February 2016 - Siena, Italy 24-25

What we should pay attention for? Key elements for an MRI differential diagnosis

IMPROVING THE PATIENT’S LIFE THROUGH MEDICAL EDUCATION Nicola De Stefano www.excemed.org Antiphospholipid Migraine CADASIL Antibodies Hypertension Hyperhomocysteinemia

Krabbe Steinert Behcet Fabry Adrenoleukodystrophy

Chronic Progressive Leber Cerebrotendinous Myotonic Dystrophy NMO External Ophtalmoplegia Xanthomatosis Multiple Sclerosis: Differential Diagnosis

Metabolic disorders: Autoimmune diseases: Psychiatric disorders: Disorders of B12 metabolism, Sjögren`s syndrome, systemic Conversion reaction, malingering Leukodystrophies lupus erythematosus, Behçet`s disease, sarcoidosis, antiphospholipid-antibody syndrome Neuromyelitis optica

Neoplastic diseases: Vascular disorders: Variants of MS: Spinal cord tumors, CNS Spinal dural arteriovenous fistula, Isolated optic neuritis, lymphoma, paraneoplastic cavernosus hemangiomata, CNS isolated brain-stem disorders vasculitis, CADASIL syndrome, transverse myelitis, ADEM, Marburg Infectious diseases: Genetic disorders: disease, Balo`s concentric HIV-associated myelopathy and Hereditary ataxias and hereditary sclerosis HLTV-1-associated myleopathy, paraplegias, Leber`s optic atrophy, Lyme disease, meningovascular mitochondrial diseases syphilis, Eales' disease

HIV=human immunodeficiency virus; Human T cell lymphotropic virus-1; CADASIL=cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; ADEM=acute disseminated encephalomyelitis. Scolding N. J Neurol Neurosurg Psychiatry. 2001;71 (Suppl 2):ii9-15; Lennon VA Lancet. 2004;364:2106-2112; Hyland MH, Cohen JA. Differential Diagnosis of MS. In: Fox RJ, Bethoux F, eds. Multiple Sclerosis and Related Disorders Rae-Grant AD. New York, NY: Demos; 2013; Luzzio C. Medscape Reference Article. January 2014. http://emedicine.medscape.com/article/1146199-differential. Accessed 17 March 2014. 3 4 Hypoxic-ischaemic cerebral small-vessel disorders

…the most common differential diagnosis of white-matter lesions in patients suspected of having multiple sclerosis is the possibility that these lesions can also be caused by hypoxic-ischaemic cerebral small-vessel disorders…. from Charil et al, Lancet Neurol 2006

Punctate WM lesions WM lesions mainly Signal increase is found Headache confined to the deep centrally in the pons border zones Arteriosclerosis Hypertension Primary CNS Angiitis

 Vasculitis affecting the CNS without an associated systemic disorder

Punctiform and simultaneous enhancement

from Charil et al, Lancet Neurol 2006 NMO

“By contrast to multiple sclerosis, most patients with neuromyelitis optica will have a normal brain MRI or only few and non-specific T2-hyperintensities“ (Charil et al. Lancet Neurol 2006)

“Brain lesions typical of neuro-myelitis optica localise at the sites where aquaporin 4 expre sion is normally highest“ (Wingerchuk et al. Lancet Neurol 2007)

7 Cox et al. Lancet Neurol 2005 NMO Pencil-thin ependimal enhancement

Cloud-like enhancement

Ito et al. Ann Neurol 2009

Banker et al. MSJ 2012 Spinal Cord involvement in Neuro-Behcet

SH Lee et al. Clinical Radiology 2001 MRI Findings in Chronic Parenchymal NBD

Farahangiz et al., J Reumatol 2012 10 Monitoring Parenchymal NBD by MRI

Time 1 Time 2

Time 1 Time 2 Infliximab

Pipitone et al. Arthritis Rheum 2008

Courtesy of Cantarini and Stromillo 11 Imaging features of NBD

Periventricular, chiasmatic, and hypothalamic edema

High signal intensity longitudinally throughout the spinal cord.

MR venography reveals left transverse sinus thrombosis.

High signal primarily within the spinal cord gray matter.

Taylor S et al. Neurology 2009 Inherited WM Disorders

Adrenoleukodystrophy Metachromatic Leukodys. Krabbe

 Adult-Onset  Variable neurological involvement  Variable MRI pattern

Ahmed et al JNNP 2013 14  Adult-Onset Leukodystrophies  Individually very rare, but prevalence increasing with use of MRI  Collectively their incidence may rival that of MS  Diagnosis might be challenging – lack of experience

Ahmed et al JNNP 2013 15 Leukodystrophies

WM lesions tend to be bilateral and symmetric even in non- classical MRI patterns Leukodystrophies Adrenoleukodystrophy

Other MRI patterns of ADL

Bilateral, symmetric hyperintensities in the different MRI patterns Leukodystrophies WM abnormalities Krabbe Disease MRI in KD (59yo man)

Bilateral hyperintensity of cortico-spinal tract Cerebrotendinous Xanthomatosis

 Rare disease due to molecular genetic defects in the sterol 27-hydroxylasegene, which causes enzyme sterol 27-hydroxylase deficiency and increased serum level of cholestanol

Conventional MRI Clinical Features Progressive neurological impairment Juvenile cataracts Tendon xanthomas

Extreme Variability of symptoms

MS-like WM Abnormalities Cerebrotendinous Xanthomatosis

Hyperintense signal in dentate nuclei Deposits of hemosiderin and calcification in the dentate nuclei

De Stefano et al Brain 2001 Barkhof et al Radiology 2000 Fraby’s Disease

 X-linked alfa-galactosidase A deficiency leading to the progressive deposition of glycosphingolipids in various cellular types (mainly endothelial, intimal and smooth- muscle cells of blood vessels).

Homozygous male (31y)

Pulvinar Hyperintensity in T1 (25%)

Heterozygous female (52y)

from Moore et al ANJR 2003 Myotonic Dystrophy Type I (Adult Form)

 Autosomal dominant progressive multisystem disorder due to an abnormal expansion of CTG repeats in a gene encoding a putative serine or threonine protein kinase (chromosome 19). This leads to a defective production of myotonin.

Clinical Features MS-like WM abnormalities in a 36yo woman with DM-1  Progressive neurological impairment  Juvenile cataracts  Endocrinological alterations Cardiac abnormalities  Myotonia phenomenon

Extreme Variability of symptoms

MRI: WM abnormalities in ~70%

Onset at 35 with generalized weakness CADASIL Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts & Leucoencephalopathy

Diagnosis of MS

Bilateral lesions in Temporal poles MRI in CADASIL MRI in CADASIL Microbleeds

Lesions in External Capsule, U fibers

from Chabriat et al, Lancet Neurol 2009

No cortical lesions on DIR

from Charil et al, Lancet Neurol 2006 Mitochondrial Disorders MS-like LHON MS-like LHON (34 year-old male)

from Tran et al Am J Ophthal 2001

Indistinguishable from MS Multimodal MR approach

van der Voom et al Radiology 2006 Summary

 No evidence-based MRI criteria for differential diagnosis, but MRI can play a role expecially with features that are “not” suggestive of MS  Cord MRI findings can often be helpful  Serial MRI studies are warranted to establish the importance of MRI abnormality progression in DD  Potential usefullness of non-conventional quantitative MR measures

Vitamin B12 Deficiency

 MRI shows extensive hyperintensity signals in the periventricular WM and along the posterior columns

Scherer NEJM 2003 Copper Deficiency

 Acquired copper deficiency is an under-recognized cause of CNS demyelination and myelopathy.  The neurological manifestations are similar to those of Vitamin B12 deficiency.

MRI shows widespread WM lesions Cervico-thoracic cord abnormalities

from Prodan et al Neurology 2002 from Kumar et al Neurology 2004 Mitochondrial Disorders Melas

from Hassan & Markus Brain 2000 Mitochondrial Disorders CPEO

CPEO (28 year-old male)

Very rare Very low lesion load Very slow dissemination Mitochondrial Disorders Melas without stroke (and with WM lesions)

Conventional MRI 1H-MRSI Lactate Image

De Stefano et al Neurol Sci 1997 Hyperhomocysteinemia Dilation Virchow-Robin spaces

from van den Berg Neuroradiology 1995  WM lesions can be indistinguishable from MS lesions, except for their tendency to be confluent Systemic Immune-Mediated Diseases

 Combination of vascular and inflammatory/demyelinating insults (APLAS, Lupus, Behcet, etc)

 MRI abnormalities often indistinguishable from MS Behcet Predominance of lesions located at the cortical or subcortical junction, Concomitant brain infarcts, calcification, or hemorrhages Rare (and long) spinal cord APLAS lesions, disappearing after steroid or immunosuppressive treatment Leukodystrophies Adrenoleukodystrophy in heterozygotes

Heterozygous woman (45 yo) with ADL

From Fatemi et Neurology al 2003

Bilateral and symmetric WM hyperintensities Leukodystrophies Adrenomyeloneuropathy

From Kumar et al AMJN 1995 Pre-Clinical CADASIL vs RIS

60%

RIS (n=23)

Pre-clinical CADASIL (n=21)

0%

Stromillo et al ECTRIMS 2015 MRI Findings in Acute Parenchymal NBD

40