Recidivující ischemická mozková příhoda při systémové skleróze – kazuistika
U systémové sklerózy (SSc) je primární postižení centrální nervové soustavy vzácné. Předkládáme případ 55letého Číňana s SSc, který trpí přetrvávající slabostí levé končetiny doprovázenou deviací bulbů doprava a dysartrií. Zobrazení mozku magnetickou rezonancí (MR) potvrdilo ischemické léze v oblasti pravé arteria cerebri media (MCA). MRA prokázala závažnou stenózu v části M1 pravé MCA. Přes každodenní užívání prednizonu a antitrombocytárních léků orálně došlo u pacienta k další ischemické mozkové příhodě o pouhý rok později doprovázené paralýzou pohledu doprava a afázií. Opakované MR mozku ukázalo akutní ischemické léze vedle levé postranní komory a postischemické léze v pravé hemisféře. MRA ukázala závažnou stenózu v části M1 pravé MCA, oboustranně. Jsme přesvědčeni, že tato progresivní cerebrální angiopatie a recidivující ischemická mozková příhoda byly způsobeny autoimunitním mechanizmem souvisejícím s SSc.
P. Lu; P. Xia; X. Hu
Authors place of work:
Department of Neurology, Sir Run Run Shaw Hospital and Institute of Clinical Medicine of Zhejiang University, Hangzhou, China
Published in the journal:
Cesk Slov Neurol N 2009; 72/105(6): 566-569
Primary involvement of the central nervous system is rare in systemic sclerosis (SSc). We present a case of 55‑year‑ old Chinese man with SSc suffering from persistent weakness of the upper left limb, accompanied by eyes gazing to right and dysarthria. Brain magnetic resonance imaging (MRI) confirmed ischemic lesions in right middle cerebral artery (MCA) territory. MRA reported a severe stenosis in the M1 portion of the right MCA. Despite oral prednisone and antiplatelet drugs daily, the patient suffered another ischemic stroke only one year later, presenting with gaze paralysis to the right and aphasia. Another brain MRI revealed acute ischemic lesions next to the left lateral ventricle and postischemic lesions in the right hemisphere. MRA showed severe stenosis in the M1 portion of MCA bilaterally. We believe that the progressive cerebral angiopathy and recurrent ischemic stroke were caused by an autoimmune mechanism related to SSc.
Key words: systemic sclerosis – ischemic stroke – central nervous system
sclerosis (SSc) is an autoimmune disorder that may affect many organs of the
body. The skin, lungs, kidneys, gastrointestinal tract and the myocardium are
the most likely to be involved. The pathogenesis is still not well understood.
Studies have hypothesized that vascular abnormalities, immune changes,
collagen proliferation and heredity may be related factors leading to systemic
manifestations . The central nervous system is rarely involved in SSc unless
there are abnormalities in renal or lung function, or hypertension. Primary
neurological dysfunction is still much less common in SSc than in other
connective tissue diseases. To date, only a few cases have been reported
and in Asia it has only been reported in Japan. The exact incidence and
prevalence of nervous system dysfunction in SSc is unknown. In one large
series, 6 out of 727 patients with SSc had clinical involvement of
the nervous system . Neurological manifestations of SSc reported came mostly
in the form of stroke, TIA, seizure, cognitive impairment, spinal cord disorder
and peripheral nerve disease. We describe a 55‑year‑old
man with SSc who suffered from recurrent ischemic stroke in the absence of
other vascular risk factors (apart from hyperhomocysteinemia) and complications
secondary to SSc such as malignant hypertension, uraemia or marked pulmonary
2003, a 51‑year-old,
right-handed man developed numbness of both hands
and Raynaud’s phenomenon. Over time, skin thickening, oedema and pigmentation
were noted, including both hands, arms, the trunk and face. A diagnosis of
SSc was made based on the above symptoms when he was 52. Skin biopsy in the
back and dorsum of the right hand showed features of SSc with pigmentation,
oedema of the epidermis, collagen hyperplasia and mild inflammatory cell
infiltration. He was treated with 15mg
oral prednisone daily. In 2005, he suffered from mild dysphagia. In 2006, he
suffered from mild weakness of the left upper limb, accompanied by eyes gazing
to the right and dysarthria. The symptoms persisted. Five days later the
symptoms were steadily progressing so he was admitted to a teaching
hospital not far from ours. His magnetic resonance imaging (MRI) and diffusion
weighted imaging (DWI) showed high signal intensity in right middle cerebral
artery (MCA) territory. Intracranial magnetic resonance angiography (MRA)
reported a severe stenosis in the M1 portion of the right MCA (Fig
1). He then received ozagrel for antiplatelet therapy. The weakness in the left
limb was partially relieved. Home therapy comprised 100mg
aspirin and 15mg oral prednisone
In 2007, he was admitted to our hospital,
presenting with a 3‑day
history of gaze paralysis to the right and aphasia. There was no history of
chronic cough, dyspnoea, hypertension, or diabetes. He had smoked for thirty
years, about 15 cigarettes a day, but had given up for nearly two
years following his first stroke. On admission, temperature was 38.6°C; blood
pressure was 140/80 mmHg; pulse
and respiration were normal. There was a marked tightening and
pigmentation of the skin with sclerosis of all the fingers, the palm and the
back. The patient was alert. He suffered from Broca aphasia and partial
Wernicke aphasia, and could not respond appropriately to our verbal stimuli. We
found that the pupils were at 3mm and reacted
to light but the eyes always gazed left. There was a mild left paresis and
contracture of the left upper limb, but this was a residue of the previous
stroke. Deep tendon reflexes were symmetrically normal. The Babinski sign on
the left was doubtful and no other pathological reflexes were observed.
Cerebellar and sensory functions could not be tested effectively because of
aphasia. MRI of the brain on the third day showed acute ischemic lesions next
to the left lateral ventricle in the FLAIR images and DWI examination. It also
showed postischemic lesions in the right hemisphere in FLAIR images (Fig 2a,
b). Intracranial MRA showed severe stenosis in the M1 portion of MCA
bilaterally and the distal branches could not be seen clearly (Fig 2c). He
immediately received 200mg aspirin.
A laboratory examination was performed later. White blood cell (WBC) was
8,800/ul with an increase in neutrophils.
Erythrocyte sedimentation rate was 11mm/h.
ANA, Scl‑70, RNP, anti‑centromere
antibody (ACA), RF, p‑ANCA
and c‑ANCA were all
negative. RPR and TPPA were normal. Mean 24‑h
urinary protein excretion was 153mg
and creatinine clearance rate (CCR) was normal. Serum chemistry revealed only
hyperhomocysteinemia, at a level of 28.7 umol/l.
Chest X‑ray showed an accentuated texture and did not
provide evidence of pulmonary fibrosis. Epiaortic and carotid duplex ultrasound
was normal and transthoracic echocardiography reported mild reflux of the
mitral, the tricuspid valve and the aortic valve, along with a mild
pericardial effusion. Considering the inefficacy of aspirin, the maintenance
therapy was changed to 75mg oral clopidogrel
daily, while the 15mg oral prednisone
every day continued for the SSc. The patient could was able to say some simple
words before discharge.
In February 2008, he reported progressive
dizziness, and brain CT scan revealed chronic spontaneous subdural haematoma in
the right hemisphere. He recovered after burr‑hole
craniostomy. From then on, antiplatelet therapy was stopped, but not the
corticosteroids. As far as we know he remains in a similar condition as
has a worldwide distribution and is more frequent in women than men.
Systemic sclerosis is characterized by three distinct pathological processes:
fibrosis, cellular/humoral autoimmunity
and specific vascular changes. Although a mild vasculitis may sometimes be
present, the vascular pathology of the scleroderma is not necessarily
inflammatory and is best characterized as a vasculopathy . It includes
a spectrum of changes that predominantly involve the microcirculation and
arterioles. The pathological changes in the blood vessels adversely influence
the physiology of many organs, with a reduction in the size of
microvascular beds that leads to a decreased blood flow and ultimately to
chronic ischemia . Macrovascular involvement was once considered rare, but
an increased prevalence of macrovascular disease has also been reported [5,6].
The nervous system, the brain in particular, is rarely involved in SSc. When
this does occur, it is generally a consequence of malignant hypertension
and uremia. To our knowledge, only scattered case reports with primary
neurological involvement have been described in the radiological literature.
Some of our angiographic findings were inconsistent with those of typical
cerebral vasculitis. The latter is characterized by a more diffuse
elongation, tortuosity and irregularity of multiple intracranial vessels. Thus
we believe our patient’s angiopathy was not a consequence of
a primary central nervous arteritis.
We present a rare case of a male
patient suffering from SSc and complicated cerebral infarction. The patient was
diagnosed with SSc, in terms of the 1980 American College of Rheumatology
(ACR) preliminary criteria for the classification of SSc. His ischemic
cerebral infarction could be documented by its clinical manifestation and MRI.
Our patient had no history of other obvious vascular risks apart from smoking
and hyperhomocysteinemia. Although he had smoked for a long time; he had
given up after the first stroke. Hyperhomocysteinemia is an independent
vascular risk; it leads to atherosclerosis of large arteries, such as the
carotid artery. Since the epiaortic, carotid duplex ultrasound and the
transthoracic echocardiography documented no abnormality, we inferred that
hyperhomocysteinemia was not the main risk factor. Intracranial MRA in our
hospital documented severe stenosis of MCA bilaterally, which showed his
neurological deficit had deteriorated compared to MRA in 2006. Further, he
experienced a recurrent stroke in 2007. On this basis, we considered the
progressive MCA stenosis was caused by an SSc autoimmune angiopathy. Our
reasoning ran: he had no other traditional risk factors, as described above;
there was no obvious family history of stroke. There was no evidence of
atherosclerosis. Using the TTE, we were unable to disclose embolic sources.
Interestingly, we noticed that our patient’s clinical manifestation was not as
severe as in patients with a similar ischemic lesion. We attributed it to
relatively good microvascular compensation, because the angiopathy of SSc had
SSc is still considered incurable, although
clinical outcomes have improved considerably, presumably due to better
management of the complications. No therapy to date has been able to reverse or
slow down the progression of tissue fibrosis or substantially modify the
natural progression of the disease . Nevertheless, studies have suggested
that treatment of pulmonary fibrosis in SSc with low‑dose
prednisolone and intravenous cyclophosphamide stabilize lung function in
a subset of patients with the disease [8,9]. Takehara K  reported
the usefulness of low‑dose oral
corticosteroid treatment for early diffuse cutaneous SSc in Japanese patients.
Until now, only scattered cases have shown good response to high‑dose
corticosteroid treatment in patients with neurological involvement within the
acute stage, but there are no large sample trials. Our patient suffered from
recurrent ischemic cerebral infarction and repeated intracranial MRA showed MCA
stenosis deteriorating despite daily oral prednisone and antiplatelet drug
therapy. Currently, targeted therapy at the cellular and molecular mechanisms
underlying the fibrotic process are being highlighted in the treatment of SSc.
Clinical success with medications targeted on logical profibrotic mediators,
such as connective tissue growth factor and transforming growth factor‑ β,
has been reported, but studies are ongoing .
Furthermore, the data have shown that SSc is
much more severe and carries worse prognosis than localized scleroderma (LS),
in which the cerebral vasculature is only partially involved. In conclusion,
a better understanding of the pathogenesis of SSc would facilitate
tailoring of the therapy and more precise evaluation of prognosis.
Hu, M.D. Department of
Neurology Sir Run Run
Shaw Hospital School of
Medicine, Zhejiang University 3# Qingchun
Zhejiang 310016 China e-mail: email@example.com
review: 16. 2. 2009 Accepted for publication: 21. 8. 2009
1. MaoSong Zhou YY. The progress of study on pathogenesis and mechanism of scleroderma. Medical Recapitulate 2008; 14: 88– 89.
2. Tuffanelli DL, Winkelmann RK. Systemic scleroderma. A clinical study of 727 cases. Arch Dermatol 1961; 84: 359– 371.
3. Fleming JN, Schwartz SM. The pathology of scleroderma vascular disease. Rheum Dis Clin North Am 2008; 34(1): 41– 55.
4. Kahaleh B. Vascular disease in scleroderma: mechanisms of vascular injury. Rheum Dis Clin North Am 2008; 34(1): 57– 71.
5. Hettema ME, Bootsma H, Kallenberg CG. Macrovascular disease and atherosclerosis in SSc. Rheumatology (Oxford) 2008; 47(5): 578– 583.
6. Youssef P, Englert H, Bertouch J. Large vessel occlusive disease associated with CREST syndrome and scleroderma. Ann Rheum Dis 1993; 52(6): 464– 466.
7. Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest 2007; 117(3): 557– 567.
8. Mouthon L, Berezné A, Brauner M, Kambouchner M, Guillevin L, Valeyre D. Interstitial lung disease in systemic sclerosis. Presse Med 2006; 35(12 Pt 2): 1943– 1951.
9. Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS et al. A multicenter, prospective, randomized, double‑blind, placebo- controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum 2006; 54(12): 3962– 3970.
10. Takehara K. Treatment of early diffuse cutaneous systemic sclerosis patients in Japan by low‑dose corticosteroids for skin involvement. Clin Exp Rheumatol 2004; 33 (Suppl 3): S87– S89.
11. Denton CP. Therapeutic targets in systemic sclerosis. Arthritis Res Ther 2007; 9 (Suppl 2): S6.