Demyelination in rheumatic diseases

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterised by multifocal areas of demyelination in the white matter of the brain and spinal cord. Autoantibodies, for example antinuclear antibodies, can also be present. MS and other demyelinating processes, such as transverse myelitis and optic neuritis (which may be clinically isolated cases or be part of the clinical spectrum of MS), are sometimes difficult to differentiate from CNS involvement in systemic autoimmune diseases like systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), Sjoegren's syndrome (SS), and Adamantiades‐Behcet disease (BD). An acute isolated neurological syndrome presents the biggest diagnostic problem, since it is common in MS, but can also be the only feature or first manifestation in SLE, APS, SS, and BD. Indeed, the clinical presentation and lesions evidenced by magnetic resonance imaging may be similar.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) and is characterised by multifocal areas of demyelination in the white matter of the brain and spinal cord, and axonal loss. The cause of MS is unknown, although viral infections and autoimmune processes have been implicated. There is no specific marker of disease and diagnosis is based on a constellation of clinical and laboratory criteria. MS can only be diagnosed when there is objective evidence of central neurological dysfunction with more than one affected area and more than one episode (other explanations excluded). In many cases, accurate diagnosis can be made after long‐term follow up.

An acute isolated neurological syndrome poses the biggest diagnostic problem, since it is the most common symptom in MS but can also be the only feature or first manifestation in antiphospholipid syndrome (APS)/systemic lupus erythematosus (SLE),¹ Adamantiades‐Behcet disease (BD), or Sjoegren's syndrome (SS), before other features of these diseases, such as thrombosis and/or miscarriages for APS, systemic manifestations for SLE, and mouth ulcers and uveitis for BD, appear. Autoantibodies, for example antinuclear antibodies (ANA), can also occur in MS. Hence a significant number of patients with demyelinating features in the course of APS, SLE, or other systemic autoimmune diseases (SID) may be given the false label of MS.¹,²,³,⁴,⁵ This can sometimes be catastrophic as the treatment for the supposed MS may exacerbate SLE (that is, interferon‐β) and of course may be expensive and ineffective.

Other demyelinating processes, such as transverse myelitis (TM) and optic neuritis, may be part of the clinical spectrum of MS or may be isolated syndromes. Optic neuritis usually presents as acute or subacute unilateral eye pain, accentuated by ocular movements and followed by scotomas mainly of the central vision. TM is an acute inflammatory process affecting a focal area of the spinal cord and characterised clinically by acutely or subacutely developing symptoms and signs of neurological dysfunction in motor, sensory, and autonomic nerves and nerve tracts of the spinal cord. TM may be secondary to viral diseases, vaccinations, acute disseminated encephalomyelitis, MS, vascular insults, SLE, spinal arteriovenous malformations, and APS. TM is a monophasic disease and when recurrent raises the possibility of SLE, MS, and APS.³

TM and optic neuritis (as clinically isolated cases) and MS are sometimes difficult to differentiate from CNS involvement in SID such as SLE, APS, SS, and BD. Indeed, the clinical presentation and the lesions evidenced by magnetic resonance imaging (MRI) may be similar. There is no specific diagnostic test for demyelinating diseases, but the most useful are MRI, CSF examination (total leucocyte count and cell type, albumin determination, serological testing for Borrelia burgdorferi and other antimicrobial Abs, IgG index, and CSF immunoelectrophoresis), visual evoked potentials (VEP), and autoantibody serology.¹,⁶,⁷ The CSF is grossly abnormal in MS. Total leucocyte count is normal in two thirds of patients, exceeds 15 cells/μl in 5%, and only rarely exceeds 50 cells/μl (a finding that should raise suspicion of another aetiology). Lymphocytes are the predominant cell type, the vast majority of which are T cells. CSF protein (or albumin) level is usually normal. Albumin determinations are preferable, since albumin is not synthesised in the CNS and therefore gives a better indication of a blood‐brain barrier disruption than does total protein, some of which may be synthesised in the CNS (for example, immunoglobulin). A common finding in MS is elevation of the CSF immunoglobulin level relative to other protein components, suggesting intrathecal synthesis. The immunoglobulin increase is predominantly IgG, although the synthesis of IgM and IgA is also increased. IgG shows an excess of IgG λ and κ light chains. Abnormal CSF IgG production as measured by the IgG index or IgG synthesis rate is found in 90% of clinically definite MS patients.⁷

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with protean manifestations. Neuropsychiatric manifestations are present in up to 60% of patients with SLE. Demyelinating syndrome and myelopathy are two of the 19 recently defined syndromes in neuropsychiatric SLE.⁸

Lupoid sclerosis is a term that has been used to describe a clinical condition in which SLE presents with widespread neurological signs and symptoms suggestive of MS.⁹

McDonald et al published revised MS diagnostic criteria, but did not provide guidelines to distinguish MS from other SID including definite SLE/CNS disease. The most common neurological manifestations of SLE (headaches, seizures), symptoms suggestive of peripheral nervous system involvement and psychiatric disorders, are not seen in MS.¹ MRI is the most important diagnostic tool and the MRI criteria from Barkhof et al¹⁰ offer the best combination of specificity and sensitivity for MS. The morphology of the lesions is important: the absence of multifocal lesions on brain MRI has a good negative predictive value for later development of MS.¹¹ Small multifocal demyelinating lesions may be produced by MS and by small strokes, as can also happen in SLE and APS, and can be clinically silent.¹,¹⁰,¹² Elongated ovoid shaped lesions (“Dawson's fingers”) and “black holes” are more characteristic of MS yet are not pathognomonic.¹¹,¹³ Lesion distribution can also be helpful since subcortical lesions predominate in APS and SLE and periventricular and especially corpus callosum lesions are more common in MS.²,⁵,¹¹ The absence of oligoclonal bands in CSF makes a diagnosis of MS unlikely.⁶,¹⁴ VEP are particularly helpful when MRI abnormalities are few or have less specificity.⁶ Normal VEP are unusual in MS.¹,⁶ In several studies,¹⁵ ANA were found in MS patients at a frequency of 2.5–81%, although no correlation between the presence of ANA and symptoms of SLE was established in most of these studies. Despite these results, when ANA titres are high and persistent, and appear in the context of other autoimmune abnormalities, a diagnosis of SID should be considered.¹

SLE associated TM has become an established clinical entity since the initial series of nine patients were described in the literature in 1968.¹⁶ TM, a demyelinating disease of the spinal cord involving its entire thickness, is very uncommon (1.34/million). SLE is one of the rarest causes of TM, while TM is a rare but serious neuropsychiatric manifestation of SLE (1–2%),¹⁷ with uncertain pathophysiology. Pathophysiological mechanisms suggested in SLE associated TM are vasculitis and arterial thrombosis. The arterial thrombosis hypothesis, the several reports indicative of a significant association of TM‐SLE and MS, and the presence and association of antiphospholipid antibodies (aPL) with MS are described in several studies.¹⁸,¹⁹,²⁰,²¹,²²,²³ Concerning the onset TM compared to that of SLE, after an analysis of published cases by Kovacs et al¹⁷ determined that TM was the initial manifestation of SLE in 39% and presented in the first 5 years of SLE in 42% of the total cases analysed. As many authors suggest, all patients with TM should be examined for SLE and/or APS by history, clinical examination, and the occurrence of aPL in the blood.¹⁸,²⁴ SLE should be suspected in every case of TM with aPL and the patient followed prospectively for several years in case features of SLE develop.²⁴

MRI findings in SLE myelopathy are T1 and T2 signal abnormalities and widening of the cord.²⁵ MRI lesions in SLE myelopathy are longer than those in most cases of MS and similar to those in Devic's syndrome. They may extend over the entire length of the spinal cord.¹⁹,²⁵,²⁶ Peripheral nervous system involvement, which is absent in MS but sometimes present in SLE and APS, can be investigated by neurographic recording and electromyography.

Outcome is poor¹⁷,²⁶,²⁷,²⁸ and not related to disease activity. It has been postulated that starting aggressive treatment early in the course of TM is important to achieve a favourable outcome.²⁹,³⁰,³¹ Treatments reported in the early and late literature,¹⁷ but not yet confirmed in trials, are iv methylprednisolone (MP), iv MP plus iv cyclophosphamide (CP), and iv MP plus iv CP plus plasmapheresis, with all treatment regimens followed by tapering doses of oral prednisolone.

Optic neuritis is associated with TM in patients with SLE¹⁷,²³,³²,³³ and was first described by Devic in 1894. Devic's neuromyelitis optica is a CNS disease in which visual involvement (retrobulbar optic neuritis or oedematous papilitis) is associated with longitudinal TM rather than TM of subacute onset; diagnostic criteria have been proposed by Wingerchuk et al.³⁴ It has been distinguished from MS³² on the basis of several characteristics (progress more severe, no fever at onset, cerebral and cerebellar lesions absent on MRI, no oligoclonal bands on CSF electrophoresis, and no albumin elevation in CSF).³⁴ The best diagnostic tool is MRI.³²,³⁴ Devic's syndrome pathophysiology is small vessel vasculitis and white matter demyelination and necrosis.³²,³⁵ The myelopathy of Devic's syndrome extends over two or more vertebrae and is characterised histologically by necrosis and cavitation. The course of this syndrome is monophasic, relapsing, or chronic,³⁵ and prognosis is often unfavourable. Various treatment regimens have been described in the literature³²: iv CP and/or pulsed iv MP, and a combination of oral prednisone and azathioprine and/or plasmapheresis.

Autoimmune optic neuropathy (AON) was first reported by Dutton in 1982. Frequently patients do not develop a defined collagen disease. AON is a well known complication of SLE, is estimated to occur in 1% of such patients, and appears to be often associated with CNS disease, particularly of the spinal cord.³⁶,³⁷ In SLE, visual field loss may precede the reduction in visual acuity. VEP can also be employed in these patients to detect optic nerve damage before it can be demonstrated by visual field examination.³³ The pathogenesis is still unclear: is it due to vasculitis or to thrombosis? According to the review by Giorgi and Balacco Gabrieli,³³ three major criteria can be used to decide which pathogenic mechanism is involved: the first criterion is the monolateral occurrence of optic neuropathy, which is a focal neurological disease, and seems to be more frequent in SLE patients with aPL and clinical manifestations of APS; another criterion is improvement of the optic nerve disease after treatment with immunosuppressive drugs; and finally, the third criterion is association of the optic neuropathy with general CNS disease, which seems to be the main neurological disease seen in SLE patients and to which vasculitis may contribute.

Antiphospholipid syndrome

The interface between MS and antiphospholipid syndrome (APS) is of importance in two common clinical settings: patients clinically diagnosed with MS who are found to have significantly high levels of aPL, and patients clinically diagnosed with APS who are found to have subcortical white matter lesions on imaging studies (table 1).

Table 1 Differential diagnosis between APS, SLE, and MS.

	PAPS APS	NPLE/APS SLE	MS
Clinical
Thrombosis
Miscarriages/pregnancy morbidity
Headaches	May be present	May be present	Absent
Livedo reticularis
Thrombocytopenia	May be present	May be present	Absent
Raynaud's phenomenon
Photosensitivity
Rash	Absent	Usually present	Absent
Arthritis/arthralgia
Sicca syndrome
PNS involvement	May be present	May be present	Absent
Optic neuritis	Unilateral, abrupt onset	Usually bilateral	May be bilateral
Laboratory
aPL	100%	50–60%	±(2–44%)
ANA	Usually negative	98%	±(2.5–25%) low titre
Anti‐DNA	Usually negative	60%	Usually negative
CSF oligoclonal bands	Usually negative	15–50%	98%
MRI
Brain MRI	High‐signal lesions	High‐signal lesions	High‐signal lesions
	Subcortical	Subcortical	Periventricular, corpus callosum, brainstem
	Static (may improve after anticoagulation)	Static	Dynamic
Spinal MRI	>4 segments in length	>4 segments in length	<2 segments; only part of cross section
	Thoracic region more common	Thoracic region more common	Cervical region more common
	Cord swelling and atrophy	Cord swelling and atrophy	No cord swelling
VEP	Normal or reduced wave	Normal or delayed conduction	Delayed conduction but well preserved
	amplitude		wave form

Adopted and modified from Ferreira et al.¹

PNS, peripheral nervous system; VEP, visual evoked potentials.

Some patients with APS may have more complex manifestations than a stroke, such as sensory and motor dysfunction, optic neuritis, and TM. MRI studies in these patients frequently show multiple T2 hyperintense brain lesions. This combination – relapsing/remitting multifocal neurological symptoms plus the MRI findings – may closely resemble MS. The prevalence of aPL in MS patients is 4.8–44% of sera according to various studies,⁴,⁵,¹⁴,¹⁵,³⁸,³⁹ with a higher frequency in MS patients with TM and optic neuritis. Although aPL are common in MS patients, these antibodies are usually not depended from the presence of serum factors for binding to phospholipids. Karussis et al and other authors¹⁴ found an association of aPL in MS with specific clinical features of chronic, slowly progressive myelopathy and optic neuropathy, and concluded that patients with a probable or definite diagnosis of MS and consistently elevated level of anticardiolipin antibodies (aCL) show a slower progression, while Roussel et al¹⁵ failed to demonstrate clinical correlates. The pathogenic role of aCL in MS is unknown. The mechanisms by which aPL may induce an MS‐like illness may be microvascular thrombotic events, vasculopathy, an autoimmune vasculitis similar to that seen in SLE, and molecular mimicry with myelin or other CNS antigens (cephalin, sphingomyelin).¹⁴,⁴⁰,⁴¹ Generally, the CNS is a system at particular risk in patients with APS, possibly because the CNS coagulation system has clear differences from those of other organs: the brain endothelium expresses little thrombomodulin compared to other tissues and aPLs may have direct antineuronal activity.⁵ Some studies appear to refute the association between APS and MS‐like disease.⁴⁰,⁴¹ The editorial by Ruiz‐Irastoza and Khamashta² reviews the most important series of patients with positive association of MS and aPL. As no single test can discriminate between ischaemic (secondary to APS) and inflammatory (secondary to MS) white matter lesions, every patient with MS should be routinely tested for aCL, IgG and IgM, and lupus anticoagulant (LA),² even though some authors⁴² say only MS patients suspected of APS should be evaluated for these antigens. The absence of oligoclonal bands in the CSF should be regarded as evidence against a diagnosis of classic MS,¹⁴ although their presence does not necessarily exclude APS.⁴,¹⁴,³⁸,³⁹ Experienced authors in the field say that MRI lesions seen in association with APS are usually static on repeat MRI compared with the dynamic nature of lesions seen in MS.¹ The application of single photon computed emission tomography has been studied in patients with APS where it can show focal low‐perfusion areas that improve with anticoagulation.⁴ According to a paper by Rovaris et al,¹² magnetisation transfer imaging combined with standard MRI can discriminate MS from APS (but not from SLE).

Based on a positive response to warfarin in case series,⁴,⁵,³⁸,³⁹ Ruiz‐Irastoza and Khamashta² recommended that a trial with anticoagulation therapy should be offered to US patients who are consistently positive for aPL (aCL and IgG and/or IgM at medium to high levels and/or LA) and in particular to those who have atypical forms of the disease (abnormal localisation of lesions, normal brain MRI, epilepsy, unusual progression, absence of oligoclonal bands in CSF, dementia, isolated neurological syndrome), livedo reticularis, previous thrombosis, migraine, obstetric complications, thrombocytopenia, and/or lupus. This trial of anticoagulation with a target INR of 3–4, should last 6 months, and the patient should receive careful counselling of the risks involved.¹

TM is a rare (0.4%) manifestation of APS, either primary or secondary to SLE.⁴³,⁴⁴,⁴⁵,⁴⁶ The association of TM and APS is not well established and the exact mechanisms are not clearly known. It is not yet clear if aPLs have a pathogenic role in TM. Vascular changes and ischaemic necrosis caused by immune complex mediated vasculitis or vascular thrombosis is a proposed mechanism, while another suggestion is that aPL may interaction directly with spinal cord phospholipids.¹⁸,⁴⁷ All patients with TM should be examined for SLE and/or APS by history, clinical examination, and the occurrence of aPL in the blood.¹⁸,²⁴ SLE must be suspected in every case of TM with aPL and such patients must be followed prospectively for several years in case features of SLE develop.²⁴

The management of these patients is not well established. In recent years, pulses of MP in combination with immunosuppressive drugs, such as CP or plasmapheresis, have been used.⁴⁴,⁴⁵,⁴⁶,⁴⁷ Other therapies include anticoagulation.³¹,⁴⁴,⁴⁶

AON was first associated with aCL in Kupersmith's series⁴⁸ and confirmed by several other reports,⁴⁹,⁵⁰ without demonstration of full blown APS in the vast majority of patients.

Optic neuropathy is a rare manifestation (1%) in the Euro‐Phospholipid Project cohort of 1000 European APS patients (primary and secondary).⁴³

Primary Sjoegren's syndrome

Sjoegren's syndrome (SS) is a chronic autoimmune exocrinopathy, which in addition to the two characteristic symptoms of dry eyes and dry mouth, may have extraglandular manifestations in various organs. SS is often unrecognised even though it is probably the most common SID. While most SS patients have positive antibodies (ANA, anti‐Ro, anti‐La, RF), the absence of antibodies does not exclude a diagnosis of SS.

Between 20 and 25% of SS patients have been reported have to CNS manifestations,¹³,⁵¹ but this is a matter of debate as some studies report a negative association.⁵²,⁵³,⁵⁴,⁵⁵,⁵⁶ MS and TM are rare events in SS patients and the relationship between SS and MS is ambiguous since SS may mimic MS both clinically and radiologically.⁵⁷,⁵⁸,⁵⁹,⁶⁰ Neurological manifestations often precede SS diagnosis at a time when immunological abnormalities are frequently lacking, although xerostomia or xerophthalmia may be present.⁶¹ In fact, many patients have been thought to have MS before a diagnosis of SS was made.⁶⁰,⁶¹ In these patients there may be changes in the CSF profile (oligoclonal banding patterns of immunoglobulin) similar to those in MS, but with the difference that MS patients most commonly have multiple bands, whereas SS patients have only one or two bands.⁶⁰

Anti‐Ro antibodies can be detected in 2–15% of MS patients.⁵⁵,⁶⁰,⁶² Some authors suggest that these antibodies represent cross‐reactivity of antibodies against myelin or viral antigens with Ro/‐SSA molecules and other autoantigens.⁵⁶ Even though anti‐Ro, ANA, anti‐dsDNA, and aCL are positive in patients with definite MS, these patients should be re‐evaluated for SID treatable with maintenance immunosuppression.

TM has been reported in patients with SS¹³,⁵⁷,⁵⁸,⁵⁹,⁶⁰,⁶³,⁶⁴,⁶⁵,⁶⁶,⁶⁷ and in four patients with primary biliary cirrhosis and SS.⁶⁸,⁶⁹,⁷⁰,⁷¹ Possible aetiologies for TM in SS patients are vasculitis,⁶⁰,⁶³,⁶⁷,⁶⁸ immunological injury of spinal vessels and/or spinal cord driven by reactive T cells, and/or the presence of antineuronal antibodies.⁶⁸,⁶⁹ Patients respond to treatment with high doses of MP and pulses of CP or chlorambucil.⁶³,⁷²

Even though the prevalence of myelopathy in SS is rather low (<1%), it should be considered when the patient first presents with TM and the following procedure followed: a) the patient should be queried about symptoms of SS; b) elevated ESR, positive ANA, a paucity of periventricular white matter lesions, and the presence of marked cord swelling on MRI (unusual in TM) should be considered; c) anti‐Ro and anti‐La tests ordered; and d) matched oligoclonal bands in the plasma and cerebrospinal fluid noted.⁶³

Optic neuropathy has been described in some patients with primary SS.¹³,⁶⁰,⁶⁵,⁶⁶ In some of these patients neurological signs occurred before or at the same time as the diagnosis of SS.⁶⁰,⁶⁴ Symptoms of dry eyes and mouth may be mild or even absent. Thus early primary SS should be considered in any patient with unexplained optic neuropathy and serological abnormalities suggestive of a connective tissue disorder, particularly when criteria for a diagnosis of SLE or other SID are absent.⁶⁴

Adamantiades‐Behcet disease

Adamantiades‐Behcet disease (BD) is an inflammatory multisystem disorder of unknown cause involving arteries and veins and characterised by uveitis, erythema nodosum, skin lesions, and recurrent oral and genital ulcers. The CNS is affected in 10–49% of patients, and MRI findings and clinical course may mimic MS.⁷³ Some neuro‐BD patients have multiple hemispherical white matter lesions⁷⁴,⁷⁵ and lesions in the spinal cord may be demonstrable if MRI is performed close to attack onset. In the later stages of the disease, atrophy of the brain stem (without cortical atrophy) is almost inevitable, which is more suggestive of neuro‐BD than of MS.⁷⁴,⁷⁵ Patients with BD and CNS involvement have a serum and CSF cytokine and chemokine profile that differs from that of other autoimmune disorders such as MS. There is evidence for lower Th1 related cytokine activity in neuro‐BD and a pattern resembling non‐specific inflammation such as following neuro‐infection, suggesting that a currently unknown infection might be involved in the vasculitic pathology in the CNS.⁷⁶ CSF in neuro‐BD may be normal or pathological. The IgG index is usually elevated and sometimes oligoclonal bands may be demonstrated. Reversibility of these bands, which is not the case in MS, has also been reported.⁷⁴ Moreover, the course of MS is more polyphasic, while that of neuro‐Behcet is more progressive.⁷⁷ In MS, optic neuritis, acute TM, and internuclear ophthalmoplegia are common, whereas in neuro‐BD the main neurological manifestation is progressive pseudobulbar palsy.⁷⁷,⁷⁸

Ocular pathology in BD is well recognised to mirror CNS pathology; foci of necrosis and perivascular demyelination with inflammatory cell infiltrate of lymphocytes can occur and there may well be an association between ischaemic demyelination of the optic nerve and the CNS.

A neurological manifestation in a patient fulfilling BD criteria usually does not cause diagnostic dilemmas. However, confusion emerges when a patient presents with an isolated neurological attack preceding the onset of BD. In this case exclusion of MS may not be possible until the extra‐neurological manifestations of BD appear.

Neuro‐BD should be suspected⁷⁴ if a young male presents with or without symptoms of BD, with predominantly motor/mental rather than sensor clinical symptoms, with more prominent PMN than LYM cells in the CSF, and an MRI showing lesions extending from the brain stem to basal ganglia. Azathioprine with prednisone may be more effective in the long term for optic nerve and CNS involvement than cyclosporine with prednisone.⁷⁸

Conclusions

In conclusion, every patient with demyelinating events should be queried as to symptoms of SID. If there are such symptoms or if there are atypical forms of MS, a full autoantibodies investigation should be carried out and the patient followed up for several years (even if the autoantibodies are negative in the first investigation) as the possibility of SID occurring is high.

Abbreviations

aCL - anticardiolipin antibodies

ANA - antinuclear antibodies

AON - autoimmune optic neuropathy

aPL - antiphospholipid antibodies

APS - antiphospholipid syndrome

BD - Adamantiades‐Behcet disease

CNS - central nervous system

CP - cyclophosphamide

LA - Lupus anticoagulant

MP - methylprednisolone

MRI - magnetic resonance imaging

MS - multiple sclerosis

NPLE - neuropsychiatric, lupus erythematosis

PAPS - primary antiphospholipid syndrome

SID - systemic autoimmune diseases

SLE - systemic lupus erythematosus

SS - Sjoegren's syndrome

TM - transverse myelitis

VEP - visual evoked potentials