J Neurol (2014) 261:98–105 DOI 10.1007/s00415-013-7166-x
ORIGINAL COMMUNICATION
Differential diagnoses to MS: experiences from an optic neuritis clinic Henrik Horwitz • Tina Friis • Signe Modvig • Hanne Roed • Anna Tsakiri • Bjarne Laursen Jette Lautrup Frederiksen
•
Received: 7 May 2013 / Revised: 14 October 2013 / Accepted: 15 October 2013 / Published online: 25 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Optic neuritis (ON) is closely linked to multiple sclerosis (MS). It may, however, also be associated to a range of autoimmune or infectious diseases. The purpose of this study was to assess the differential diagnoses in patients with suspected ON. In this retrospective study, we reviewed the files of all patients referred to the Clinic of Optic Neuritis, Glostrup Hospital, University of Copenhagen, Denmark, between January 2000 and November 2011. All patients were referred by ophthalmologists with possible ON. Patients diagnosed with MS prior to referral were excluded from the study. A total of 643 patients were included in the study. Apart from ON, the most frequent diagnoses were tumors (n = 15), ischemic or hypertensive neuropathies (n = 13), and retinal or choroid disorders (n = 9). Six patients were diagnosed with neuromyelitis optica. Rarer causes of visual loss were infections (n = 5), giant cell arteritis (n = 4), sarcoidosis (n = 3), thyrotoxicosis (n = 2), and hereditary or toxic neuropathies (n = 2).
Nine percent of patients referred to the Clinic of Optic Neuritis had symptoms caused by medical, neurosurgical or ophthalmic disorders, and 0.9 % of our patients had NMO. Though most of these conditions are rare, it is of importance to keep them in mind upon encountering patients with symptoms of ON.
H. Horwitz (&) S. Modvig Clinic of Optic Neuritis, Glostrup Hospital, University of Copenhagen, 2600Glostrup, Copenhagen, Denmark e-mail:
[email protected]
A. Tsakiri J. L. Frederiksen Department of Neurology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark e-mail:
[email protected]
S. Modvig e-mail:
[email protected]
J. L. Frederiksen e-mail:
[email protected]
H. Horwitz Pile Alle 5b st. tv., 2000 Frederiksberg, Denmark
B. Laursen Statens Institut for Folkesundhed, University of Southern Denmark, Odense, Denmark e-mail:
[email protected]
T. Friis Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark e-mail:
[email protected] H. Roed Department of Ophthalmology, Næstved Sygehus, Naestved, Denmark e-mail:
[email protected]
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Keywords Optic neuritis Differential diagnoses Neuromyelitis optica Multiple sclerosis
Introduction The incidence of optic neuritis (ON) is around 5 per 100,000 person-years in Western countries [28]. ON is characterized by an sub-acute decrease in visual acuity along with dyschromatopsia and peri- or retrobulbar pain accentuated by eye movement. Visual loss gradually
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recovers within weeks to months [13]. ON is closely linked to multiple sclerosis (MS) [1]. MS-related cases comprise roughly half of the total number of ON [1]. Most of the remaining cases are idiopathic [1, 13]. However, a broad range of conditions can give rise to or mimic ON. Infectious and systemic diseases have been reported to cause ON, and ON has been linked to sarcoidosis [6], systemic lupus erythematosus [11], Sjo¨gren’s syndrome [23] and inflammatory bowel disease [9], as well as syphilis [3], HIV [19], Lyme0 s disease [5], cat scratch disease [12] and various other infectious and inflammatory conditions [8, 13]. ON can also be a symptom of neuromyelitis optica (NMO). Since 2004, there has been an increasing focus on NMO, a severe, demyelinating disorder of the central nervous system, predominantly affecting the optic nerves and spinal cord, and may lead to paralysis and blindness [36]. Lennon et al. [22] found that most of these patients have antibodies directed towards the water channel aquaporin 4 (AQP4), which are now part of the NMO diagnostic criteria. Through the analysis of AQP-4-abs, it has been possible to broaden the NMO spectrum to include certain patients with recurrent or bilateral ON [37]. Data from a large European multicenter study suggest that 6 % of patients with monosymptomatic ON are positive for AQP4 antibodies [17]. In addition to this, ischemic neuropathies, Leber0 s hereditary optic neuropathy (LHON), retinal disorders, meningiomas and pituitary tumors may initially mimic ON [13]. The aim of this study was to assess the differential diagnoses in patients referred on suspicion of ON.
Materials and methods Referral population In this retrospective study we thoroughly reviewed files of all patients consecutively referred to the Clinic of Optic Neuritis, Glostrup hospital, University of Copenhagen, Denmark, from January 1, 2000, to November 1, 2011. The clinic offers a fast-track diagnostic program of ON for all patients in Eastern Denmark an area with a population of 2.9 million. All patients were referred by ophthalmologists with possible ON. Only patients who were not diagnosed with MS prior to referral were included in the study. In total 643 patients were included. Average age was 35.6 (SD 10.2) years and 71 % were female. Diagnostic workup All patients underwent a clinical and neurological examination, including standardized assessment of the pupillary
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response and fundoscopy, along with tests of visual acuity, contrast- and colour vision and autoperimetry. Blood analyses were performed including red and white blood cell counts, c-reactive protein (CRP), sedimentation rate (ESR), vitamin B12, thyroid stimulating hormone (TSH), ANA autoantibody- and syphilis-screening. Furthermore, patients underwent VEP, MRI of the brain and a lumbar puncture. On indication and in cases of poor visual recovery, patients were tested for angiotensin converting enzyme, homocysteine, methylmalonic acid, folic acid, HIV-, borrelia-ANCA and AQP4 antibodies, as well as the three most common LHON mutations [40]. Registries and follow-up The national registry of patients has collected discharge diagnoses from all public and private hospitals in Denmark since 1977. Since 1994, the registry has used diagnoses as coded in the ICD-10. Information was obtained from medical records and patients were followed up through the National Registry of Patients in the period from 1994 to 2011. We searched for the following main diagnoses in all patients : Lupus, Becterew, Sjo¨gren syndrome, Behcet0 s, vasculitis [giant cell arteritis, granulomatosis with polyangiitis (Wegener’s granulomatosis), Churg–Strauss] (DM30-35 and DM45), NMO (DG36.0), colitis ulcerosa and Crohn0 s disease (DK50-51), sarcoidosis (DD86 and DG532), syphilis (DA52-53), HIV (B20-24), bartonella (A28.1 and A44.9), borreliosis (A69.2), cobalamin or folic acid deficiencies (D52-53 and E53) and ocular disorders (DH30, DH32, DH35-35 and DH47). For NMO the search period was extended until July 2012. Furthermore, our database was merged with the Danish MS Register, the Danish Multiple Sclerosis Treatment Register and the Danish Leber0 s Register. Subsequently, all diagnoses were validated. Patients were classified as MS-patients if they were diagnosed with MS or treated with immunomodulatory drugs for clinically isolated syndrome. NMO was diagnosed on the basis of the 2006 Wingerchuk criteria (ON and simultaneous transverse myelitis) [36, 38]. Aquaporin-4 antibodies AQP4-Ab analysis was only available in the second half of the inclusion period, and by August 2012, 163 patients had been tested for AQP4-Ab. For AQP4-Ab analysis, three different methods were used. Initially, serum samples (n = 44) were tested for AQP4-Ab using a radioimmunoprecipitation assay (RIPA) with a sensitivity of 62.8 % and a specificity of 98.3 % [25]. This method was first replaced by a fluorescence-based immunoprecipitation assay (FIPA)
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Table 1 Paraclinical findings Number examined
Proportion
Age
643
35.6 (SD 10.2)
Female
643
70.8 %
VEP abnormal
639
81.5 %
Oligoclonal bands
553
59.5 %
MRI abnormalities
621
70.0 %
Aquporin-4 AB
163
0.6 %
with a sensitivity of 76 % and a specificity of 100 % [34] (n = 78) and finally replaced by indirect immunofluorescence on AQP4 transfected HEK cells from Euroimmun with a sensitivity of 78 % and a specificity of 100 % [18] (n = 104). A total of 48 samples had been analyzed by more than one method. Statistics were applied for the normal and binomial distribution, calculating confidence intervals using the Fig. 1 Differential diagnoses. Upper left: LETM-NMO see arrowhead. Upper right: l large meningioma compressing the optic nerve. Lower left: thyroidassociated orbitopathy. Lower right: large sarcoma compressing the optic nerve (metastasis)
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Clopper–Pearson exact method, because of small proportions. Ethics the study was approved by the Danish Data Protection Agency and the National Board of Health. Because of the retrospective nature of the study, ethics approval was not required.
Results During this 12-year period, 643 patients with no previous diagnosis of MS were referred to the Clinic of Optic Neuritis in Copenhagen, Denmark. Of the patients, 71 % were female and the average age was 35.6 years (range 15–63). A total number of 25 patients (4 %) had bilateral symptoms. In 639 patients (99.4 %) a VEP was obtained and in 81.5 % of these VEP was pathological; 621 patients underwent MRI of the brain, which revealed some kind of
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abnormality in 70 % of the cases. In 553 patients, a lumbar puncture was performed and oligoclonal bands were detected in 59.5 % (Table 1). We were able to follow all patients through the Danish registries, and median time of follow-up was 5.7 years (range 0.7–12.5 years). By the end of follow-up, three patients were deceased and all deaths were cancer related. Patients with a normal VEP had a better prognosis with regard to progression to MS than patients with a pathological VEP, and follow-up time between the two groups was comparable (P = 0.16). Thus, 7.6 % of patients with a normal VEP had been diagnosed with MS or treated with immunomodulatory drugs for this disorder, as opposed to 52.8 % of patients with a pathological VEP (P \ 0.0001). Diagnoses other than MS were made in 16.9 % of patients with a normal VEP and in 7.7 % of patients with an abnormal VEP (P = 0.002). (Fig. 1; Table 2). The most frequent differential diagnoses to ON in this cohort are shown in Table 2 and Fig. 2. Infiltrative or compressive causes Tumors (meningiomas, metastases, pituitary tumors, retinoblastomas, astrocytomas and sarcomas) were found to be causative in 2.3 % of our patients. Two patients had thyrotoxicosis, and were recognized by measurements of TSH (see Fig. 1). Three patients, with no visual recovery,
Fig. 2 Differential diagnosis: see Table 1 MS patients who had initiated treatment against MS or were diagnosed with CDMS. Still at risk patients who did not fulfill the categories above
were diagnosed with sarcoidosis. The diagnosis was established upon measurement of elevated serum ACE, chest X-ray and on one occasion a PET/CT scan was also performed. In our cohort there were no cases related to pituitary apoplexy or intracranial aneurysms. Vascular causes In eleven patients, visual loss was due to non-ateritic ischemic optic neuropathy (NAION), and in another two patients, symptoms were due to severe hypertension.
Table 2 The differential diagnoses among 643 patients referred to the clinic of optic neuritis in Copenhagen Group
Diagnosis
Frequency
Vascular
Anterior ischemic optic neuropathy
11
Percent (CI-95)
VEP-abormal
1.7 % (0.9–3.0)
6/11
Malignant hypertension
2
0.3 % (0–1.1)
1/2
Toxic/nutrional
Giant cell arteritis Tobacco amblyopiaa
4 1
0.6 % (0.2–1.6) 0.2 % (0–0.9)
3/3* 0/1
Hereditary
Leber
1
0.2 % (0–0.9)
1/1
Infections
Toxoplasmosis ? HIV
1
0.2 % (0–0.9)
1/1
Syphilis ? HIV
1
0.2 % (0–0.9)
1/1
Sinusitis
3
0.5 % (0–1.4)
2/3
Glaucoma
1
0.2 % (0–0.9)
1/1
Retina/choroidea
9
1.4 % (0.6–2.6)
3/8*
Refraction
2
0.3 % (0–1.1)
0/2
Sarcoidosis
3
0.5 % (0–1.4)
1/2*
Myositis
1
0.2 % (0–0.9)
0/1
2
Ocular
Infiltrative/compressive
Thyrotoxicosis Tumorb NMO
NMO
Total a
0.3 % (0–1.1)
1/2
15
2.3 % (1.3–3.8)
13/15
6
0.9 % (0.3–2.0)
6/6
9.8 % (7.6 –12.4)
40/60*
63
Patient with severe cobalamin deficiency and heavy tobacco consumption
b
Tumors: pituitary tumors (n = 7), myosarcoma (n = 1), astrocytoma (n = 1), meningioma (n = 3), craniopharyngioma (n = 1), retinoblastoma (n = 1), metastases (n = 1) * Missing data
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We found giant cell arteritis to be causative in four patients, and these were easily detected by clinical appearance and measurement of ESR and CRP.
combined with severe cobalamin deficiency was thought to be causative. Comorbidity
Ocular causes In two percent of patients referred with ON an ophthalmic disorder was found, predominantly serous retinitis. Other causes were white dot syndrome, cone rod dystrophy, and uveitis.
Table 4 shows autoimmune comorbidity in our patients. Twelve patients had inflammatory bowel disease or rheumatological autoimmunity, eleven of these were diagnosed prior to onset of ON. One patient had NMO and was shortly hereafter also diagnosed with rheumatoid arthritis.
NMO Six patients developed NMO. Four of these patients had an acute onset of simultaneous and ON and myelitis, and two patients developed myelitis with some delay after the first attack of ON (Table 3). One of these patients was positive for AQP-4-ab. Additionally 157 patients (25 %) including 54 patients with bilateral or recurrent ON, were tested for AQP-4-ab. The test was obtained when it was found relevant based on symptomatology and paraclinical findings. None were positive for AQP-4-ab (Table 3). Infectious causes Infectious causes of ON were seldom found, and only nine patients had a CSF leukocyte count over 50. Two patients with HIV had MRI findings compatible with MS. One of these had syphilis as a comorbid condition and the other patient also had cerebral toxoplasmosis. The patient with toxoplasmosis had a poor outcome. In two patients sinusitis seemed to explain the symptoms. One patient had a severe pan-sinusitis, and the other patient primarily had a pain problem and VEP was normal. Another elderly patient just had new dental implants. Inherited and toxic neuropathies In this 12-year period, only one patient was diagnosed with LHON, and in another patient a high tobacco consumption
Discussion This is a large cohort of patients examined for ON in the period of 2000 to 2011. The Danish registries offer a unique opportunity for follow-up, and thus our results are based on follow-up made by the entire Danish healthcare system. The data presented in this article are minimum estimates, since an unknown number of patients with transient symptoms of ON in this period of time may not have been in contact with the healthcare system. With the broad and free Danish healthcare system, we assume that this is a minor problem. A major challenge of this study was to differentiate between causality, co-morbidity, and coincidence. In our study, a diagnosis not related to MS was made in one out of ten patients. Forty to eighty percent of patients with ON will later develop MS [1, 10, 15, 28, 31], and we anticipate that the symptoms in several patients will remain idiopathic. Only a few studies have analyzed the differential diagnoses in ON in the context of a denominator. In a prospective single-center study of 289 patients suspected of ON, So¨derstro¨m et al. found that 24 % of the patients already had MS and 25 % suffered from a non-MS diagnosis, which is substantially higher than the 10 % we found in our study. In a recent study from Finland, Siuko et al.
Table 3 NMO patients Patient
Onset
Brain MRI
Medullary lesion
Bilateral/unilateral ON
AQP4-AB
OCB*
CSF-Leukocytes (per lL)
1
Acute
Normal
2–3 lesions, each the length of 1 vertebra
Bilateral
Negative
No
2
Acute
Normal
2 vertebras
Bilateral
Negative
No
7
3
Acute
Normal
[3 vertebras
Bilateral
Positive
No
3
3
4
Acute
Normal
[3 vertebras
Bilateral
Negative
No
173
5
Delayed onset of myelitis
Normal
2 vertebras
Unilateral
Negative
Yes
11
6
Delayed onset of myelitis
Normal
[3 vertebras
Unilateral
Negative
No
1
OCB CSF IgG oligoclonal bands
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Table 4 Autoimmune comorbidity in the cohort Disorder
Ocular disorders (n = 12)
NMO (n = 6)
MS (n = 284)
‘‘Non-MS’’ (n = 341)
Total (n = 643)
Unspecified* Sjo¨gren0 s Syndrome
0
1
1
0
2
0
0
0
0
0
Rheumatoid Arthritis
0
1
0
2
3
Behcet0 s, Churg-Strauss, Wegener0 s granulamotosis
0
0
0
0
0
Bechterew
0
0
0
1
1
Chrohn0 s Disease
0
0
2
0
2
Ulcerative colitis
0
0
2
2
4
Autoimmune disorders previously reported to be associated with ON MS patients diagnosed with CDMS during follow up or in treatment with immunomodulatory drugs for MS (see text) Non-MS patients who did not qualify to the three other categories * These two patients did not fulfill the criteria for SLE, but were ANA positive and under rheumatologic observation
[32] reported that only 63 % of patients suspected of ON fulfilled their diagnostic criteria of this disorder. However the study did not reveal the diagnosis of the remaining 37 % [32]. Tumors were found in 2.3 % of the cases, and this emphasizes the need of radiological diagnostics for other purposes than the evaluation of MS risk. Ischemic damage to the optic nerve is more common in the elderly [30]. The ischemic and the inflammatory optic neuropathies are reported to have overlapping clinical profiles [27]. Whether it is possible to completely distinguish between these two disorders is unclear. Ocular disorders mimicking ON can pose a significant proportion of non-ON cases, but these diseases should be detected by the referring ophthalmologist. So¨derstro¨m and coworkers found ischemic neuropathies and ocular disorders to be causative in 15 % of their referrals [33]. Thus, these disorders might be underdiagnosed in our material.
on patients in the acute settings. Kim et al. [21] reported on seroconversion from positive to negative during a followup period, where patients received immunotherapy. Moreover, the AQP-4-ab analysis was only available in the second half of the inclusion period and initially only the low-sensitivity RIPA analysis was used. Miscellaneous autoimmune disorders In our study, ON was rarely associated with Bechterew, Sjo¨gren0 s syndrome, Lupus or inflammatory bowel disease. These observations are in line with previous publications from the optic neuritis treatment trial (ONTT) [4]. Therefore, a causal relationship between these disorders and ON is unlikely, and a diagnostic investigation for non-neurological autoimmunity in an otherwise young and healthy patient is not mandatory. Infections
NMO NMO was rare in this cohort, and our data correspond with two other large Northern European studies on ON [32, 33]. The epidemiology and aetiology of NMO is still to a large extent uncertain. The prevalence is estimated to be around 1–4 per 100.000 in Caucasians [2, 7, 16]. The Clinic of Optic Neuritis is primarily an outpatient clinic, and the number of patients with NMO is possibly underestimated in our cohort due to the frequently severe symptoms and subsequent hospitalization in these patients. Nevertheless, our data suggest that NMO is extremely rare in Denmark. In this limited material, AQP-4-abs were only detected in one of the six NMO patients or in 0.6 % of the 163 patients from the cohort that were tested for AQP4-Ab. There are, however, reports on AQP-4-abs fluctuating with disease activity [21], and our analyses were not always performed
The most commonly reported causes are HIV, syphilis, Lyme disease and toxoplasmosis [13]. Diseases such as HIV and syphilis are rare in Denmark, and the frequency of ON in these disorders is unknown. Furthermore, there may be retinal exudates (a macular star) in patients with infectious causes of ON, and the term neuroretinitis is often used [26]. The most frequent cause of neuroretinitis is cat scratch disease (caused by the bacteria Bartonella henselae) [26]. The ONTT group and So¨derstro¨m also reported low frequencies of infectious ON [4, 33]. Inherited and toxic neuropathies Inherited optic neuropathies affect 1 in 10,000 individuals, the most common and most likely to mimic ON is LHON [13, 40]. Characteristic for LHON is an acute or sub-acute,
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bilateral or sequential painless visual loss predominantly in younger males, and the visual prognosis is poor [40]. Pathophysiology of LHON is due to mutations in the mitochondrial DNA, which lead to a decreased oxidative phosphorylation and an increased oxidative stress [40]. The pathological mechanisms in most toxic and nutritional optic neuropathies are believed to be somewhat similar to that of LHON. Optic neuropathy has also been related to low vitamin B status as well as toxins and drugs such as methanol, toluene, ethambutol, isoniazid, chloramphenicol, linezolid and disulfiram [20, 24, 40]. The visual symptoms are often bilateral, symmetric and painless, and may improve upon drug discontinuation or vitamin supplementation [20, 24]. Naturally, optic neuropathy is a rare side effect to pharmaceutical agents and those drugs associated with optic neuropathy are rarely prescribed in the demographic subpopulation at risk of ON [39]. Psychiatric disorders are considered by some researchers to be the most common differential diagnosis to MS [29]. The non-organic visual loss is a diagnosis of exclusion and is rarely diagnosed in studies of ON [33]. It is important to recognize that there are also positive signs and criteria for psychiatric illness [14], and to be aware that the relative afferent papillary defect can be detected in healthy controls [35] or be falsely induced. In summary, 9 % of patients referred to the Clinic of Optic Neuritis had symptoms caused by medical, neurosurgical or ophthalmic disorder, and 0.9 % of our patients had NMO. Further studies of idiopathic ON are warranted. Acknowledgments Anja Francis Madsen, Ali Wafik Awade, Bente Fabild and Jytte Horne Pedersen are thanked for excellent technical assistance. This study was funded by: The A.P. Møller and Hustru Chastine Mc-Kinney Møller Foundation. Fabrikant Einar Willumsen Foundation. Aase og Ejnar Danielsen Foundation. The Danish Multiple Sclerosis Foundation. Conflicts of interest Henrik Horwitz: Nothing to disclose. Tina Friis: Nothing to disclose. Signe Modvig: Nothing to disclose. Hanne Roed: Nothing to disclose. Anna Tsakiri: Nothing to disclose. Bjarne Laursen: Nothing to disclose. Jette Lautrup Frederiksen has served on scientific advisory boards for and received funding for travel related to these activities and honoraria from Biogen Idec, Sanofi-Aventis, Genzyme, Teva, Novartis and Almirall. Jette Frederiksen has received speaker honoraria from Biogen Idec, Merck Serono and Teva. She has served as advisor on preclinical development for Takeda.
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