Acta Clin Croat 2009; 48:345-348 Review

DIFFERENTIAL DIAGNOSIS AND DIAGNOSTIC ALGORITHM OF DEMYELINATING DISEASES

Lidija Deimalj-Grbelja, Ruiica Covic-Negovetic and Vida Demarin

University Department of Neurology, Reference Center for Neurovascular Disorders and Reference Center for Headache ofthe Ministry of Health and Social Welfare of the Republic of Croatia, Sestre milosrdnice University Hospital, Zagreb, Croatia

SUMMARY - Demyelinating diseases ofthe central nervous system include a wide spectrum ofdifferent disorders that may resemble multiple sclerosis (MS). The diagnosis of MS is based on typical clinical and parac1inical criteria. The simplified McDonald's criteria, which combine clinical picture, NMR findings, CSF analysis and visual evoked potentials, are appropriate for daily neuro­ logic routine. Ifsome of these criteria are atypical, diagnostic algorithm should be extended to some otherprocedures to excludeother diseases that can mimic MS not only in symptoms, signs or course of the disease but also in laboratory findings. In such a case, an alternative, better explanation for the clinical manifestations should be considered and performing specific tests is helpful to exclude alternative diagnoses. Key words: Neurology - standards; Diagnosis, differential; Nervous system diseases - diagnosis; Algo­ rithms; Demyelinating diseases- diagnosis

Introduction frequently needed to make the diagnosis and to start the treatment. Demyelinating diseases of the central nervous Fifty years ago, the diagnosis of MS was exclu­ system are divided into inflammatory and non-in­ sively based on 'dissemination in time and space', i.e. flammatory diseases. Inflammatory diseases can be occurrence of two different symptoms at different idiopathic and include clinical isolated syndrome, time point, as the result of involvement of different multiple sclerosis (MS), acute disseminated enceph­ parts of the central nervous system. Today, a variety alomyelitis (ADEM) and optic neuromyelitis, and of diagnostic methods (nuclear magnetic resonance specific demyelinating diseases that include neurosar­ (NMR) of the brain and spinal cord, specific finding coidosis, neuroborreliosis, and demyelinating diseases in cerebrospinal fluid (CSF) and visual evoked poten­ in connecting tissue disorders. Non-inflammatory tials (VEP)) are available upon which the paraclini­ demyelinating diseases are vascular, metabolic, toxic cal criteria are based--'. However, despite their high and different genetic disorders. All of these demyeli­ sensitivity, these methods are not specific enough to nating diseases can mimic MS as the most common make an accurate diagnosis due to different clinical demyelinating disease in clinical features, course of presentation, especially in the early course of the dis­ the disease and paraclinical criteria. Therefore, a wide ease, which can pose a major problem. spectrum of diagnostic procedures is by no means in- Differential Diagnosis ofDemyelinating Diseases Correspondence to: Lidija De.zmalj-Grbelja, MD, University De­ partment of Neurology, Sestre milosrdnice University Hospital, Vi­ The most common presentations in a clinical iso­ nogradska c. 29, HR-l0000 Zagreb, Croatia lated syndrome are optic neuritis and transverse my­ E-mail: [email protected] elitis. Fifty percent of patients presenting with optic

Acta Clin Croat, Vol. 48, No.3, 2009 345 Lidija Deimalj-Grbe1ja et al. Differential diagnosis and diagnostic algorithm of demyelinating diseases neuritis develop MS within the next 15 years.'. Bi­ Inherited disorders of adrenoleukodystrophy and lateral or rapidly sequential optic neuritis could be metachromatic leukodystrophy can resemble progres­ caused by the toxic effect of methanol or tobacco, or sive MS. These disorders are specific for positive fami­ by vitamin B12 deficiency, and can be part of a spe­ ly history, disturbed intellectual development, adrenal cific inflammatory disease such as sarcoidosis, vascu­ gland insufficiency and abdominal symptoms. aCB litis or sistemc lupus erythematosus (SLE), or may be are absent. due to infection, ischemia, tumor growth or Leber's In the group of infectious diseases, neuroborre­ hereditary optic neuropathy. liosis, neuroAIDS and neurosyphilis can present as Transverse myelitis mostly affects thoracic spi­ demyelinating diseases. Neuroborreliosis is character­ nal cord. Idiopathic form affects the whole transverse ized by myelitis, cerebellar ataxia and recurrent crani­ course ofthe cord causing progressive motor weakness, al neuropathies". NMR and CSF findings can be very sensory loss and incontinence". Partial cord lesion is a similar to those in MS, so that definitive diagnosis more specific manifestation of transverse myelitis in depends on ELISA and Western blot serologic analy­ MS. The primary causes to be considered include post­ sis ofserum and CSF. Demyelinating changes seen in infection (varicella, Epstein-Barr virus, mycoplasma, neuroAIDS are mostly caused by progressive multifo­ herpes zoster), post-vaccination (influenza), systemic cal leukoencephalopathy as a consequence of]C virus. inflammatory disorders (sarcoidosis, SLE, Sjogren's Neurosyphilis is increasing in frequency, but due to syndrome, antiphospholipid syndrome, giant cell ar­ NMR rarely causes a picture confused with MS. teritis). Typical CSF findings are pleocytosis, proteino­ Cerebral vasculitis presents as primary vasculitis rachia, and rarely oligoclonal bands (aCB). of the brain and spinal cord, or more commonly as A combination of optic neuritis and severe form part of systemic diseases (Wegener granulomatosis, of transverse myelitis is typical for Devic's disease or SLE, Sjogren's syndrome, rheumatoid arthritis), or it neuromyelitis optica. Brain NMR is normal in more can be seen in drug addicts (cocaine, heroin)". Neuro­ than 50% of cases, and aCB are positive in a small logic complications are the second cause of morbidity percent. A specific finding are serum anti-aquaporin-4 in SLE, next to nephrologic ones". It can presentwith IgG antibodies'. headache, epilepsy, ischemic attacks, encephalopathy, Disseminated demyelinating diseases include myelopathy, or optic neuropathy. aCB are found in ADEM and variants of MS (Marburg disease, about 50% of patients and disappear with immuno­ Shilder's diffuse sclerosis and Baloo's concentric scle­ suppressant therapy. Sjogren's syndome can present rosis). as optic neuropathy, cerebellar ataxia or internuclear ADEM occurs predominantly in children and ophthalmoplegia, resembling MS. Characteristic young adults as a consequence of prior virus infec­ signs are xerostomia, xerophthalmia, involvement of tion or vaccination, or it can be idiopathic". Typical peripheral nervous system, and epileptic and ischemic is the syndrome of meningoencephalomyelitis. CSF attacks. and NMR findings are very similar in MS, although Neurosarcoidosis presents with cranial nerve in­ demyelinating lesions are more symmetric and usually volvement, involvement of peripheral nerovus system larger. aCB are transiently positive and disappear in and cognitive impairment. aCB can be found in CSF. 6 months. ADEM can be multiphasic or recurrent, NMR of the brain is specific due to white matter le­ which is hardly distinguishable from MS. sions and leptomeningeal enhancement". Marburg disease and Schilder's diffuse sclerosis Behcet's disease is a multisystemic inflammatory have an aggressive course leading to death in weeks disease that affects CNS in about 5% of cases. aCB to months. Schilder's diffuse sclerosis is characterized are uncommon, and NMR abnormalities are nonspe­ by cortical dysfunction (dementia, hemiplegia, corti­ cific, so brain biopsy may be required. cal blindness and deafness). Baloo's concentric sclero­ Vascular diseases of the CNS, especially arterio­ sis is characterized by specific demyelinated plaques venous malformations, embolization of endocarditic in which concentric rings of demyelination alternate vegetations or atrial myxoma can mimic the symp­ with normal myelin? toms ofMS.

346 Acta Clin Croat, Vol. 48, No.3, 2009 Lidija Deimalj-Grbe1ja et al. Differential diagnosis and diagnostic algorithm of demyelinating diseases

Malignant diseases such as lymphoma, foramen some other demyelinating disease. After all the above magnum tumors or multifocal gliomas can resemble mentioned diseases have been ruled out, a finding MS. of demyelinating lesions in the brain or spinal cord points to two options: MS or possible MS. Then, we DiagnosticAlgorithm ofDemyelinating Diseases are exactly where we were 50 years ago: waiting for According to all these possible differential diag­ 'dissemination in time and space'. noses, a broad spectrum ofdiagnostic procedures may occasionally be required. We usually start with thor­ References ough history and physical examination, then the fol­ lowing studies are performed": 1) NMR of the brain 1. POLMAN CH, REINGOLD SC, EDAN G, FILIPPI M, and spinal cord using T1, T2 and FLAIR sequence HARTUNG HP, KAPPOS L, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the McDonald Criteria. and gadolinium as a paramagnetic contrast medium, Ann NeuroI2005;58:840-6. to asses the activity ofdemyelinating disorder; 2) lum­ 2. COMPSTON A, COLES A. Multiple sclerosis. Lancet bar puncture with analysis of IgG index and aCB in 2002;359:1221-31. serum and CSF, MRZ reaction; 3) neurophysiologic 3. Optic Neuritis Study Group. Multiple sclerosis risk after op­ studies: visual, auditory and somatosensory evoked tic neuritis: final optic neuritis treatment trial follow-up. A potentials; 4) hematologic and biochemical analysis Neuro12008;65727-32. of peripheral blood (complete blood count, eryth­ 4. BARKER RA, SCOLDING N, ROWE D, LARNER AJ. rocyte sedimentation rate (ESR), coagulogram, C­ Transverse myelitis. In: BARKER RA, et aI., eds. The A-Z reactive protein (CRP), protein S, antithrombin III, of neurological practice. A guide to clinical neurology. Cam­ serum immunoelectrophoresis); 5) molecular analy­ bridge: Cambridge University Press, 2005:858-9. sis of prothrombotic factors (FII, factor V Leiden, 5. LENNON VA, et al. IgG marker of optic-spinal multiple MTHFR, PAI-1); 6) immunologic analysis (ANCA, sclerosis binds to the aquaporin-4 water channel. J Exp Med ANA, ENA, antiDNA, aCL, C3, C4, CIC); 7) thy­ 2005;202:473-7. roid gland hormones; 8) vitamin B12 and folic acid; 9) 6. BARKER RA, SCOLDING N, ROWE D, LARNER serologic analysis for neurotropic viruses and Borrelia AJ. Acute disseminated encephalomyelitis. In: BARKER burgdorftri, and serologic analysis for HIV, hepatitis B RA, et aI., eds. The A-Z of neurological practice. A guide to clinical neurology. Cambridge: Cambridge University Press, and C; 10) VLDRL, TPHA; 11) cardiac studies; and 2005:13-5. 12) brain biopsy. 7. STADELMANN C, LUDWIN S, TABIRA T, GUSEO A, LUCCHINETTI CF, LEEL-OSSY L, et al. Tissue p"­ Conclusion conditioning may explain concentric lesions in Baloo's type of multiple sclerosis. Brain 2005;128:979-87. Due to the very broad spectrum of differential di­ 8. HALPERIN JJ, LOGIGIAN EL, FINKEL MF, PEARL agnosis of demyelinating diseases, we have to strictly RA. Practice parameters for the diagnosis of patients with follow the eligible diagnostic algorithm for MS. Most nervous system Lyme borreliosis (Lyme disease). Quality of these procedures are not obligatory if the main Standards Subcomittee ofthe American Academy ofNeurol­ ogy. Neurology 1996;46:619-27. clinical and paraclinical criteria are present. Atypical systemic features such as fever, night sweats, weight 9. CALABRESE LH, MOLLOY ES, SINGHAL AB. P,i­ mary central nervous system vasculitis: progress and ques­ loss, arthropathy, rash, ulcers, dry mouth and eyes, tions. Ann NeuroI2007;62:430-2. ocular disease; atypical neurologic features such as 10. SCOLDING NJ, JOSEPH FG. The neuropathology and persistent headache, fits, encephalopathy, meningi­ pathogenesis of systemic lupus erythematosus. Neuropathol tis, movement disorders, stroke-like events, periph­ Appl NeurobioI2002;28:173-89. eral neuropathy; and atypical laboratory findings such 11. NOWAK DA, WIDENKA DC. Neurosarcoidosis: a review as raised ESR and/or CRP, absent aCB, persistent ofits intracranial manifestations. J NeuroI2001;248:363-72. pleocytosis, normal NMR or pronounced meningeal 12. PAPATHANASOPOULOS PG, NIKOLAKOPOULOU enhancement, should prompt a doubt in the diagnosis A, SCOLDING NJ. Disclosing the diagnosis of multiple of MS, although it is possible that MS coexists with sclerosis. J NeuroI2005;252:1307-9.

Acta Clin Croat, Vol. 48, No.3, 2009 347 Lidija Deimalj-Grbe1ja et al. Differential diagnosis and diagnostic algorithm of demyelinating diseases

Saietak

DIFERENCIJALNA DIJAGNOSTIKA I DIJAGNOSTICKI ALGORITAM ZA DEMIJELINIZACIJSKE BOLESTI

L. DeimalJ-GrbelJa, R. Covii-Negovetii i V Demarin

Demijelinizacijske bolesti sredrsnjega zrvacnog sustava cine sirok spektar razlicitih poremecaja koji mogu nalikovati multiploj sklerozi. Dijagnoza multiple skleroze temeljena je na tipicnim kl inickim i paraklnnckim kriterijima. Pojedno­ stavljeni McDonaldovi kriteriji u kojima se kl inicka slika kombinira s nalazom magnetske rezonancije, nalazom cere­ brospinalne tekucine i vidnim evociranim potencijalima korisni su u svakodnevnoj neuroloskoj praksi. Ako [e neki od tih kriterija atipican, treba prosirrti dijagnosticki po stupak kako bi se iskljuctle druge bolesti koje mogu oponasati multiplu sklerozu ne sarno u simptomima, znacima iii tijeku bolesti, nego i u nalazima laboratorijskih pretraga. U svakom slucaju. treba razrmsljati 0 drugom, boljem objasnjenju klmickih manifestacija te je izvedba specificnrh testova korisna u iskljuce­ nju alternativne dijagnoze. Key words: Neurologija ~ standardi; DiJagnostika, diftrenciJalna; Bolesti zivcanog sustava - diJagnostika;Algoritmi; Demije­ linizaciJske bolesti - diJagnostika

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