White Matter Diseases

Multiple Sclerosis

Multiple sclerosis (MS), first described by Charcot in 1868, is the most common demyelinating disease encountered in clinical practice (as well as in imaging). Affecting over 2 million worldwide, it is the leading cause of nontraumatic neurologic disability in young and middle-aged adults.

MS has a peak age range of 30 years with a female predominance; however, it can occur in children and adolescents (3% to 12%) and in those over 50 (10% to 20%). The authors feel that age is a state of mind and the authors’ immaturity level as evidenced by the attempts at so-called humor suggests a prolonged “at-risk” stage.

Symptoms range from isolated cranial nerve palsy, optic neuritis, and vague sensory complaints including paresthesias and numbness, to paresis and paraplegia of limbs, and myelopathy. Subtle and obvious changes in intellectual capacity are also identified in patients with MS.

The diagnosis of MS has recently been revisited at the International Panel of the Diagnosis of MS in Dublin, 2010 ( Table 6-1 ). The diagnosis can now be made based on clinical findings alone (2 events, 2 objective clinical findings) or in combination with clinical findings and MR findings. For MR, things have been simplified in that, if two or more of four possible locations of plaques are identified (those being the periventricular region, subcortical region, infratentorial region, and spinal cord), the MR scan meets the criteria of “dissemination in space” (DIS). If nonenhancing plaques and enhancing plaques coexist on the same scan or a second scan shows new enhancing or nonenhancing plaques, the criteria for dissemination in time (DIT) have been met. The full slate of possibilities for diagnosing MS is described in Table 6-1 .

As noted in Table 6-2 , two new entities have been described; one is clinically isolated syndrome (CIS), where only a single episode which may be unifocal clinically is identified. Eighty percent of patients with CIS at 15 years will meet diagnostic criteria for MS if they have positive MR findings but only 20% at 15 years get diagnosed with MS if they have a normal MR when staged as CIS. Seventy-seven percent of patients presenting with an isolated brain stem syndrome have been reported to have asymptomatic supratentorial white matter abnormalities. Progression to MS occurs in about 57% of patients with isolated brain stem syndrome and in 42% of patients with spinal cord syndrome.

The second entity is the radiologically isolated syndrome (RIS). In RIS, the patients have fulfilled the three of the four 2010 McDonald criteria for MS: (1) at least one gadolinium-enhancing lesion or nine T2 hyperintense lesions if there is no gadolinium enhancing lesion; (2) at least one infratentorial lesion; (3) at least one juxtacortical lesion; (4) at least three periventricular lesions. However, clinically they have not had an MS episode. In this situation, one third progress to a diagnosis of MS in 3 years and the rate increases significantly if there are enhancing plaques.

Laboratory tests for MS including visual, auditory, and somatosensory evoked responses can confirm the presence of lesions, but they are nonspecific and provide no clue to the cause of the abnormal finding. Approximately 70% of patients with MS have elevated cerebrospinal fluid (CSF) levels of IgG, and approximately 90% have elevated oligoclonal bands.

MS is a disease characterized by a variety of clinical courses. Terminology about clinical classification can be confusing and even contradictory. Relapsing remitting (RR) MS is the most common course of the disease initially occurring in up to 85% of cases. At the beginning, exacerbations are followed by remissions. However, over years additional exacerbations result in incomplete recovery. Within 10 years, 50% (and within 25 years, 90%) of these cases enter a progressive phase, termed secondary progressive (also termed relapsing progressive) MS. During this phase, deficits are progressive without much remission in the disease. Less commonly, the disease is progressive from the start, termed “primary progressive MS.” These patients (5% to 10% of the MS population) may present at a later age with progressive neurologic findings including paraparesis, hemiparesis, brain stem syndromes, or visual loss, and typically have a more severe disability. They may have occasional plateaus and temporary improvements, but do not have distinct relapses. Progressive-relapsing MS, a rare clinical course, is defined as progressive disease with clear acute relapses, with or without full recovery, and with the periods between relapses characterized by continuing progression. Benign MS describes those cases, where after initial clinical symptomatology, there is no clinical progression over, approximately, a 10- to 15-year course. Conversely, a rapid progressive disease leading to significant disability or death in a short time after the onset has been termed malignant MS.

The Kurtzke Expanded Disability Status Scale (EDSS) is often used to assess the deficits of patients with MS. The EDSS relies on an assessment of gait and eight functional systems: pyramidal motor function, cerebellar, brain stem, sensory, bowel and bladder, visual, cerebral or mental, and other. EDSS scores below 4.0 have normal gait and scores are determined by functional system deficits, if any. People with EDSS scores of 4.0 and above have some degree of gait impairment. Scores between 4.0 and 9.5 are determined by both gait abilities and the eight functional system scores.

Magnetic Resonance Findings

Brain Lesions

Fluid-attenuated inversion recovery (FLAIR) and T2-weighted imaging (T2WI) are the most useful MR sequences for identifying MS plaques. On both of these sequences MS plaques are seen as individual flame-shaped or confluent high-intensity areas in the white matter. MS lesions have a predilection for certain regions of the brain including the periventricular region, corpus callosum (best visualized on sagittal FLAIR images; Fig. 6-1 ), subcortical region (best seen on FLAIR), optic nerves and visual pathways, posterior fossa, the interface between the corpus callosum and septum pellucidum, and the cervical region of the spinal cord ( Fig. 6-2 ). However, MS lesions can and do occur in any location in the brain. This includes the cortex (6%), where white matter fibers track up to the superficial cortical cells, and the deep gray matter (5%), best seen on FLAIR. Caution to those of you who rely so heavily on FLAIR imaging and skip T2WI fast spin echo images—FLAIR imaging does not detect lesions in the posterior fossa, brain stem, and spinal cord as well as T2WI scans. In addition, very hypointense lesions on T1WI (see “black holes” below) may look similar to CSF on FLAIR, that is, not bright (like some of your professors) and thereby be overlooked (see Fig. 6-2 ).

High-intensity lesions at the callosal-septal interface (sagittal MR either proton density [PD] or FLAIR) have been suggested to have 93% sensitivity and 98% specificity in differentiating MS lesions from vascular disease (see Fig. 6-1 ). The shape of these MS plaques may be variable. However, ovoid lesions are believed to be more specific for MS. Their morphology has been attributed to inflammatory changes around the long axis of a medullary vein (Dawson fingers; Fig. 6-3 ).

On T1WI, plaques are isointense or hypointense regions, whereas on T2WI, the lesions are high intensity (see Fig. 6-2, A ). Uncommon hypointense lesions on T1WI that approximate CSF intensity have been termed “black holes” and have been reported to be associated with areas of greatest myelin loss. The volume of black holes correlates most closely with disability as determined by the EDSS.

Postcontrast MR images in patients with plaques may show no enhancing plaques, or a wide variety of patterns of enhancement indicating active demyelination. These include solid nodular, solid linear, complete ring, open ring/arcs, and punctate enhancement. All different types may coexist ( Fig. 6-4 ). Meningeal irritation near demyelination can cause meningeal enhancement as well. Cranial nerves (besides the optic nerve) can also enhance in MS as can superficial brain stem enhancement, but it does mean that other diagnoses should be considered ( Fig. 6-5 ). The normal window of enhancement is from 2 to 8 weeks; however, plaques can enhance for 6 months or more. Enhancement cannot be viewed as “an all or none” phenomenon, rather it is dependent on the time from injection to imaging, the dosage of contrast agent, the magnitude of the blood-brain barrier (BBB) abnormality, and the size of the space where it accumulates. Delayed imaging (usually 15 to 60 minutes following injection) increases the detection of enhancing MS lesions (and decrease patient throughput and revenue). Triple doses of gadolinium (0.3 mmol/kg) or a single dose (0.1 mmol/kg) with magnetization transfer (MT) to suppress normal brain can increase the number of detectable MS lesions (and fill the coffers of drug companies, while bankrupting radiology departments).

Lesions may display mass effect that can mimic a tumor (tumefactive MS) and have been associated with seizures ( Fig. 6-6 ). There are several hints that aid in suggesting this diagnosis including the history, which is usually acute or subacute onset of neurologic deficit(s) in a young adult, and other white matter abnormalities unassociated with the mass lesion, but characteristic of MS, such as in the periventricular zone, spinal cord, or callosal-septal interface. Tumefactive MS lesions often have a leading edge of enhancement and an incomplete “horseshoe-shaped” ring. Perfusion in tumors is usually increased and in MS it is typically not. Veins are displaced by neoplasms but course through MS lesions. There have also been rare reports of hemorrhage into demyelinating lesions.

Other findings include atrophy of the brain and spinal cord. The greater the loss of myelin and axons, the more likely there is atrophy and that the lesion becomes hypointense on T1WI. High intensity on unenhanced T1WI can be observed infrequently, most often in the periphery of the plaque (see Fig. 6-2, B ). The cause of this phenomenon is unknown, but hypotheses include a small amount of paramagnetic accumulation from hemorrhage, myelin catabolites including fat, free radical production from the inflammatory response, or focally increased regions of protein.

Increased iron deposition (in the thalamus and basal ganglia) producing low intensity on T1 and T2∗ or susceptibility-weighted sequences has been reported in patients with long-standing MS. This latter finding is nonspecific, having been described in a variety of different conditions including Parkinson disease, Wilson disease, multisystem atrophy, and other degenerative conditions.

With MS, one must recognize that there is disease in the normal appearing white matter (NAWM) which is beyond the resolution of standard imaging and contrast techniques. There are many new MR methods (diffusion tensor imaging [DTI], magnetization transfer imaging [MTI], magnetic resonance spectroscopy [MRS], susceptibility-weighted imaging [SWI]) that clearly demonstrate that the NAWM in MS is not normal, that is, there are lesions that we cannot detect by conventional MR. This is important, as the extent of disease in MS patients is generally greater than the visible T2 lesion load.

Multiple Sclerosis Syndromes

Many syndromes are associated with MS. Balo disease (concentric sclerosis) represents a histologic MS lesion with alternating concentric regions of demyelination and normal brain ( Fig. 6-7 ). Rarely, a similar pattern may be observed on T2WI scans. Diffuse sclerosis (Schilder disease) is an acute, rapidly progressive form of MS with bilateral relatively symmetric demyelination. It is seen in childhood and rarely after the age of 40 years. It is characterized by large areas of demyelination that are well circumscribed, often involving the centrum semiovale and occipital lobes. The Marburg variant of MS is defined as repeated relapses with rapidly accumulating disability producing immobility, lack of protective pharyngeal reflexes and bladder involvement.

Optic Neuritis

There are numerous causes of optic neuropathy. The most frequent, usually seen in the elderly, is acute ischemic optic neuropathy, which occurs in patients with atherosclerotic risk factors, particularly diabetes. This is more of a vascular insult than an inflammatory one. When one refers to optic “neuritis,” we are usually thinking about infectious (viral usually), inflammatory (e.g., sarcoidosis), or demyelinating disorders ( Box 6-4 ). It has been said that a person with an optic neuritis at first presentation has a 50% chance of carrying the diagnosis of MS in 5 years; that rate increases if there are MS-like plaques on their brain MRI scan but is less if the brain MRI scan is negative. All told, 80% of MS patients have an episode of optic neuritis at some point in their lives. Thus, the entity is considered separate from MS, but may overlap MS at the same time (50/50). For best visualization of optic neuritis, fat-suppressed scans through the orbit using FLAIR or T2 weighting is best ( Fig. 6-8 ). This nulls the orbital fat and/or the CSF around the nerve. That said, there have been studies suggesting that optic nerve enhancement may actually precede signal intensity abnormalities on T2WI scans in some cases of optic neuritis.