

Nil

11

26

F

Cerebrovascular accident -

IC/BG

Nil

12

21

F

Epilepsy

-

N

Nil

13

36

F

Psychosis

-

N

Nil

14

33

F

Psychosis

-

SCWM

Nil

15

29

F

Migraine

-

N

Nil

tion sense and vibration sense were impaired in the lower limbs and in both little fingers. The cerebrospinal fluid contained 12 white cells/mm 3 (mononuclears), protein 1.3 g/l, glucose 2.8 mmol/ l, and no oligoclonal bands. Brain MRI revealed a few small nonenhancing subcortical white matter lesions. Spinal MRI displayed marked swelling of the cervical cord with prominent Gd-DTPA enhancement involving the posterior cord from C4 to T t (Fig. 2a-c). Treatment was instituted with intravenous cyclophosphamide and high-dose intravenous methylprednisolone. One week later, the enhancement had disappeared and swelling had subsided (Fig. 2d). There had been a marginal clinical improvement.

Case 2. A 28-year-old female presented with sudden onset of speech difficulties. Six months earlier, she developed arthralgia and emotional lability and SLE was diagnosed by the presence of high titres of anti-nuclear and anti-DNA antibodies. On admission, she exhibited an expressive dysphasia, dyslexia, dyscalculia and constructional apraxia. There was a moderate right hemiparesis and mild pyramidal weakness in the left arm. Tendon reflexes were generally brisk with flexor plantars. There was a cortical type of sensory loss involving the right arm and leg. Brain MRI revealed multiple cortical and subcortical lesions in both cerebral and cerebellar hemispheres. A large left parietal lesion displayed Gd-DTPA enhancement (Fig. 3). She was treated with oral cyclo-

phosphamide and corticosteroids. One month later, there was marked resolution of her neurological symptoms. Repeat MRI showed persistence of the brain lesions on the unenhanced scan, but the left parietal lesion no longer enhanced.

Results

Qualitative analysis ( T a b l e 1) B r a i n M R I was a b n o r m a l i n 9 o f t h e 15 p a t i e n t s , o f whom 8 displayed parenchymal abnormalities, while 1 displayed mild, generalised atrophy only. White matter lesions were seen in 8 patients: multiple subcortical l e s i o n s o f v a r y i n g size w e r e s e e n in 6, a n d p e r i v e n t r i c u l a r c h a n g e s , w h i c h w e r e g e n e r a l l y m i l d , w e r e also s e e n i n 5. Cerebral cortex, cerebellar and basal ganglia lesions w e r e e a c h p r e s e n t in 2 p a t i e n t s a n d i n 1 t h e r e was a lesion in the internal capsule (associated with contralateral h e m i p a r e s i s ) . A n e x t e n s i v e i n t r i n s i c c o r d l e s i o n was s e e n in the patient who p r e s e n t e d with a progressive cervical m y e l o p a t h y (case 1). G d - D T P A e n h a n c e m e n t was s e e n

462 in two lesions, both of which were associated with active neurological symptoms.

Quantitative analysis (Table

rained from normal-appearing white matter, caudate nucleus and putamen, before or after G d - D T P A administration.

2)

Although there was a wide range of values in different patients, there was no difference in the m e a n T1 ob-

Fig. la, b. Calculated images of T1. Readings were taken from the frontal white matter (a), caudate nucleus (b) and putamen (b), as illustrated

Discussion

Clinical CNS involvement occurs in up to 50% of SLE patients [7]. At present there is no reliable laboratory investigation with which to diagnose CNS lupus and to monitor its activity. Sometimes the clinical distinction of CNS lupus from other multifocal relapsing CNS diseases, most notably mutliple sclerosis (MS), may be difficult [14]. Features such as optic neuropathy, subacute myelopathy and internuclear ophthalmoplegia are comm o n to both SLE and MS, as are CSF oligoclonal bands [22]. A t other times, it is difficult to decide whether neurological features in known SLE patients are due to active CNS lupus or secondary to other factors such as steroid therapy, uraemia or hypertension. U n e n h a n c e d M R I sometimes reveals multifocal white matter lesions in SLE essentially indistinguishable from those of MS [1, 16, 21], although, as demonstrated in this study and others [16, 19], the lesions often predominate in the subcortical white matter in SLE, whereas the periventricular regions are m o r e frequently involved in MS. In the present study the size and location of enhancing lesions in the SLE patients is not like that seen in

Fig. 2a-d. Case 1. Gd-DTPA

enhanced Tl-weighted MRI of the cervical cord, The first scan shows swelling on sagittal slices (a, b) from C4-T1, with enhancement confined to the posterior cord on both sagittal and axial (e) slices. The follow-up scan 1 week later shows resolution of swelling and enhancement (d) Fig. 3a, b. Case 2. a Unenhanced T2-weighted MRI; b Gd-DTPA enhanced Tl-weighted MRI. Note the large left parietal lesion, which displays extensive enhancement of its cortical component

463 Table 2. The measured T1 values of regions of the brain before and after administering Gd-DTPA

Patient no.

3 4 5 8 9 12 13 14 15

Corpus striatum

Caudate nucleus

White matter

Pre

Post

Pre

Post

Pre

Post

506 548 572 509 533 480 555 584 464

507 469 561 583 539 471 565 578 448

581 574 616 581 583 556 597 638 509

567 585 626 617 601 544 625 643 471

401 372 409 397 376 330 385 409 308

397 370 434 449 378 333 421 427 270

587 (53)

376 (35)

387.5 (56)

Prednisolone treated at time of MRI Yes Yes Yes

No No Yes Yes Yes Yes

Mean (standard deviation) 531 (44)

MS. In the latter, it would be unusual to find such a large enhancing lesion essentially confined to the cerebral cortex (small cortical enhancing lesions are not uncommon [17]), and while enhancing lesions occur in the spinal cord in MS, our experience and that of others [11, 15] suggest that they are generally smaller than the region affected in our SLE patient. Thus, G d - D T P A enhanced MRI may provide additional information to help differentiate CNS lupus from MS. Although G d - D T P A enhancement was seen in only 2 patients, in both cases the enhancing lesions were large, and were located in a site appropriate to the patients' active neurological symptoms. The rapid resolution of enhancement in conjunction with immunosuppressive treatment was also striking, although without controls one can not be sure that this evolution is different from the natural history of the untreated disease. Nevertheless, these cases suggest that in some patients, GdD T P A enhanced MRI provides an indication of disease activity in CNS lupus. What is the pathological basis of the enhancing CNS lesions in SLE? Post-mortem studies in the brain frequently identify small vessel vasculopathy and occasional vasculitis, with infarcts in both grey and white matter [6, 10]. The location and shape of the enhancing parietal lesion is consistent with a superficial infarct involving cortex and subcortical white matter, and the evident BBB breakdown is characteristic of recent infarction [9]. Post-mortem studies of the spinal cord have also identified vascular lesions along with inflammation and necrosis within the spinal cord, sometimes over many segments [10]. The cord enhancement could indicate an active inflammatory lesion secondary to an underlying vasculopathy with resultant BBB leakage. It is conceivable that the posterior spinal arteries were involved in the vasculopathy given the exclusively posterior location of the enhancement. The extensive swelling of the cord is probably due to vasogenic oedema, since it resolved rapidly with treatment. In one other case of lupus myelopathy, unenhanced MRI also revealed extensive swelling involving much of the cervical cord, with an equally

524 (51)

582 (36)

rapid resolution following immunosuppressive treatment [3]. The pathogenesis of CNS lupus is poorly understood. Some of the clinical manifestations undoubtedly result from cerebral infarction, which is probably due to multiple factors [5, 8], but such lesions do not appear to be the sole explanation. Thus clinical syndromes such as encephalopathy and chorea may occur without evidence of infarction or other structural abnormalities on CT or MRI, and these states may reverse spontaneously or with immunosuppressive therapy. One suggestion is that anti-neuronal antibodies may cause such syndromes [23]. Such antibodies have been found in the serum of SLE patients, and have also been associated with cognitive changes [12] and psychosis [2]. One possibility is that they enter the CNS via an abnormal BBB. We therefore obtained computer-generated images of T1 relaxation time before and after G d - D T P A administration to look for evidence of a subliminal BBB abnormality. In this study, there was no detectable BBB abnormality in the frontal white matter or basal ganglia. However, for several reasons, the result does not exclude the possibility of a defect ever occurring in SLE. Firstly, most patients did not have active CNS lupus at the time of the scan; it is possible that defects might be seen in a more active group. Secondly, most patients were on corticosteroids at the time of scanning - in other disorders, steroids are known to reverse BBB abnormalities [4, 13, 18]. Finally, in spite of an ongoing quality assurance program there were substantial changes in machine performance during the study period (6 months); measurements on test samples with relaxation times similar to grey and white matter varied by up to 30% during this period, so the marked inter-patient variations are not surprising. However, short-term reproducibility is likely to have been much better than this and pre- and postG d - D T P A measurements from the same patients usually showed only small differences. We therefore think that the results exclude a substantial BBB leak to G d - D T P A in the structures studied in these patients, but not a minor abnormality.

464

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Gadolinium-enhanced magnetic resonance imaging of the central nervous system in systemic lupus erythematosus.

Gadolinium (Gd)-DTPA enhanced magnetic resonance imaging (MRI) was performed in 15 systemic lupus erythematosus patients with past (12) or present (3)...
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