These 6 diseases may be misdiagnosed as "primary central nervous system vasculitis". How much do you know?

Primary central nervous system vasculitis (PACNS) is a unique inflammatory vascular disease of the central nervous system (brain, spinal cord and meninges).
Due to the lack of specific biomarkers, clinical diagnosis is difficult, and it is difficult to distinguish from other diseases on imaging.
, It is mainly diagnosed by excluding other diseases.

This article will focus on PACNS and his mimickers.

This article is published by Yimaitong authorized by the author, please do not reprint without authorization.

 01 PACNSPACNS is a rare autoimmune disease with unknown etiology, mostly in the small and medium blood vessels of the central nervous system.

Localized narrowing or occlusion of blood vessels leads to tissue ischemia and even necrosis.

There are three main pathological types of PACNS: granulomatous vasculitis (the most common), lymphocytic vasculitis, and necrotizing vasculitis.

The annual incidence rate of PACNS is 2.
4 per million, and the proportion of men is slightly higher, and it is more common in 60-year-old people.

Acute manifestations of PACNS usually include ischemic or hemorrhagic stroke, leading to new focal neurological deficits such as ataxia, aphasia, sensory changes, paresis or paralysis.

The most common symptoms are occult headache and confusion.
Other non-specific manifestations include fever, nausea, Parkinson's disease, or myelopathy.

PACNS examinations include blood tests, head MRI, lumbar puncture (LP), digital subtraction angiography (DSA) and biopsy.

Although there is no specific blood test for PACNS, the selected test is mainly used to exclude mimickers from PACNS.

In PACNS, since the inflammatory response is limited to the central nervous system, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are usually in the normal range.

Head MRI is the most sensitive detection method for PACNS, but it is still not specific.

However, domestic scholars included 18 cases of PACNS in the study [1] showed that bilateral lesions are more common than unilateral lesions; the most commonly affected site is the frontal lobe, followed by the parietal and occipital lobe; the subcortical white matter is often affected, while the basal ganglia and meninges And spinal cord are not common.

Because PACNS usually involves small and medium blood vessels, DSA usually shows "beading"-like changes, and occasionally an aneurysm is found.

Vascular wall magnetic resonance imaging (VW-MRI) is helpful in the diagnosis of PACNS.
VW-MRI is characterized by smoothness and centripetal enhancement and thickening of the involved arteries (Figure 1).

LP is common with increased cerebrospinal fluid cells and increased protein.

The gold standard diagnosis of PACNS is brain biopsy.

However, the sensitivity of biopsy is only 50%, which is limited by the plaque nature of the disease and the biopsy technique.

 Figure 1 Data A and B of a PACNS patient: T1 axial (A) and sagittal (B) show the enhancement of the right middle cerebral artery vascular wall in the sylvian fissure (arrow).

Image source: Best Pract Res Clin Rheumatol.
2020 Aug;34(4):101569[2] Regarding the diagnosis of PACNS, Calbrese and Malle proposed simple criteria: ➤ The clinical manifestations of acquired neurological deficits are still unusable after comprehensive evaluation Other etiological explanations; ➤ Typical angiography (beaded changes) or histopathological findings of PACNS; ➤ No evidence of systemic vasculitis.

Although these criteria are simple, in practice, diagnosis is still a challenge due to the poor sensitivity of DSA and biopsy.

To this end, a study [3] summarized 24 case series studies and concluded: ➤ Main clinical features (≥42.
7%): headache, stroke, cognitive impairment and focal neurological deficit; ➤ Secondary clinical features ( <42.
7%): epileptic seizures, changes in the level of consciousness, mental disorders; ➤ main imaging features (≥46.
6%): multiple parenchymal lesions, parenchymal or meningeal enhancement, vascular abnormalities (single or multiple stenosis/occlusion), and vessel wall enhancement ; ➤ Secondary imaging features (<46.
6%): substantial or subarachnoid hemorrhage, single parenchymal lesion.

If the patient has: 1 clinical feature (primary or secondary) and one main imaging feature, or two clinical features (at least one of the main feature) and one secondary imaging feature, which cannot be explained by other causes, then it should be Initially suspected PACN.

The treatment of PACNS includes high-dose corticosteroids (methylprednisolone 1 g intravenously for 5 days, then prednisone 1 mg/kg/d for at least 4 weeks, and then slowly reduce the dose) and cyclophosphamide (15 mg/ kg, once every 2 weeks, a total of 3 times; the next every 3 weeks, a total of 3 times).

Various immunosuppressive agents including mycophenolate mofetil, azathioprine and rituximab have been used to maintain remission.

 02 RCVS reversible cerebral vasoconstriction syndrome (RCVS) is a reversible, non-inflammatory, self-limiting CNS arterial disease, which leads to multifocal segmental cerebral vasoconstriction, followed by normal arteries or diastolic blood vessels.

The incidence of RCVS is currently unclear, but it is estimated to be much higher than that of PACNS.
The average age of onset is 40 years old, and the proportion of women is higher than that of men.

The acute stage of RCVS manifests as severe sudden headache, called lightning headache, with or without other neurological symptoms, including paresis, sensory changes, vision changes, or aphasia.

Ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage, seizures and even death are rare.

The pathophysiology of RCVS is still unclear, and it may be related to changes in the tension of the arterial vascular wall, which may cause localized wave contraction of blood vessels.

The histopathology of RCVS is non-specific, without inflammatory lesions.

RCVS often occurs due to various triggers, including drugs, hypertension, drug use, and postpartum states; possible drugs include selective serotonin reuptake inhibitors (such as paroxetine), cough suppressants or ergotamine, cocaine, marijuana, and safety Phetamine and its derivatives and illegal drugs such as ecstasy; other less common triggers include emotional stress, recent surgery, intercourse, bathing, and high altitude areas; some patients may also have no triggers.

For RCVS, head CT should be performed first to rule out subarachnoid hemorrhage or other causes that may cause sudden changes in neurological status.

DSA can be used to find the typical manifestations of RCVS: segmental and multifocal vasoconstriction and cerebral artery dilation (Figure 2A).

CTA and MRA can often identify the type of disease and make a diagnosis under non-invasive and low-risk conditions.

MRI is essential for the evaluation of RCVS, but as many as one-third of RCVS patients can have normal MRI findings.
Abnormal findings include "spots" on the FLAIR sequence, appearing in the sulci space, which may be caused by slowing cerebral blood flow.
Cause, or the infarct area caused by RCVS (Figure 2B).

LP is essential for the diagnosis of RCVS.
One is to help rule out occult subarachnoid hemorrhage with negative head CT, and the other is to help evaluate other possible causes of vascular disease, such as PACNS.

Generally speaking, the CSF of RCVS patients is normal or mildly abnormal (mildly elevated total protein).

Figure 2 Data of a RCVS patient A: DSA shows multifocal arterial irregularities; B: FLAIR sequence shows "dot" sign.

Picture source: Best Pract Res Clin Rheumatol.
2020 Aug;34(4):101569.
A study [4] compares RCVS and PACNS: both headaches are common, but the onset of RCVS headaches is sudden, usually lightning-like headaches.
PACNS has an insidious onset, and headaches are dull in nature and accompanied by neurological deficits; focal dysfunctions such as hemiplegia and aphasia are more common in PACNS, while Balint syndrome and cortical visual symptoms are common in RCVS; RCVS The patient may have normal neuroimaging findings, while the brain scan of PACNS patients is basically abnormal when they are admitted to the hospital; the infarction in RCVS is located in the superficial junction or watershed area, usually does not involve the cortex, and rarely involves deep structures, while PACNS patients have Disseminated small infarcts and microangiopathic white matter changes are consistent with diffuse involvement of distal arteries.

A recent study [5] proposed the RCVS2 scoring system (Table 1) for the diagnosis of RCVS.
The specificity of RCVS diagnosis with score ≥5 is 99%, and the sensitivity is 90%; the specificity of score ≤2 to exclude RCVS is 100% , The sensitivity is 85%; the specificity of the diagnosis of RCVS with a score of 3–4 is 86%, and the sensitivity is 10%.

Table 1 RCVS2 scoring system Note: vasoconstriction predisposing factors: drugs, postpartum, orgasm Regarding the treatment of RCV, there is still a lack of evidence from randomized controlled trials, which is mainly based on expert opinions.

Some experts recommend supportive treatment and relaxed blood pressure management, because most patients will recover on their own, and a drop or rise in blood pressure may bring about the risk of ischemia or reperfusion injury.

Other experts recommend oral calcium channel blockers such as nimodipine and verapamil as first-line drugs.

Glucocorticoids are usually used empirically when PACNS is suspected, but they may aggravate RCVS and usually need to be avoided.

 03 Sneddon syndrome Sneddon syndrome includes lively reticularis and ischemic stroke or transient ischemic attack.
The disease is a rare vascular disease with an annual incidence of 4 per 1 million people, the most common in 20-42 For young women, the ratio of male to female is 1:5.

The underlying cause of Sneddon syndrome is not yet clear.
Autoimmunity may be one of the mechanisms.
Autoimmunity causes endothelial dysfunction, which ultimately leads to small and medium blood vessel congestion and thrombosis.

The disease is related to antiphospholipid antibody syndrome, systemic lupus erythematosus, valvular disease and genetic susceptibility.
About 50%-80% of patients are also positive for antiphospholipid antibodies.

The diagnosis of Sneddon syndrome is mainly based on the simultaneous occurrence of skin disease and stroke history (Figure 3).

Laboratory tests should include screening for antiphospholipid antibodies, systemic lupus erythematosus, and other causes of hypercoagulability.

MRI shows infarcts in the acute phase, and abnormal signal changes on T2/FLAIR in the chronic phase, usually located in the deep white matter and pons around the ventricle.

DSA found typical vascular lesions in 75% of Sneddon syndrome cases, the most common being occlusive non-inflammatory arterial lesions, accompanied by intracranial vascular stenosis and/or occlusion.

Skin pathology shows that the proliferation of intimal endothelial cells and the proliferation of smooth muscle cells in the middle layer lead to the formation of subcutaneous arterioles, and the compensatory expansion of capillaries leads to impaired blood flow, leading to lively reticularis.

Patients with Sneddon syndrome usually do not need a brain biopsy, but when a brain biopsy is performed, the most prominent findings include non-specific vascular disease, thickening of the intima of small and medium blood vessels, and arterial thrombosis without inflammatory lesions.

Treatment options for Sneddon syndrome include antiplatelet therapy or anticoagulation therapy.

There are also studies using immunosuppressive agents for treatment, but the effects are different; and hypertension and hormone exposure are related to disease progression.

 Figure 3 Data of a patient with Sneddon syndrome.
A: skin reticularis (asterisk); B: skin biopsy showing extensive thrombosis in capillaries; scale bar 100μm; C: FLAIR/T2 MRI showing multiple ischemic lesions ( White arrow) and cortex atrophy (red arrow).

Image courtesy of Orphanet J Rare Dis.
2014 Dec 31;9:215.
04 ABRA Cerebral amyloid angiopathy (CAA) is a non-inflammatory disease that deposits β-amyloid protein in the middle of the brain, arterioles and pial vessels Caused by the epimuscular membrane and the media.

The deposition of beta amyloid protein causes blood vessels to become fragile and easy to bleed.

Almost all CAA patients have subclinical parenchymal and subarachnoid microhemorrhage.

The immune response to amyloid deposits leads to inflammatory reactions in or around blood vessels, which are called β-amyloid-associated vasculitis (ABRA) and CAA-associated inflammation, respectively.

ABRA is a vascular destructive disease, accompanied by transmural inflammation, and granulomas are often seen in pathological examination.

The incidence of ABRA is unclear.
The ratio of men to women is equal.
Most ABRA patients are ≥50 years old, and half of PACNS patients appear before this age.

.

The most common manifestations of ABRA include behavioral changes and subacute cognitive decline, especially hallucinations.
Other common manifestations include focal weakness, sensory changes, seizures, headaches, ataxia, or aphasia.

Because the spinal cord blood vessels are free from β-amyloid deposition, ABRA generally has no symptoms of myelopathy.
If it occurs, PACNS should be considered.

MRI is particularly important for ABRA.
Common MRI manifestations include asymmetric T2 hyperintensity extending to the paracortical area.
Studies have shown that the posterior circulation is more likely to be involved, but studies have also shown that the frontal lobe is more common.
The enhancement sequence shows characteristic pial enhancement.
It reflects the involvement of small blood vessels in the pia mater; susceptibility weighted imaging shows micro hemorrhage (Figure 4) and even cerebral lobe hemorrhage.

Other tests include serum inflammatory markers, such as erythrocyte sedimentation rate and CRP, which are occasionally elevated.

Cerebrospinal fluid has elevated protein and mild cell increase.

The oligoclonal band has nothing to do with ABRA.

The important thing is that DSA is usually normal.

The diagnosis of ABRA is usually confirmed after histopathological examination confirms transmural inflammation and persistent β-amyloid protein in the vessel wall (Figure 5).

Figure 4 Data of an ABRA patient A: FLAIR shows no inhibition of T2 in the left frontal groove; B: T1 enhancement shows the corresponding focal pial enhancement in the same area.

C: SWI shows multifocal magnetic sensitivity artifacts (blooming artifact).

Picture source: Best Pract Res Clin Rheumatol.
2020 Aug;34(4):101569.
Figure 5 Data of a PACNS and an ABRA patient And erythrocyte extravasation, but no β-amyloid deposits; B: The brain MRI of patients with ABRA showed T2 hyperintensity lesions.
Pathological examination showed lymphocytes and granulomas infiltrated blood vessels, fibrinoid necrosis, and β-amyloid deposits.

Image source Stroke, 2015 Sep;46(9):e210-3.
The treatment of ABRA is based on expert opinions and usually refers to the treatment plan of PACNS.

Most patients receive high-dose corticosteroids (methylprednisolone 1 g intravenously for 5 days, then 1 mg/kg/d prednisone, and the dose is gradually reduced within 4-8 weeks).

In severe cases, cyclophosphamide is sometimes used.

Compared with PACNS, some patients with ABRA have a uniphasic course and only need to take high-dose corticosteroids for a short period of time.

 05 Susac syndrome Susac syndrome is a rare vascular disease that affects the small arteries of the brain, inner ear and retina, leading to ischemic stroke, hearing loss and vision loss.

The disease is more common in women (3.
5:1), aged between 30-40 years old.

The clinical manifestation of Susac syndrome is the result of occlusion of small blood vessels in diseased tissues, but the mechanism of vascular occlusion is not clear, and it is likely to be an autoimmune process.

Common neurological symptoms of Susac syndrome include cognitive impairment, headache, confusion, mood disorders, behavioral changes, and apathy.

In the early stage of the disease, the patient usually does not have a complete triad of symptoms, and usually occurs at 21 weeks of the course of the disease.

The typical MRI manifestations of the acute phase of Susac syndrome are "snowball lesions" of the corpus callosum (Figure 6).
Other MRI manifestations include ischemic stroke, manifesting as a small area of ​​diffusion limitation and pia mater enhancement; chronic MRI manifestations include small T1 hypointensity lesions, atrophy and thinning of the corpus callosum.

Retinal fluorescein angiography for ophthalmic examinations usually shows branch retinal artery occlusion (BRAO) and high fluorescence in the vessel wall.

Hearing examination revealed sensorineural hearing loss.

Lumbar puncture is not necessary, but it is usually used to rule out other causes; the CSF of Susac syndrome is usually non-specific, usually manifested as elevated protein, and sometimes slightly elevated cells (about 12 white blood cells on average), rarely oligoclonal band.

Figure 6 Data A and B of a patient with Susac syndrome: MRI FLAIR sequence axial (A) and sagittal (B) images show high signal "snowball"-like lesions in the corpus callosum.

Picture source: Best Pract Res Clin Rheumatol.
2020 Aug;34(4):101569.
A study [6] compares 13 cases of Susac syndrome with 15 cases of PACNS: Susac syndrome patients with cognitive impairment, ataxia and hearing Disorders are more common than PACNS; seizures are more common in PACNS patients.

The involvement of the corpus callosum (CC) is more common in Susac syndrome.
Among 13 patients with Susac syndrome, 13 have CC knee abnormalities, while only 2 of 15 PACNS patients have CC knee abnormalities (p<0.
001); among 13 patients with Susac syndrome There were 13 cases of CC body involvement, and 1 case of CC body involvement in 15 cases of PACNS patients (p<0.
001); cortical lesions, hemorrhage and basal ganglia infarction were more common in PACNS patients.

But in general, there is no formal standard for the diagnosis of Susac syndrome, which is mainly based on the triad and excluding other causes.

The treatment of Susac syndrome is based on expert opinion, similar to PACNS, with high-dose corticosteroids with or without cyclophosphamide (or rituximab).

06 CADASIL with subcortical infarction and leukoencephalopathy with autosomal dominant cerebral artery disease (CADASIL) is an autosomal dominant inheritance model that leads to non-inflammatory vascular disease.
The incidence is equal between men and women.
It is most common in European Caucasian families.

CADASIL is caused by a mutation of the chromosome 19p13 gene to cause a defect in the NOTCH3 protein, which causes the dysfunction of the transmembrane receptor in the blood vessel, which causes the accumulation of particles and osmophilic substances and Notch3 itself on the smooth muscle wall of the blood vessel.

Although it exists in blood vessels throughout the body, it mainly affects small cerebral arteries (arterial disease).

Patients usually present with migraine, which is most common in 60-year-olds, and ischemic stroke may also occur; other manifestations include cognitive changes, dementia, personality changes, and depression.

The typical imaging manifestations of CADASIL are white matter T2-weighted/FLAIR sequence hyperintensity changes, diffusion-weighted imaging shows subcortical infarction, and susceptibility-weighted imaging shows cerebral microhemorrhage.

The most commonly affected areas are the periventricular area, the anterior temporal pole, the outer capsule, and the frontal and parietal areas (Figure 7).

The severity of MRI changes is directly related to the severity of symptoms, and MRI changes usually occur 10 years and 15 years before clinical symptoms appear.

 Figure 7 Data of a CADASIL patient.
AC: Head MRI FLAIR sequence shows T2 hyperintensity changes in the anterior temporal lobe (A), outer capsule (B), and periventricular white matter (C).

Picture source: Best Pract Res Clin Rheumatol.
2020 Aug;34(4):101569.
For patients with high clinical and MRI suspicion of CADASIL, regardless of whether there is a typical family history, the initial confirmation test is usually genetic screening or skin biopsy for NOTCH3 Mutation immunohistochemical staining; brain biopsy is usually not required and is not recommended (Figure 8).

Figure 8 Data of a 47-year-old CADASIL patient A: MRI of the head showed multiple chronic subcortical lesions on both sides, and an acute ischemic lesion in the right internal capsule.

B: DSA shows segmental stenosis of multiple peripheral arterial branches in the bilateral anterior cerebral artery (ACA), middle cerebral artery (MCA), and posterior cerebral artery.

Skin biopsy and genetic testing confirmed CADASIL.

Image source Arch Neurol.
2002 Sep;59(9):1480-3.
CADASIL has no specific treatment, except for the typical secondary prevention of stroke, there is no special treatment, mainly antiplatelet therapy and reduction of cardiovascular risk factors.
Such as high blood pressure, cholesterol, smoking and diabetes.

 07 Neurosarcoidosis Sarcoidosis is a systemic inflammatory non-granulomatous disease that usually affects the lymphatic system and lungs.
It is seen in people aged 30-50, with a slightly higher proportion of women.

The pathophysiology and etiology of sarcoidosis are unclear, but at least part of it is an autoimmune disease, which is also closely related to genetic predisposition and certain environmental exposures (including infectiousness and toxicity).

When sarcoidosis affects the nervous system, it is called neurosarcoidosis.

Neurosarcoidosis causes central and peripheral neuropathy, including cranial nerve palsy, vascular disease, headache, neuroendocrine dysfunction, hydrocephalus, neuropsychiatric symptoms, epilepsy, myelopathy, neuropathy, or myopathy.

Stroke in the form of ischemic or hemorrhagic disease or cerebral venous thrombosis is relatively rare.

But in patients with known sarcoidosis or young patients with few or no vascular risk factors, neurosarcoidosis should be considered a factor in stroke.

The vast majority of patients with sarcoidosis involving cerebral blood vessels have other symptoms of active neurosarcoidosis, especially meningopathies.

Although clinical stroke is a rare manifestation of neurosarcoidosis, in autopsy studies, most patients with neurosarcoidosis are known to have microvascular involvement in the central nervous system, and related inflammatory processes can penetrate the endothelial cell wall.

Most commonly, granulomatous inflammation of the adventitia causes compression of the lumen, resulting in arterial occlusion and infarction (Figure 9A).

Head MRI is the most sensitive examination method for neurosarcoidosis.
It can show various manifestations of neurosarcoidosis, including pial enhancement, dural enhancement, tumor-like lesions, inflammatory changes involving cranial nerves, and non-specific periventricular white matter changes Or ischemic stroke.

Because neurosarcoidosis tends to affect the capillaries, angiography is usually normal, but it may sometimes show irregularities in the lumen (Figure 9B).

Figure 9 Data of a patient with neurosarcoidosis.
A: DWI axial image shows acute left temporal infarction; B: DSA shows multifocal arterial stenosis.

Image source Best Pract Res Clin Rheumatol.
2020 Aug;34(4):101569.
Recent studies have shown that perivascular enhancement and magnetic sensitivity artifacts (involving the periventricular vein structure, but the deep nuclei are not involved) are neurosarcoidosis Features (Figure 10).

Figure 10 Data A and B of a 14-year-old male patient with neurosarcoidosis: SWI sequence shows that the subcortical periphery mostly diverges in magnetic sensitivity artifacts, while the deep gray matter nuclei are not involved.

Image source Clin Radiol 2018;73(10):907.
e15e23.
LP is often non-specific inflammatory manifestations, including increased protein, increased cells, oligoclonal bands, hypoglycemia and increased IgG index.

Compared with PACNS, the cerebrospinal fluid of patients with neurosarcoidosis is more prone to obvious cell increase and hypoglycemia.

Angiotensin-converting enzyme (ACE) has low sensitivity and specificity and is of little value in diagnosis.

The diagnosis of neurosarcoidosis is mainly based on the pathological results of biopsy.

However, since PACNS and neurosarcoidosis are both related to granulomatous inflammation, efforts should be made to find evidence of sarcoidosis outside the nervous system to help distinguish the two.

The treatment of neurosarcoidosis is mainly based on expert opinions, and corticosteroids are generally the initial treatment.

Recent studies have reported the use of infliximab for refractory or severe neurosarcoidosis.

08 Summary PACNS is a life-threatening disease that requires rapid identification and treatment.

Due to the lack of sensitive and specific biomarkers, a clear diagnosis is still challenging.

Understanding the mimickers of the above-mentioned PACNS is helpful for clinical diagnosis of PACNS.

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