INTRODUCTION
Misinterpretation for several times before finally being diagnosed with Multiple Sclerosis (MS) is not uncommon, with true reverse: to be stamped by MS erroneously is widespread1. This is partly because there is no single diagnostic test to establish a definite MS diagnosis and partly because there are many diseases which manifest symptoms similar to MS2. Some are called MS varients3 who share MS the same pathophysiology but with different patterns. Others are termed MS mimics4 who share MS pattern but with totally different pathophysiology.
MS mimics include varieties of pathologies5-7. Hughes syndrome8 is one of the common MS mimics, where the most commonly cited scenario is to develop Deep Venous Thrombosis (DVT), history of abortion and positive laboratory testing for Lupus Anticoagulant (LA), Anticardiolipin (ACL) or Antiphospholipid (APL) antibodies. Central Nervous System (CNS) Angiitis (a synonym for vasculitis) that when confined to the brain and/or spinal cord is termed primary angiitis of the central nervous system (PACNS)9; usually manifest granulomatous inflammation affecting arterioles and small arteries of the cerebral parenchyma and/or
leptomeninges. The triad of headache, organic brain syndrome and multifocal neurologic deficits is most suggestive aided mildly by positive laboratory testing of antinuclear antibodies (ANA) and Antineutrophil Cytoplasmic antibodies (ANCA)10.
Visual Evoked Potential (VEP) has the capability to spot optic nerve delayed P100 absolute latency owing for demyelination and by the same time its decreased amplitude may occur in minute ischemia of the optic head11. Electroretinography (ERG) is a measure of the functional state of the retina and to define the pathophysiology of the lesion either neural or vascular is as sudden loss of vision can be attributed to either optic nerve demyelination12 versus tiny blood vessel ischaemia13. The auditory brainstem evoked potential response (ABR) provides a sensitive recording of the electrical events along the brainstem auditory pathway in response to external acoustic stimuli. It may confirm the presence of brainstem lesions in MS patients without clinical signs in addition to its prognostic value in disease progression14.
Conventional Magnetic Resonance Imaging (MRI) has a high MS lesion detection sensitivity but poor specificity thus can be “mimicked” in other diseases rather than MS15. New advents of MRI modalities tend to measure signal primarily from the macromolecular associated hydrogen nuclei via their magnetic interaction with the observable water as magnetization transfer imaging (MTI) and Diffusion Weighted Images (DWI), so may define existence of fluid content (hemosiderin deposition) of a lesion owing for vasculitis16.
The aim of this study is to attest new implements for differentiation between MS and MS mimics specifically vasculitis, urging a clear-cut of both for best management.
SUBJECTS AND METHODS
Subjects
Our study was case-control series; where thirty eight patients were included gathered from the inpatient and out-patient clinics, Neurology Departments; Kasr el Ainy Hospitals from November 2009 to May 2010. Included in this work: MS patients according to Modified McDonald criteria17; of either sex and ages between 15-50 years, with remitting relapsing course and maximum one year duration and Expanded Disability Status Scale (EDSS) 18 score not more than 4.5 (ambulant patient). Excluded from this work: Patients with history of stroke in young age and systemic diseases as diabetes and hypertension. Patient's privacy was maintained. Patients were classified into 2 groups:
- Group 1 (G1): 19 patients with Definite MS according to McDonald criteria with no better explanation for the disease serving as Control Group.
- Group 2 (G2): (Study Group) 19 patients having similar clinical and imaging picture of MS according to the same criteria, but can be attributed to another explanation rather than MS. These are termed MS mimics. These include those having long history of headache, DVT, miscarriage, seizures, aphasia; unusual neurological signs as preserved abdominal and flexor planter reflexes; Atypical MRI as: normal MRI, mass lesion, cortical grey matter, atypical white matter lesions that may be tiny, subcortical, symmetric and confluent, basal ganglionic involvement and extensive spinal lesions.
Methods
All patients and controls were subjected to the following:
1. Careful history taking and neurological examination for spotting past history of headache (any type) and DVT with insisting on soft neurological signs as abdominal and planter reflexes.
2. Visual Neurophysiologic Studies: A reporter Esaotebiomedica medical diagnostic equipment was used for obtaining VEP and ERG studies in the Neurophysiology Outpatient Clinic.
a. Visual Evoked Potential (VEP): A pattern reversal stimulus (with an alternating checkerboard stimulus and a rate of reversal (1 Hz) was used. Delayed P100 absolute latency favors the diagnosis of MS and decreased its amplitude favors the diagnosis of vasculitis.
b. Electroretinography (ERG): The waveforms were analyzed for: (a) and (b) wave latency, flicker response, oscillatory potentials and b/a ratio. Retinal vascular disease may show subnormality in the form of increasing (b) wave amplitude with dark adaptation, reduced rod function or disturbed (b/a ratio). In cases of optic nerve demyelination, (b-wave) is reduced and (b/a ratio) is also reduced with depression of ERGs mediated by the macular cones.
3. Auditory Brainstem Evoked Potential Response (ABR): Done in the Audiology Outpatient Clinic of the Otolaryngology Department, Kasr el Ainy Hospitals. ABR was recorded (using Biologic Navigator, EP 317) in response to rarefaction clicks with 21.1 repetition rate and 100-3000 Hz filter settings at intensity of 100 dBnHL. Delayed I-III or III-V interpeak latencies were considered positive for demyelination.
4. Laboratory tests to detect:
a. Any vascular risk factor to serve in exclusion criteria.
b. Antinuclear antibody (ANA), Anti Neutrophil Cytoplasmic Antibody (ANCA), Anti Cardiolipin (ACL) immunoglobulin (IgG) and (IgM) antibodies and Lupus Anticoagulant(LA).
5. MRI Brain (T1, T2, T2 MTI, FLAIR & DWIs) were done in the Radiology Department of Kasr-El-Ainy Hospital using 1.5 tesla (General Electric Medical System (Milwaukee). MRI picture for MS was as Modified McDonald criteria17. MRI picture of subcortical lesions that vary in the number, size, and location suggest vasculitis. The MTI tended to be lower in patients with multiple sclerosis, where the presence of a peripheral rim around the lesions of blood degradation products is used to define vasculitis.
Statistical Analysis
The statistical analysis was done using an IBM compatible computer. The data were analyzed using the data analysis tools in Microsoft Excel spread sheet Windows 7. Descriptive statistics were carried out using the median, minimum, maximum, mean and standard deviation for quantitative data and the frequency distribution for qualitative data. The qualitative data statistical differences and potential relations were assessed using Chi-Square test. P<0.05 is considered to be statistically significant.
RESULTS
Clinical results of the present study are demonstrated in Table (1): No statistical difference for mean age or mean EDSS scores indicating homogenous groups (P=0.4) and (P=0.3) respectively. G1 (Controls) included 6(31.57%) males and 13(68.42%) females, while G2 (Study) included 5(26.31%) males and 14(73.68%) females.
As regard positive history of abortion, aphasia, convulsion, each occurred once in 3 patients of the study group (G2). Table 2 shows full statistical analysis of results among our patients. A statistically significant difference was noticed for the presence of history of headache and DVT among the study group (G2) (P=0.03 and 0.001) respectively in comparison to control group (G1). On the other hand, a statistically significant (P=0.03) increase of percentage of patients having lost abdominal reflexes (94.73%) for (G1) in comparison to (31.57%) of (G2) was noted.
Moreover, a statistically significant difference was noticed between both groups for the positive detection of ACL (IgG and IgM) antibodies, LA, ANA and ANCA in the study group (G2) in comparison to the control group (G1).
As regard the neurophysiological workup; a decrease of amplitude of P100 VEP in (G2) was noticed but didn't reach a significant level with positive ERG results suggestive of vasculitis were found in the study group (G2) in comparison to control group (G1). VEP results also revealed a statistically significant (P=0.01) delay of P100 latency among (G1) in relation to (G2). Although our ABR results detecting demyelination suggestive of MS only were depicted in (26.31%) of (G1); yet, didn’t reach a significant level (P=0.4) between the two groups.
MTI and DWI MRI had a utility to unmask vasculitis only in (21.05%) of the study group (G2) which was statistically significant (P=0.04) between both groups. On the other hand, MTI and DWI MRI results suggestive of demyelination of MS were detected in (94.73%) of G1 (controls) as one of our controls had normal MRI.
Figure (1) shows: 1A: Axial FLAIR T2MRI showing multiple bright signals of a patient of the study group (G2). 1B: Axial MTI/ MRI for the same patient with peripheral rim around lesions suggesting vasculitis.
DISCUSSION
To reach the accurate diagnosis of MS out of its mimics is a stiff job due to close similarities. The demographic features of our cohort were similar to previous studies showed a female predominance. This can be credited to sex hormones in which testosterone protects against brain damage19 or variation of a gene that produces high levels of a protein called interferon gamma that can aggravate MS20. Furthermore, autoimmune diseases in general are more prevalent in women than in men, reaching 9:1 in lupus21. As well, a tendency of our both groups to affect similar ages was detected similar to previous reviewers22. In contrast to a previous study10 that revealed a wide age range from 3 years up to elderly ages to be the seat of vasculitis as well as slight male predominance (4:3). Yet, we cannot generalize this results on population due to the limited number of the included study sample as well as it was noted also in the control group.
Headache may coexist in MS patients in the form of migraine-like23 or cluster24 headaches more than in the general population. It could be attributed to lesions, depression or specific medications. On the other side, none specific chronic headache commonly patronize vasculitis25 by different etiologies: Hughes syndrome, primary angiitis of the CNS (PACNS), temporal arteritis, Reversible vasoconstriction syndrome, etc. In line of our study that revealed a high statistically significant incidence of headache in the study group (G2) in relation to MS group (G1). In the present study, we found a statistically significant difference for the presence of history suggestive of DVT among the MS mimic group (G2) against the controls (G1). DVT is considered as major criteria in the definite diagnosis of Hughes syndrome26.
In congruence to many studies27-29 that insisted the peculiar role of lost abdominal reflex early in MS, a statistically significant difference was perceived for increased affliction of such soft clinical sign in MS group (G1) (94.73%) in comparison to (52.63%) in MS mimic group (G2). Abdominal reflexes are formed by slowly conducting pathways reflecting the good integrity of corticospinal (pyramidal) tract. Pyramidal tract dysfunction allow for a release phenomenon owing for their loss in the absence of focal lesion affecting the local reflex arc27.
The same applies for the extensor planter reflex, as since one hundred years after its description, the Babinski sign remains a faithful and precise indicator of pyramidal tract dysfunction which maintains a suppressor action on the ‘flexion reflex’ synergy30. However, this was not statistically significant in the present study. Reversible (functional) pathophysiologic conditions as vasculitis result in, or produce, a transient extensor plantar response, where, structural lesions (demyelination) produce more lasting effects31.
Our study could depict a statistically significant difference of positive (ACL) antibodies and (LA) among (G2) indicative of vasculitis in relation to (G1). As a screening test for Hughes syndrome, ACL antibodies were positive in 80% of cases and LA is positive in 40%of cases32. This could be endorsed to the limited number of our study group (G2) as the main issue was to spot the MS mimic cases rather that to detect all cases of Hughes syndrome.
In addition, evaluation of ANA and ANCA in the present study revealed a statistically significant difference in specking positive vasculitis among MS mimics(G2) in comparison to controls (G1). As our criteria in the present study excluded patients with systemic lesions, so PACNS is taking place here. Going with other reviewers33 who reported cases with biopsy-proven PACNS with giant cells had positive ANA and ANCA uncovered active vasculitis.
VEP could have an opportunity in drawing dissimilarities between MS and vasculitis. Coinciding with other results34 that revealed statistically significant delayed P100 latency among MS patients, we found similar data in the present study. More important is the ability of VEP to detect decreased amplitude of P100 among MS mimics (G2) against controls (G1), yet, it was borderline statistically significant (P=0.05). This could be credited to be a sort of neuroretinitis as anterior ischemic optic neuropathy or retinal vein occlusion suggesting vasculitis35.
A growing interest in the use of retinal imaging for tracking disease progression is encountered now in multiple sclerosis and also to mark vasculitis. Our study revealed a statistically significant difference between both groups in ERG suggesting vasculitis over MS. Going with similar investigators who suggested that vasculitis may cause a lesion in the inner nuclear layer of the retina due to vessel pathology, in addition to rods lesions36. Retinal damage in MS is not due to loss of myelin as retina is devoted of myelin, but preferentially affects probably the glial cells of Müller and decreased number of cones37.
Selective spotting of pathology stamping the sensorineural system in the brainstem as demyelination in MS35 is peculiar for ABR. Thus previous studies stressed the importance of this test in examining patients clinically suspected for demyelinating disease, although it varies considerably38. A recent study reported that 36% of 25 patients with clinically diagnosed MS had positive brainstem alterations in ABR test39. In contrast to our study that did not reveal statistical difference among both groups considering ABR testing. This can be attributed to our selective inclusion criteria to be early diagnosed patients before being afflicted by numerous attacks.
Our study showed a statistically significant difference (P=0.04) between both groups of altered MTI and DWI suggestive of active small vessel disease in MS mimic group (G2) in comparison to controls. MTI and DWI are considered a new promising sensitive tool for detecting diffuse microscopic brain damage in grey and white matter in cerebral vasculitis, being based on the association between the presence of autoantibodies and cerebral damage40.
Conclusion
The puzzlement in diagnosing MS versus its mimic (vasculitis) is not simple as petite dissimilarities are always coexisting. Vasculitis is not an easy diagnosis as it may need a long latency to be picked. The coalition between clinical data as history of headache and previous thrombosis with preserved abdominal reflex examination; positive specific laboratory autoantibodies testing; decreased amplitude of P100 by VEP and increased (b) wave on dark adaptation by ERG may direct the attention to vasculitis rather than MS. The conjoint use of novel MRI techniques may elaborate suggestion of vasculitis to take place and be managed accordingly. Although it is not uncommon, the presence of ABR subtle changes may draw attention for more MS weight rather than vasculitis.
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