Bobbye Thompson, MD University of Texas Medical Branch, Galveston Division of Neurosurgery

       51yo F w/several months progressive BLE weakness; pain greater in LLE Bilateral numbness just above breasts & inferiorly Muscle aches cramps spasms falls Urinary incontinence & saddle anesthesia Constipation 2wks (manual disimpaction) No history of spinal operation, injury, or trauma No F/C/N/V

       Sensory deficit inferior to T1 bilaterally Decreased rectal tone Motor: LLE 2/5, RLE 5/5 Increased tone/spasticity Hyperreflexia Babinski: Bilateral upgoing toes Gait: Able to stand with asisstance; drags LLE, circumduction

    Gram stain & culture: rare monocytes, no organisms isolated CSF glucose: 69 CSF protein: 31 Oligoclonal bands: negative

 Tumor  Astrocytoma   Ependymoma Demyelinating lesion:  Multiple sclerosis  Neuromyelitis optica  Transverse myelitis  ADEM

       Progressive LE weakness Imaging consistent with Intramedullary tumor at T1 Oligoclonal bands negative Probable tumor, likely glioma Proceed with C6-T2 laminectomy with biopsy and/or resection Midline myelotomy firm, tan tissue Frozen section: gliosis vs. low-grade glioma ▪ Inflammatory infiltrate

Surgical Pathology

CD68

CD45

     Inflammatory demyelinating lesion Multiple Sclerosis No further surgical intervention Neurology for management of MS Follow up in clinic 2 months postop  Motor LLE improved  MRI Brain & C-spine

 Multiple Sclerosis (MS)  Neuromyelitis Optica (NMO)  Transverse Myelitis  Acute Disseminated Encephalomyelitis (ADEM)



Relapsing-remitting MS

(RRMS):  Most common  85% of MS initially diagnosed  Partial or total recovery between attacks 

Secondary-progressive

MS (SPMS):  RRMS course, but becomes

gradually progressive

 Attacks & partial recoveries may continue to occur  Over 60% initially RRMS progress to SPMS in 10 yrs



Primary-progressive MS

(PPMS):  Progressive from onset  Symptoms generally do not remit  Progressive disability w/o acute attacks  15% of MS initially diagnosed 

Primary-relapsing MS

(PRMS):  Same as PPMS, but with acute attacks

   Clinical: Episodic, relapsing-remitting neurologic symptoms in a young adult (typically)  Neurological symptoms disseminated in time & space  Common presentations: monocular visual disturbances (optic neuritis), paresthesias/weakness (myelitis), incoordination (cerebellar), and/or diplopia (brainstem) Labs: Oligoclonal bands positive, MBP elevated  Not specific, new tests improving sensitivity/specificity  Early MS vs Clinically definite  MBP elevated in various disease processes MRI: T2 intense foci in white matter (UBOs), juxtacortical (G W junction involving U-fibers), periventricular lesions, involve corpus collosum (perpendicular extensions)

   Clinical: Visual loss eye(s) w/myelopathy, usually over several months; may occur simultaneously. Course can be monophasic, but ~2/3 relapsing.  In children: usually monophasic & preceded by infection. Recovery is often complete. ADEM variant.

Labs: Oligoclonal bands negative. NMO-IgG serum can be sent (indirect immunofluorescence assay) MRI: Spinal cord lesions extend > 3 levels, w/o brain lesions. SC lesions are cavitating, necrotic, w/acute axonal pathology.

  Clinical: focal inflammatory disorder of spinal cord; acute or subacute combination of motor, sensory, and autonomic deficits.  Up to 50% pt will have LE paralysis/paresis  >80% have numbness, paresthesias, or dysesthesias, often with a well-defined sensory level  vast majority experience impaired bladder function.

 1/3 complete recovery, 1/3 moderate disability, 1/3 severe disability.

Labs/MRI/Treatment: Variable

      Findings that herald diagnosis of MS: asymmetric clinical findings predominance of sensory deficits MRI lesions <3 spinal cord segments, MRI Brain: occult white matter lesions (“dirty white matter”) CSF: Oligoclonal bands positive

    Clinical: “Postinfectious Encephalomyelitis”  Presents as ACUTE neurological symptoms  Fever, nausea, vomiting, positional vertigo, and altered consciousness (drowsy or lethargic)  Children following viral infxn or immunization Labs: ESR, CRP, CSF pleocytosis MRI: extensive lesions, many enhance w/gad (ring enhancing lesions)  Basal ganglia and/or thalami involvement  Spares corpus collosum Molecular mimicry: viral epitope & myelin epitope

  Sjögren’s syndrome: mimics MS by producing recurrent multifocal neurological manifestations; white-matter lesions on MRI and oligoclonal bands in CSF. Differentiate by: systemic manifestations (sicca dry eyes, mouth & rheumatic features), abnormal serology (antinuclear, SSA-Ro, or SSB La antibodies), and findings of inflammatory foci on salivary gland biopsy.

  Behçet’s disease: Most common CNS presentation is a subacute brainstem syndrome. Differentiate by: recurrent oral ulcerations (at least 3 times in 12 months), MRI in Behçet’s disease: brain abnormalities tend to be large, diffuse lesions confined to the brainstem.

Atypical features that may portend alternative diagnosis (not MS):    Onset: too early/late (before 15-20y, after 50y) Early onset may point to a genetic etiology Family history: less likely MS (weak genetic assoc)   Normal CSF, MRI, and/or Evoked potential studies     Systemic signs  Anemia Angiokeratomas Cardiomyopathy Proteinuria Metabolic acidosis

MS NMO TM

Optic Neuritis

  No ADEM No

Spine

   

Brain

 No No 

Course Infection

Usually relapsing No, may trigger exacerbation/ attack 2/3 relapsing 1/3 monophasic Precedes in children Both Variable; usually no Monophasic Yes

    History & Physical Exam, Labs & MRI findings, AND exclusion of alternative diagnoses. ~90% of patients ultimately diagnosed with MS initially present with a clinically isolated syndrome (CIS), such as optic neuritis.

MRI can be valuable in differentiating.

American Academy of Neurology: on value of MRI

predicting eventual conversion of a clinically isolated syndrome to clinically definite MS:

 >3 white-matter lesions in T2 MRI is sensitive predictor (>80%) of clinically definite MS within 7-10 years  In Normal MRIs, <20% will have 2nd attack w/in 10y

  Development of more highly specific criteria for this spectrum of diseases.

Development of more reliable biomolecular markers.

Always consider demyelinating diseases in the differential diagnosis of enhancing intramedullary lesions.

 If index of suspicion is high, further testing may be warranted.

References

1.Natowicz MR, Bejjani B. Genetic disorders that masquerade as multiple sclerosis. Am J Med Genet. 1994;49:149-169. 2.Trojano M, Paolicelli D. The differential diagnosis of multiple sclerosis: classification and clinical features of relapsing and progressive neurological syndromes. Neurol Sci. 2001;22(suppl 2):S98-S102. 3.Frohman EM, Goodin DS, Calabresi PA, et al. The utility of MRI in suspected MS: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003;61:602-611. 4.Brinar VV. Non-MS recurrent demyelinating diseases. Clin Neurol Neurosurg. 2004;106:197-210. 5.Wingerchuk DM. Postinfectious encephalomyelitis. Curr Neurol Neurosci Rep. 2003;3:256-264. 6. Alexander EL, Malinow K, Lejewski JE, Jerdan MS, Provost TT, Alexander GE. Primary Sjogren’s syndrome with central nervous system disease mimicking multiple sclerosis. Ann Intern Med. 1986;104:323-330.

7 Siva A, Altintas A, Saip S. Bechet’s syndrome and the nervous system. Curr Opin Neurol. 2004;17:347-357. 8.Schwarz S, Mohr A, Knauth M, Wildemann B, Storch-Hagenlocher B. Acute disseminated encephalomyelitis: a follow-up study of 40 adult patients. Neurology. 2001;56:1313-1318. 9.Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology. 2002;59: 499 505. 10.Sakakibara R, Hattori T, Yasuda K, Yamanishi T. Micturition distur- bance in acute transverse myelitis. Spinal Cord. 1996;34:481-485. 11.Bakshi R, Kinkel PR, Mechtler LL, et al. Magnetic resonance imaging findings in 22 cases of myelitis: comparison between patients with and without multiple sclerosis. Eur J Neurol. 1998;5:35-48. 12.Cree BAC, Goodin DS, Hauser SL. Neuromyelitis optica. Semin Neurol. 2002;22:105-122. 13.Wingerchuk DM, Hogancamp WF, O’Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology. 1999;53:1107-1114. 14.Rodriguez M, Siva A, Cross SA, O’Brien PC, Kurland LT. Optic neuritis: a population-based study in Olmsted County, Minnesota. Neurology. 1995;45:244-250. 15.Wingerchuk DM, Pittock SJ, Lennon VA, Lucchinetti CF, Weinshenker BG. Neuromyelitis optica diagnostic criteria revisited: validation and incorporation of the NMO-IgG serum autoantibody [abstract]. Neurology. 2005;64(suppl 1):A38.

16.Pittock SJ, Wingerchuk DM, Krecke K, Lennon VA, Lucchinetti CF, Weinshenker BG. Brain abnormalities in patients with neuromyelitis optica (NMO) [abstract]. Neurology. 2005;64(suppl 1):A39. 17.Lucchinetti CF, Mandler RN, McGavern D, et al. A role for humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica. Brain. 2002;125:1450-1461. 18.Bergamaschi R, Tonietti S, Franciotta D, et al. Oligoclonal bands in Devic’s neuromyelitis optica and multiple sclerosis: differences in repeated cerebrospinal fluid examinations. Mult Scler. 2004;10:2-4. 19.Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364:2106-2112. 20.Sourander P, Walinder J. Hereditary multi-infarct dementia. Morphological and clinical studies of a new disease. Acta Neuropathol (Berl). 1977;39:247 254. 21.Haritoglou C, Rudolph G, Hoops JP, Opherk C, Kampik A, Dichgans M. Retinal vascular abnormalities in CADASIL. Neurology. 2004;62: 1202 1205. 22.Viitanen M, Kalimo H. CADASIL: hereditary arteriopathy leading to multiple brain infarcts and dementia. Ann N Y Acad Sci. 2000;903:273-284. 23.Desmond DW, Moroney JT, Lynch T, Chan S, Chin SS, Mohr JP. The natural history of CADASIL: a pooled analysis of previously published cases. Stroke. 1999;30:1230-1233. 24.Chabriat H, Levy C, Taillia H, et al. Patterns of MRI lesions in CADASIL. Neurology. 1998;51:452-457. 25.Joutel A, Vahedi K, Corpechot C, et al. Strong clustering and stereo- typed nature of Notch3mutations in CADASIL patients. Lancet. 1997; 350:1511 1515. 26.Joutel A, Dodick DD, Parisi JE, Cecillon M, Tournier-Lasserve E, Bousser MG. De novo mutation in the Notch3gene causing CADASIL. Ann Neurol. 2000;47:388-391. 27.De Strooper B, Annaert W, Cupers P, et al. A presenilin-1-dependent secretase-like protease mediates release of Notch intracellular domain. Nature. 1999;398:518-522. 28.Brex PA, Ciccarelli O, O’Riordan JI, Sailer M, Thompson AJ, Miller DH. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med. 2002;346:158-164. 29.Rudick RA, Schiffer RB, Schwetz KM, Herndon RM. Multiple sclerosis: the problem of incorrect diagnosis. Arch Neurol. 1986;43:578-583.

30. Images from wikicommons, mmorris.com, devic.org