Ms. L, a 31-year-old woman, presents with a history of 2 headaches and an abnormal magnetic resonance imaging (MRI) scan. Her first headache woke her from sleep with severe right retro-orbital throbbing pain associated with nausea, vomiting, and photophobia. The headache lasted approximately 24 hours and improved with rest and as-needed ibuprofen. A week later, she experienced another migrainous headache, albeit less severe. She was thereafter referred to a neurologist who requested a brain MRI, which demonstrated multiple white matter lesions âsuspicious for chronic demyelinating disease.â She denies any prior history of episodic neurologic symptoms. There is no history of paresthesias, motor weakness, vision loss, optic neuritis, Bellâs palsy, trigeminal neuralgia, vertigo, or Lhermitte's phenomenon.
The patient's medical history includes Graves disease, diagnosed in March 2003, for which she takes propylthiouracil. She has no other comorbidities, takes no other medications, and has no known drug allergies. She denies any history of miscarriages or thrombosis. There is no history of rashes, arthralgias, or myalgias. Review of systems is otherwise unremarkable.
Ms. L is married and has a 19-month-old daughter. She does not smoke and drinks an average of one alcoholic beverage weekly. She works as a reporter for a newspaper in New Jersey.
Her father is 64 years of age and has suffered multiple strokes, 2 prior to the age of 40 years. He was initially told that he might have multiple sclerosis (MS). He is presently wheelchair bound with a feeding tube and requires full assistance with activities of daily living. Three of her 6 paternal aunts died in their late sixties, all having suffered strokes. A paternal uncle also suffered a stroke and is aphasic and wheelchair bound. Her paternal grandfather passed away at about age 42 years, she believes from a stroke. Her mother is 55 years old and healthy. She has 2 sisters, aged 19 and 28 years, both healthy. Aside from her fatherâs possible diagnosis, there is no family history of MS.
Neurologic examination is entirely normal. Laboratory studies include normal visual and brainstem auditory evoked potentials. Her MRI brain report describes âinnumerable lesions in the periventricular white matter with involvement of the callosal-septal interface. The findings are suspicious for chronic demyelinating disease.â Importantly, the brain MRI satisfies the revised McDonald criteria (discussed below) for dissemination in space by involving at least 9 T2 hyperintense lesions, at least 3 periventricular lesions, and a single juxtacortical lesion in the left frontoparietal white matter. The MRI scan is shown in Figure 1.
Brain MRI: axial fluid attenuated inversion recovery (FLAIR) images showing:
(A) multiple periventricular and subcortical ovoid hyperintense white matter
lesions, some oriented perpendicular to the ventricular surface; (B) increased
signal involving the periventricular white matter of the frontal horns as well
as involvement of the left external capsule; and (C) compelling involvement of
the anterior temporal white matter.
Courtesy of Tracy M. DeAngelis, MD
testing is negative for antinuclear antibody (ANA), rheumatoid factor, rapid
plasma reagin (RPR), Lyme antibody, anti-SS-B, and anti-SS-A.
Angiotensin-converting enzyme level is 63 Âµg/L (reference range, 12-68 Âµg/L).
She has normal anticardiolipin antibody titers; normal levels of proteins S and
C; and negative lupus anticoagulant, wild-type factor V Leiden, and prothrombin
gene mutation. Neuromyelitis optica-immunoglobulin gamma G (NMO-IgG)
antibody is negative.
How Useful Is MRI as a Diagnostic Tool?
Decision Point 1: What would your next step be in the management of this
- Additional testing, such as lumbar
- Wait 3 months and perform a second MRI
- Tell the patient she probably has MS and arrange a
follow-up clinical visit in 3 months
- Start disease-modifying therapy for MS
Answer: (a) MRI has become an invaluable tool
in the early diagnosis of MS and can be used to satisfy the diagnostic criteria
of dissemination in both space and time; nevertheless, MRI alone is generally not
sufficient to make a diagnosis. Many patients with radiologically isolated
syndromes suggestive of demyelinating disease develop MS, but other possible
clinical explanations for this process must first be ruled out. Thus, further
diagnostic information is needed for this patient, and a lumbar puncture would
be a logical next step.
MS lesions typically appear on T2/fluid
attenuation inversion recovery (FLAIR) MRI images as hyperintense ovoid-shaped
periventricular white matter lesions oriented perpendicular to the ventricular
surface (known as Dawson's fingers). They also commonly appear as corpus
callosal, juxtacortical, and infratentional lesions involving the posterior
fossa and spinal cord. (See Table 1 and Figure 2)1,2
Table 1. MRI Lesion Characteristics Suggestive of MS1
|High signal on T2-weighted and FLAIR MRI sequences
||1 or 2 vertebral segments in length
|When actively inflamed, often enhanced with gadolinium contrast
||Generally incomplete cross-sectional involvement (dorsolateral common)
|Position abutting ventricles (often perpendicular)
||Less likely to enhance with gadolinium contrast
|Juxtacortical position (gray-white junction)
||No cord swelling
|Involvement of brainstem, cerebellum, or corpus callosum
||Better seen with STIR MRI sequences
FLAIR = fluid attenuation inversion recovery; STIR = short-tau inversion recovery.
Reprinted from Calabresi PA, et al. Am Fam Physician. 2004;70:1935-1944, with permission from the American Academy of Family Physicians.
Figure 2. Typical MRI Lesions in MS.2
A, B and D: Courtesy of Tracy M. DeAngelis, MD.
C, E and F: With permission from Barkhof F, Filippi M, Miller DH, et al. Brain. 1997;120:2059-2069.
T1- and T2-weighted images each provide relevant information. Gadolinium-enhancing lesions on T1-weighted scans reflect areas of active inflammation. Gadolinium-enhancing lesions correlate with number of prior relapses and predict relapse in the next 12 months.3 T2-weighted MRI provides information about overall lesion burden. Hyperintense T2 lesions can reflect a variety of pathologic processes in addition to demyelination, such as inflammation, edema, axonal loss, and remyelination.4 Over time, MS lesions can evolve into hypointense areas (also called "black holes") on T1-weighted images, which represent irreversible tissue damage secondary to axonal loss.3
Interestingly, clinical symptoms and MRI lesions do not always correlate well, with many lesions occurring in "silent" areas of the brain. This clinicoradiologic paradox of MS likely reflects limitations in disability score measures and conventional MRI metrics. Several studies, however, have suggested a modest correlation of T2-weighted lesion load with progression of disability.3 Furthermore, the presence of lesions at the time of initial presentation does appear to be associated with a substantial risk for development of clinically definite MS. Within 5 years, about 60% of patients with an abnormal MRI will develop MS,5 as will nearly 90% of patients after 14 years.6
Audio Commentary by Dr. Miller
In 2001, an International Panel on the Diagnosis of Multiple Sclerosis defined diagnostic criteria for MS, which incorporated MRI findings as well as paraclinical studies such as cerebrospinal fluid (CSF) and visual evoked potentials, with neurologic history and examination.7 These criteria, which became known as the McDonald criteria after W. Ian McDonald, chair of the consensus panel, were revised in 2005. According to the McDonald criteria, a diagnosis of MS requires either clinical or radiographic evidence of one or more âattacksâ (dissemination in time) in conjunction with objective evidence of lesions (dissemination in space). Clinically, MS âattacks,â also referred to as relapses or exacerbations, consist of neurologic symptoms typical of MS lasting at least 24 hours in the absence of fever or infection.7 Revised MRI criteria for dissemination in time requires either gadolinium-enhancing lesion(s) at least 3 months after onset of a clinical event but not corresponding to the site associated with the event, or detection at any time of a new T2 lesion that was not present on a reference scan performed at least 30 days after an initial event.8 Clinically, dissemination in space requires objective clinical evidence on neurologic examination of 2 or more lesions. Revised MRI criteria for dissemination in space are listed in Table 2.
Table 2. Updated McDonald
Recommendations for MRI Evidence of Abnormalities Associated With MS8
- Evidence of at least 3 of the following on brain MRI:
At least 1 gadolinium-enhancing lesion or 9 T2-hyperintense lesions if there is no gadolinium-enhancing lesion
- At least 1 infratentorial lesion
- At least 1 juxtacortical lesion (ie, with subcortical U-fiber involvement)
- At least 3 periventricular lesions
NOTE: A spinal-cord lesion can be considered equivalent to a brain infratentorial
lesion; an enhancing spinal-cord lesion is considered to be equivalent to an
enhancing brain lesion; and individual spinal-cord lesions can contribute
together with individual brain lesions to reach the required number of T2
for primary progressive MS are not included in this discussion and will be
reviewed and discussed in an upcoming case study in this series.
Reprinted from Polman CH, et al. Ann Neurol. 2005;58:840-846, with permission from John Wiley & Sons.
Audio Commentary by Dr. Miller
MRI alone, in the absence of clinical symptoms, cannot be used to diagnose MS.8,9 While a recent study suggested that patients presenting with a radiographically isolated syndrome did have a high probability for risk of conversion to clinically definite MS,10 lack of the appropriate clinical context should raise consideration for alternative diagnoses. As the McDonald criteria demonstrate, there must be "no better explanation" for the clinical picture and some objective evidence to support a diagnosis of MS.7 Many other diseases can mimic MS on MRI, and the McDonald criteria have a specificity of only 73%.5 In the future, nonconventional MRI metrics (eg, volume measures, diffusion tensor imaging, magnetization transfer) may help provide additional diagnostic and prognostic information.4 In the meantime, it is important to consider clinical features and results of other evaluations in conjunction with conventional MRI in making the diagnosis of MS.1,11
Lumbar puncture can be helpful in confirming the diagnosis in patients with MRI evidence suggestive of MS. Oligoclonal bands of immunoglobulins, especially immunoglobulin gamma G (IgG), are found in 92% of children and 98% of adults with MS.12 These results, however, were recorded from a research laboratory. CSF examination appears to be much less sensitive when performed by commercial laboratories. The McDonald criteria state, "For the purpose of diagnosing MS, CSF abnormality is defined (preferably using isoelectric focusing) by the presence of oligoclonal IgG bands different from any such bands in serum and/or presence of an elevated IgG index."8
The most common risks associated with lumbar puncture include postprocedure headache (30%) and mild back or leg pain during or sometimes after the procedure.7 Rare but serious complications include infection, spinal hematoma, subdural hematoma, and cerebral tonsil herniation through the foramen magnum. Contraindications to lumbar puncture include conditions suggesting raised intracranial pressure (eg, headache, vomiting, focal neurologic signs, papilloedema, reduced consciousness), bleeding diatheses, and local infection.13
Audio Commentary by Dr. Miller
The patient undergoes lumbar puncture for oligoclonal bands and IgG synthetic studies, in addition to cell count, chemistries, Gram stain and culture, Lyme polymerase chain reaction, and Venereal Disease Research Laboratory (VDRL) testing for neurosyphilis. All results are normal.
Lumbar Puncture as a Diagnostic Tool
Decision Point 2: What would your next step
- Additional diagnostic testing
- Tell the patient she probably has MS and arrange a follow-up clinical visit in 3 months
- Start disease-modifying therapy for MS
Answer: (a) The lumbar puncture results do not support a diagnosis of MS. Approximately 90% of MS patients have an increased IgG concentration in the CSF compared with other CSF proteins, as well as oligoclonal bands that are evident on CSF gel electrophoresis. However, the remaining 10% of patients with MS do not show these changes, so negative results do not rule out MS. Moreover, as with MRI, these tests are not specific enough to be diagnostic even when positive.
Decision Point 3: Which of the following
is/are important to consider in the differential diagnosis of MS?
- Systemic lupus erythematosus
- Cerebral autosomal dominant
arteriopathy with subcortical infarcts and leucoencephalopathy
- Antiphospholipid antibody syndrome
- All of the above
Answer: (d) All of these and a number of other conditions should be considered in the differential diagnosis of MS (Table 3).1,11,14,15
Table 3. Differential Diagnosis of MS
||Vasculitis, antiphospholipid antibody syndrome, CADASIL, cerebrovascular disease, Susac syndrome
||Bacterial (Lyme disease, syphilis, Whipple's disease), viral (HIV infection, human T-lymphotrophic virus type-1 infection, herpes viruses, progressive multifocal leukoencephalopathy, JC virus)
||Primary brain tumor (ie, CNS lymphoma), metastatic tumors, paraneoplastic syndromes
|Structural or compressive conditions
||Cervical spondylosis, degenerative disc disease, Chiari malformation, dural arteriovenous fistulas, syrinx
||Collagen vascular diseases (SLE, Sjogren's syndrome), neurosarcoidosis, Bechet's disease
||Leukodystrophies (adrenoleukodystrophy, adrenomyeloneuropathy), lysosomal storage diseases, Fabry's disease, mitochondrial diseases
||Vitamin B12 deficiency, acquired copper deficiency, folate deficiency, hyperhomocysteinemia, vitamin E deficiency
||Conversion disorder, depression, anxiety
CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and
HIV = human immunodeficiency
virus; CNS = central nervous system; SLE = systemic lupus erythematosus.
Courtesy of Tracy M. DeAngelis, MD
Systemic lupus erythematosus (SLE) would be important to consider in a young woman with migraine presentation and evidence of white matter disease on imaging. SLE may present with relapsing multifocal neurologic symptoms similar to those of MS, as well as neuropsychiatric symptoms, aseptic meningitis, vascular events, movement disorders, optic nerve involvement, cranial or peripheral neuropathy, or transverse myelitis.15 In addition, systemic findings of rash, arthralgias, myalgias, and renal disease suggest a possible underlying collagen vascular disorder. MRI findings typical of SLE include subcortical white matter lesions and brain atrophy, as well as cortical and deep gray matter lesions. Laboratory findings associated with SLE include high titer of ANA and other autoantibodies, such as anti-double stranded DNA.15 Patients with MS may also have positive ANA; therefore, in the absence of additional systemic findings, ANA findings should be regarded as nonspecific. Similarly, oligoclonal bands and increased IgG index may be evident on CSF analysis in SLE and in MS; their presence does not secure a diagnosis of MS either.15
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary autosomal dominant disorder characterized by widespread microangiopathy in small arterioles, with medial thickening.15 The disease leads to accumulation of neurologic deficits presenting typically as migraines, recurrent stroke, and progressive cognitive impairment and dementia.16 A positive family history of migraine and early onset strokes and dementia in the third to fourth decade should raise suspicion for CADASIL. MRI lesions associated with CADASIL can appear as diffuse T2 hyperintensity involving the periventricular and subcortical white matter (see Figure 1A), creating diagnostic confusion with MS. In comparison with MS, however, involvement of the anterior temporal lobe and external capsular white matter is a relatively specific marker for CADASIL (see Figure 1B and C). In addition, rarely, CADASIL can affect the cortex, corpus callosum, and infratentorial regions other than the pons.14 CSF analysis is usually normal or reveals pleocytosis and can demonstrate evidence of oligoclonal bands.15 Other vascular diseases such as vasculitis or small vessel ischemic disease also can appear as MRI abnormalities that mimic those associated with MS.11
Antiphospholipid antibody syndrome (APS) is another vascular disease that can overlap clinically and radiographically with MS. Classically, APS is associated with migraines, venous or arterial thrombosis, a history of recurrent miscarriage (generally beyond the first trimester), and neurologic symptoms including transient stroke-like episodes, seizures, optic neuritis, and myelitis.17 Systemic findings include skin changes, such as livedo reticularis, Raynaudâs phenomenon, and thrombocytopenia. In contrast to MS, MRI findings are generally subcortical and nonenhancing. Because antiphospholipid antibodies (aPLs) titers have been reported elevated in 2% to 44% of MS patients,17 their presence in the absence of the appropriate clinical scenario remains nondiagnostic. Of note, Ms. L, the case patient, had normal titers of aPLs.
Audio Commentary by Dr. Miller
Decision Point 4: What additional testing would be of greatest diagnostic yield in this patient?
- 4-Vessel cerebral angiography
- Metabolic testing for leukodystrophies, including VLCFA (very long-chain fatty acids), and arylsulfatase A level
- MRI of the cervicothoracic spine with and without gadolinium contrast
- Notch3 gene mutation and/or skin biopsy
Answer: (d) Given this patientâs MRI findings, history of migraine, and family history of stroke, CADASIL is a strong consideration. Since CADASIL is attributed to mutations in Notch3 on chromosome 19q12,18,19 genetic testing would be useful to confirm the diagnosis. In addition, skin biopsy can demonstrate the characteristic small vessel microangiopathy seen in CADASIL, involving pathognomonic ultrastructural deposition of granular osmophilic material in the vessel wall.
Dedicated 4-vessel cerebral angiography would not be an appropriate next step because Ms. L has not presented with typical findings of CNS vasculitis, such as encephalopathy and stroke-like episodes. Imaging studies do not demonstrate the diffuse symmetric confluent white matter lesions typical of a metabolic leukodystrophy. Furthermore, the patient does not have any symptoms or examination findings suspicious for myelopathy; therefore, cervicothoracic MRIs would likely be of low yield. However, they can be considered in a diagnostic evaluation for cases more suspicious for demyelinating to identify silent areas of involvement.
Notch3 testing is positive, and Ms. L is diagnosed with CADASIL. There are currently no proven therapies for CADASIL. The patient is started on symptomatic treatment for her migraines, a calcium channel blocker, and an antiplatelet agent for secondary stroke prophylaxis. Her family is referred to a genetics specialist for counseling, and she is currently being followed closely by a metabolic specialist.
Incorporation of MRI results into diagnostic criteria for MS represents an important advance that has facilitated early diagnosis and intervention. However, despite accuracy and utility of MRI in the diagnosis of MS, MRI abnormalities alone are not pathognomonic for MS. Diagnosis of MS requires there be âno better explanationâ for a patientâs clinical and radiographic findings. Numerous conditions can present with symptoms or imaging results that mimic those of MS, and evaluation for other possible causes is paramount. Accurate diagnosis therefore depends on careful consideration of the patientâs history, neurologic examination, imaging results, laboratory tests, CSF analysis, evoked potentials, and results of tests specific to other conditions in the differential diagnosis. Furthermore, a possible or probable diagnosis of MS should be continually challenged at follow-up visits based on current or changing symptomatology and/or paraclinical studies.
- Calabresi PA. Diagnosis and management of multiple sclerosis. Am Fam Physician. 2004;70:1935-1944.
- Barkhof F, Filippi M, Miller DH, et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain. 1997;120:2059-2069.
- Bar-Zohar D, Agosta F, Goldstaub D, Fillippi M. Magnetic resonance imaging metrics and their correlation with clinical outcomes in multiple sclerosis: a review of the literature and future perspectives. Multiple Sclerosis. 2008;1-9. Epub ahead of print. http://msj.sagepub.com.
- Rashid W, Miller DH. Recent advances in neuroimaging of multiple sclerosis. Semin Neurol. 2008;28:46-55.
- TintorÃ© M, Rovira A, Rio J, et al. Baseline MRI predicts future attacks and disability in clinically isolated syndromes. Neurology. 2006;67:968-972.
- 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.
- McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol. 2001;50:121-127.
- Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria." Ann Neurol. 2005;58:840-846.
- Weinshenker BG. Review: magnetic resonance imaging alone is of limited usefulness in diagnosing multiple sclerosis. Evid Based Med. 2006;11:155.
- Lebrun C, Bensa C, Debouverie M, et al. Unexpected multiple sclerosis: follow-up of 30 patients with magnetic resonance imaging and clinical conversion profile. J Neurol Neurosurg Psychiatry. 2008;79:195-1980.
- Bastianello S, Pichiecchio A, Spadaro M, et al. Atypical multiple sclerosis: MRI findings and differential diagnosis. Neurol Sci. 2004;25(suppl 4):S356-S360.
- Pohl D, Rostasy K, Reiber H, Hanefeld F. CSF characteristics in early-onset multiple sclerosis. Neurology.2004;63:1966-1967.
- Webb G, Turner M. Lumbar puncture. Medical Sciences Division Web site. http://www.medsci.ox.ac.uk/gazette/previousissues/Issue56vol2/56vol2%20part16. Accessed June 8, 2008.
- Charil A, Yousry TA, Rovaris M, et al. MRI and the diagnosis of multiple sclerosis: expanding the concept of "no better explanation." Lancet Neurol. 2006;5:841-852.
- 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.
- O'Riordan S, Nor AM, Hutchinson M. CADASIL imitating multiple sclerosis: the importance of MRI markers. Mult Scler. 2002;8:430-432.
- Ferreira S, D'Cruz DP, Hughes GRV. Multiple sclerosis, neuropsychiatric lupus and antiphospholid syndrome: where do we stand? Rheumatology. 2005;178:88-90.
- Tournier-Lasserve E, Joutel A, Melki J, et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy maps to chromosome 19q12. Nat Genet. 1993;3:256-259.
- Tournier-Lasserve E, Iba-Zizen MT, Romero N, Bousser MG. Autosomal dominant syndrome with stroke-like episodes and leukoencephalopathy. Stroke. 1991;22:1297-1302.