One of the most capricious conditions in neurology is also one of the hardest to diagnose due to the slew of imposters. Here’s how to identify the true culprit.

By Jeffrey I. Greenstein, MD Philadelphia

52 Practical Neurology February 2005

ultiple sclerosis can present with a multiplicity the majority of patients with optic neuritis. The amplitude of of symptoms and signs, making it a challenge to the wave is usually reduced if there is axonal injury. Magnetic differentiate this disorder from a variety of neu- resonance imaging of the optic nerve can be applied by using rological or systemic diseases involving the fat suppression. Increased T2-weighted signals and gadolini- Mbrain, optic nerve, spinal cord or all of the um-enhancement may also be present in the affected portion of above. Adding to the complexity, one must take into account the nerve. that MS can present with either a relapsing or progressive If the systemic manifestations of other conditions are not onset, making it particularly important to be certain of your present, then the major decision one has to make when consid- diagnosis. Given the severity of the condition, prompt recogni- ering a diagnosis of multiple sclerosis depends primarily on the tion is critically important in forestalling disability by allowing presence of cerebral or spinal cord lesions on MRI. If three or immediate treatment intervention, which further increases the more ovoid, periventricular or gadolinium-enhancing lesions challenge of making the diagnosis in the earliest stages when are present then the likelihood of MS developing increases con- the clinical picture may still be hazy. siderably.4,5 The presence of oligoclonal bands also increases the Many of the diseases considered to be in the differential likelihood of MS developing but does not have the same prog- diagnosis for MS in the past can now be easily detected by nostic strength of the MRI findings.6 using neuroimaging (MRI in particular) as well as biochemical, In the absence of prior episodes consistent with MS, there is genetic or immunologic tests. However, some of these disorders a wide differential diagnosis to consider (see Table 1). The onset are still worth considering in any formal review of the differen- of optic neuropathy in systemic vasculitis is usually painless, sim- tial diagnosis for MS. ilar to acute ischemic optic neuropathy. A positive antinuclear The differential diagnosis of multiple sclerosis may be con- antibody will differentiate optic neuritis occurring in systemic sidered by disease course or by the affected location. For the lupus erythematosis. Isolated optic neuritis is a rare manifesta- scope of this article, we will consider cerebral, optic nerve and spinal cord presentations and comment within these diseases’ different divisions and tempos. To narrow the field of suspects Table 1. yet further, we will focus on the most common conditions that Differential Diagnosis of Optic Neuritis mimic MS in adults. Steroid-responsive optic neuritis Broadly speaking, MS can present initially with optic neuri- • Idiopathic inflammatory optic neuritis tis, cognitive impairment and cerebral or spinal long-tract and • Neuromyelitis optica (Devic’s disease) brain-stem signs. Here are the telltale distinctions between MS • Systemic lupus erythematosis • Sarcoidosis and other disorders with cerebral presentations (this discussion • Chronic relapsing inflammatory optic neuropathy excludes spinal cord presentations). Inflammatory optic neuritis • Acute disseminated encephalomyelitis Seeing Through Optic Neuritis —Post-infectious This can present acutely, sub-acutely or occasionally with a rare —Post-vaccinal form of chronic inflammatory optic neuropathy.1-3 Patients Infectious optic neuropathies with this condition are typically between 15 and 45 years of age • Lyme disease and predominantly female (75 percent). • Syphilis The most common clinical presentation is monocular visu- • Tuberculosis • Viral optic neuritis al loss associated with periocular pain and pain on eye move- ment. Light flashes—phosphenes or photopsias—are also Toxic and metabolic neuropathies noted occasionally. Examination usually reveals that visual acu- • Vitamin B12 deficiency • Tobacco-alcohol amblyopia ity is decreased to absent (a majority of cases range between • Methanol intoxication 20/25 and 20/200), with poor color vision and contrast sensi- tivity. A variety of visual field defects occur and an afferent pap- Inherited optic neuropathy • Leber’s optic neuropathy illary defect is often present. The disc may be normal or swollen. Pallor of the temporal margin may be present, indicat- Ischemic optic neuropathies ing prior demyelination if the patient is seen early. • Anterior ischemic optic neuropathy • Posterior ischemic optic neuropathy Optic disc swelling with a macular star may be found in • Giant cell arteritis optic neuritis due to Lyme disease or sarcoidosis. Visual evoked potentials demonstrate prolonged latencies of the P100 wave in

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Differential Diagnosis of MS

tion of sarcoidosis. Optic disc swelling may be present. transmitted and males predominate here, unlike the hereditary Optic neuritis may also occur with a basilar meningitis in occurrence of multiple sclerosis which is transmitted more com- sarcoidosis. Mediastinal lymphadenopathy, a positive ACE monly to females. It may approximate multiple sclerosis in level and non-caseating granulomas on tissue biopsy are help- younger individuals with milder fundal abnormalities. The usual ful in the diagnosis of sarcoid optic neuropathy. Neuromyelitis age of onset of this disorder is between 15 and 40, with an acute optica (to be considered later) is suspected with a combination painless monocular loss of vision, an afferent papillary defect and of optic neuritis and transverse myelitis with relatively exten- central or centrocecal visual field abnormality. sive rostral-caudal spinal demyelination (see Table 2).7 Optic atrophy develops months after disease onset. Visual One should be sure there are no brain lesions to confirm the acuity progressively worsens to less than 20/200 and subse- diagnosis. Chronic relapsing inflammatory optic neuropathy is quently the other eye is affected. Improvement may occur in a characterized by a pre- minority of affected individuals. Visual evoked potentials may dominantly bilateral be absent, or painful optic neuropa- demonstrate de- thy with disc swelling layed latency and or pallor. Visual loss is Patients with decreased P100 usually more severe Leber’s hereditary amplitude. A vari- than what is seen in ety of signs may optic neuritis. optic neuropathy suggest multiple Cerebral MRI is nor- can be sclerosis, including mal but the optic differentiated increased reflexes, nerves have high T2- spasticity, ataxia, weighted lesions, from MS patients and a myelopathy. often with gadolini- by the However, this dis- um-enhancement. former’s lack of order can be dif- Chronic steroid ferentiated from administration is MRI or CSF multiple sclerosis required to control abnormalities. because no MRI this condition. or cerebrospinal Bilateral optic neuri- fluid abnormali- tis is often seen in ties occur. A de- acute disseminated finitive diagnosis can made through genetic testing. encephalomyelitis, a feature that serves to support this diagno- sis rather than multiple sclerosis (discussed below). Cerebral Presentations of Mimickers Anterior ischemic optic neuropathy needs to be considered in At times, clues provided by the patient during the history can older individuals with acute visual loss.8 It should not be difficult help you identify some of the most common cases, but a host to distinguish this condition from multiple sclerosis. This condi- of conditions require more specialized observation via neu- tion is the result of ischemia in the post laminar optic nerve and roimaging. Here are some of the mimickers to keep in mind usually occurs in the over-55 age group, but may be seen in any while looking over the scans. individuals over 40. It presents with acute, painless, uniocular Subcortical arteriosclerotic encephalopathy/leukoariosis is visual loss on waking. Visual perception is reduced, but by no due to fibrohyalinosis of the deep penetrating vessels supplying more than 20/60 in as many a half of affected individuals. An the periventricular white matter.10 The strongest correlations afferent papillary defect is present, with altitudinal or inferonasal are with hypertension, diabetes mellitus and episodes of arcuate visual field defects. Optic disc swelling occurs with hypotension. It results in demyelination and astrocytic gliosis flame-shaped hemorrhages and cotton wool spots on the disc or of the deep white matter but spares the subcortical u-fibers. In its margin. The other eye may be affected in 25 percent of cases. its full-blown form it presents with subcortical dementia, gait Unfortunately, there is little visual recovery. Diabetes, hyper- and disturbance and incontinence in elderly patients. hypotension are common accompaniments. Practitioners have described a similar presentation in multi- Leber’s hereditary optic neuropathy is caused by mutations in ple sclerosis, but this can be distinguished from leukoaraiosis mitochondrial DNA coding, mostly for complex I of the oxida- by characteristic antecedent clinical events and cerebrospinal tive phosphorylation pathway.9 The mutations are maternally and evoked potential findings.11

54 Practical Neurology February 2005

From a clinical perspective, the greatest difficulty in distin- guishing between leukoaraiosis and multiple sclerosis occurs in Table 2. younger individuals who may present with neurologic com- Proposed Diagnostic Criteria for 7 plaints and have MRI changes. On the scans there are corpus Neuromyelitis Optica callosum and periventricular T2-weighted hyperintensities, Absolute Criteria: and ventriculomegaly in leukoaraiosis; however, the T2-lesions • Optic neuritis • Acute myelitis often occur with a gap between them and the ventricular sur- • No other CNS lesions face, in contrast to multiple sclerosis. Involvement of the cor- pus callosum and the occurrence of T1 hypointensities are Supportive Criteria: • Major more characteristic of multiple sclerosis but can occur in —Negative brain MRI leukoaraiosis. Spinal cord lesions are only seen in multiple scle- —Spinal cord lesion ≥ 3 vertebral segments rosis and cervical MRI are a helpful way of alleviating diagnos- —CSF pleocytosis >50 WBC/mm3 or >5 neutrophils/mm3 • Minor tic difficulty. —Bilateral optic neuritis Cerebral autosomal dominant arteriopathy with subcortical —Severe optic neuritis VA< 20/200 infarcts and leukoencephalopathy (CADASIL) is a rare disor- —Severe fixed attack-related weakness limbs (MRC ≤ 2/5) der of vascular smooth muscle due to notch3 gene mutations The diagnosis requires all absolute and one major or two in the coding region for the extracellular domain of the pro- minor supportive criteria. tein.12 After proteolytic cleavage, this portion of the molecule accumulates at the cytoplasmic membrane of smooth muscle cells in vessels. It is associated with the accumulation of a gran- Another condition, acute disseminated encephalomyelitis, ular material in the media and adventitia of vessels. These is primarily a monophasic disorder that frequently follows changes produce an arteriopathy due to thickening of vessel infections or vaccinations within a 14 day period.15 It most walls and luminal narrowing, with resultant ischemia and often occurs in male children but is seen in adults, where a infarction in the periventricular white matter, centrum semio- higher proportion of affected individuals experience recur- vale and basal ganglia. rences of demyelination and are subsequently diagnosed as The mean onset age for patients is 37, with the occurrence having multiple sclerosis.16,17 The onset is rapid with maximal of transient ischemic attacks and strokes. Migraine headaches progression occurring in a few days. with aura precede these events in up to 30 percent of affected It is characterized by an encephalopathy with fever, individuals. Progressive subcortical dementia ensues, associat- headache, meningeal signs and multifocal neurologic signs. ed with pyramidal signs and pseudobulbar palsy, gait disorders MRI patterns overlap with multiple sclerosis, but this condi- and urinary incontinernce. T2 hyperintense and T1 tion is associated with more extensive and asymmetric lesions hypointense lesions are seen in the periventricular white mat- involving cerebral and cerebellar white matter as well as the ter, centrum semiovale and basal ganglia early, spreading to basal ganglia, thalami, brainstem and on occasion the spinal involve the white matter diffusely including the u-fibers with cord. The periventricular white matter and corpus callosum the passage of time. The family history, basal ganglion involve- are relatively spared. The lesions are hyperintense on T2- ment and stroke-like events serve to differentiate CADASIL weighted imaging with acute T1 hypointensity, and are from multiple sclerosis. The cerebrospinal fluid is usually nor- gadolinium-enhancing. Recurrent MRI lesions are uncom- mal but oligoclonal bands and pleocytosis have been mon. The presence of T1 “black holes” favors pre-existing described. disease and is more compatible with a diagnosis of multiple Migraine is associated with T2-weighted hyperintense sig- sclerosis. Oligoclonal bands appear less frequently in this con- nals on cerebral MRI.13 It is wise to entertain the possibility of dition and resolve in contrast to multiple sclerosis where they multiple sclerosis in the setting of migraine equivalents associ- are more frequent and where they are persistent. ated with these MRI lesions.14 The presence of a normal neu- Recovery from acute disseminated encephalomyelitis is rologic examination and the predominence of centrum semio- better in children than adults and a higher proportion of vale lesions and the absence of T1 hypointensities, callosal and adults progress to recurrent disease, when they are often diag- periventricular lesions perpendicular to the ventricular surface nosed with multiple sclerosis. suggest that multiple sclerosis is not the case in these individu- als. In addition, the presence of a normal cerebrospinal fluid More Suspects Out There picture and evoked potentials can effectively exclude multiple While these are some of the more common suspects a neurol- sclerosis. ogist should consider when evaluating a suspected case of

February 2005 Practical Neurology 55

Differential Diagnosis of MS

MS, they are certainly not the only ones. There are still more share some attributes of MS but are beyond the scope of this subtle conditions out there, such as Sjögren’s Syndrome and discussion. A future article will cover these in detail. Behcet's disease, that may show fit a basic profile of MS to Ultimately, diagnosing MS can quickly become a matter the extent they can fool someone who does not think critical- of noting the atypical symptoms that would imply another ly during the evaluation. Also, there are a number of condi- condition. Accounting for these can help you be sure you are tions that affect the spinal cord and nervous system which diagnosing the right disease. PN

Slasor PJ, Sandrock AW. Intramuscular inter- Table 3. feron beta-1a therapy initiated during a first Differenting MS From Acute Disseminated Encephalomyelitis demyelinating event in multiple sclerosis. CHAMPS study group. N Engl J Med. 343:898- 904, 2000. Acute Disseminated Multiple Sclerosis 6. Soderstrom M, Ya-Ping J, Hillert J, Link H. Encephalomyelitis Optic neuritis: prognosis for multiple sclerosis from MRI, CSF and HLA findings. Neurology. Age at onset Childhood Adulthood 50:708-714,1998. 7. Wingerchuk DM, Weinshenker BG. Sex predominance Male Female Neuromyelitis optica: Clinical predictors of a relapsing course and survival. Neurology Mode of onset Acute Subacute 60:848-853, 2003. • Exanthemata 8. Trobe JD. Optic nerve and chiasm II: Antecedent events Upper respiratory/GI infections Dysplastic, neoplastic, aneurismal, hereditary, • Immunizations toxic, nutritional, traumatic, and glaucomatous disorders. In: The neurology of vision. Trobe Common • Encephalopathy • Monosymptomatic JD. Oxford University Press. Oxford 2001. pp237-274. presentations • Fever • Optic neuritis 9. Newman NJ. Leber’s hereditary optic atrophy. Arch Neurol. 50:540-548:1993. • Meningeal signs • Partial myelopathy 10. Ward NS, Brown MM. Leukoaraiosis. In: Subcortical stroke. 2nd Edition. Donnan G, • Multifocal signs • Brain stem symptoms Norrving B, Bamford J, Bogousslavsky J, Eds. Oxford University Press. Oxford. • Bilateral optic neuritis 2002. pp47-66. 11. Greenstein JI, Diehl L, Gould J, Maurer A. • Complete myelopathy Impaired supraspinal motor control of gait in multiple sclerosis. Can J Neurol Sci Suppl • Seizures 4:S130, 1993. 12. Chabriat H, Bousser MG. Cerebral autoso- • Pleocytosis to 1000cells/mm3 3 Cerebrospinal fluid • Pleocytosis to 100cells/mm mal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. In: • Protein to 100mg/dl • Protein to 100mg/dl Subcortical stroke. 2nd Edition. Donnan G, Norrving B, Bamford J, Bogousslavsky J, Eds. • Oligoclonal bands infrequent and • Oligoclonal bands frequent and Oxford University Press. Oxford. Pp111-120. transient persistent 13. Swartz RH, Kern RZ. Migraine is associated with magnetic resonance imaging white matter Within six months; associated with Ongoing beyond six months; not abnormalities: A meta-analysis. Arch Neurol Relapses 61:1366-1368, 2004. steroid withdrawal associated with steroids 14. Silberstein SD, Saper JR, Freitag FG. • Large, extensive asymmetric Migraine: diagnosis and treatment. In: Wolff’s MRI • Ovoid lesions headache and other head pain. 7th Ed. lesions with edema and mass effect Silberstein SD, Lipton RB, Dalessio DJ. Eds. —similar age • Perpendicular lesions to ventricu- Oxford University Press. 2001. pp 121-237. lar surface; callosal lesions 15. Bennetto L, Scolding N. Inflammatory/post- • Grey matter involved infectious encephalomyelitis. J Neurol • T1 holes Neurosurg Psychiatry 75(Suppl 1):22-28, • Uniform gadolinium enhancement 2003. • Heterogeneous gadolinium 16. Dale R, de Sousa C, Chong WK, Cox TCS, • Subsequent resolution—some to Harding B, Neville BGR. Acute disseminated enhancement encephalomyelitis, multiphasic disseminated normal appearances encephalomyelitis and multiple sclerosis in • New lesions occur in time children. Brain 123:2407-2422, 2000. 17. Schwarz S, Mohr A, Knauth M, Wildemann B, Storch-Hagenlocher B. Acute disseminated encephalomyelitis: a follow-up study of 40 1. Hickman SJ, Dalton CM, Miller DH, Plant vision. Trobe JD. Oxford University Press. Thompson AJ, Miller DH. A longitudinal study adult patients. Neurology 56:1313-1318, 2001. GT. Management of optic neuritis. Lancet. Oxford. 2001. pp202-236. of abnormalities on MRI and disability from 18. Trojano M, Paolicelli D. The differential 360:1953-1962, 2002. 3. Kidd D, Burton B, Plant GT, Graham EM. multiple sclerosis. N Engl J Med. 346:158- diagnosis of multiple sclerosis: classification 2. Trobe JD. Optic nerve and chiasm I: Chronic relapsing inflammatory optic neuropa- 164,2002. and clinical features of relapsing and progres- Inflammatory, ischemic, and increased intracra- thy (CRION). Brain. 126:276-284, 2003. 5. Jacobs LD, Beck RW, Simon JH, Kinkel RP, sive neurological syndromes. Neurol nial pressure disorders. In:The neurology of 4. Brex PA, Ciccarelli O, O’Riordan JI, Sailer M, Brownscheidle CM, Murray TJ, Simonian NA, Sci.Nov;22 Suppl 2:S98-102, 2001.

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