Multiple sclerosis

Differential diagnosis
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By Anthony T Reder MD

Monosymptomatic illnesses from focal or multifocal insults can mimic the first attack of multiple sclerosis and cover a wide spectrum of n

Monosymptomatic illnesses from focal or multifocal insults can mimic the first attack of multiple sclerosis and cover a wide spectrum of neurologic diseases.

Postinfectious and postvaccinal encephalomyelitis follow inflammation-induced sensitization to myelin antigens. Postvaccinal or postinfectious reactions cause inflammatory demyelination that is localized (eg, transverse myelitis, optic neuritis) or diffuse (eg, encephalomyelitis). The symptoms often develop after upper respiratory tract infections (usually viral or mycoplasma) or vaccinations, leading to acute disseminated encephalomyelitis. Oligoclonal bands in CSF are less common than in multiple sclerosis and, if present, often disappear. MRI lesions should all be of the same age, but several weeks after onset, partially-resolved lesions can appear to be different ages. The perivascular inflammation and demyelination is similar to the pathology of multiple sclerosis, but these fever-associated disorders are monophasic (Tselis and Lisak 1995). Experimental allergic encephalomyelitis is the animal model. If multiple sclerosis patients are vaccinated with porcine myelin basic protein, they can develop postinfectious encephalomyelitis. Nonrecurring demyelinating disease suggests (1) a primary response to the antigen and (2) that myelin basic protein does not trigger multiple sclerosis.

Recurrent symptoms that mimic relapsing-remitting multiple sclerosis may be caused by focal repetitive insults such as transient ischemic attacks or exacerbations of connective tissue disease. Vascular insults usually have a rapid onset (Hamamcioglu and Reder 2005). In hypertensive vascular disease, MRI lesions are in the centrum semiovale instead of periventricular sites, are not in cerebellar outflow pathways, and do not spare subcortical U fibers. Some authors have implicated anticardiolipin antibodies and granulomatous angiitis in multiple sclerosis-like syndromes. CADASIL, Binswanger disease, hemiplegic migraine, Sjögren syndrome, and Behçet disease can cause episodic, multifocal central nervous system lesions that can be confused with multiple sclerosis clinically and on MRI.

Progressive cord symptoms can be caused by subacute combined degeneration, adrenoleukodystrophy, chronic fatigue syndrome, and tropical spastic paraparesis from human T cell lymphotropic virus infection. Damage from a spinal dural arteriovenous fistula, cavernous hemangioma, or tumor can cause indolent cord symptoms. Progressive symptoms also suggest metabolic problems (copper, vitamin B12, vitamin E, or folate deficiency—often from complications of gastric bypass surgery), genetic disorders (adrenoleukodystrophy, sometimes with a late inflammatory phase; hereditary spastic paraplegia; Wilson disease), and mitochondrial disorders (Natowicz and Bejjani 1994). Magnetic resonance spectroscopy can help differentiate plaques from central nervous system tumors.

“Phenocopies” of multiple sclerosis appear on MRI scans. CADASIL, hypertensive vascular disease, Susac syndrome, leukodystrophies, vanishing white matter disease, Alexander disease, sarcoid, and migraine all cause MRI changes that overlap with the appearance of multiple sclerosis.

Transverse myelitis can be an isolated event or the first sign of multiple sclerosis or neuromyelitis optica. The cord lesion in multiple sclerosis is more often partial, patchy, and asymmetric, and not symmetrical and bilateral as in idiopathic transverse myelitis. MRI abnormalities and local demyelination may be extensive in transverse myelitis, but CSF abnormalities are less common than in multiple sclerosis.

Optic neuritis is often the first sign of multiple sclerosis. Isolated optic neuritis involves only the optic nerves, without dissemination of other lesions in time and space. CSF oligoclonal bands are less common than in multiple sclerosis. However, one third of patients with optic neuritis will eventually develop multiple sclerosis. Demyelination of the optic nerve is often pronounced in isolated optic neuritis. Optic neuritis must be differentiated from ischemic optic neuropathy, increased intracranial pressure causing papilledema, vitamin B12 deficiency, vasculitis (temporal arteritis), viral infections, and Devic disease.

Conditions that can be confused with multiple sclerosis:

  • Acoustic neuroma. Nerves VIII, V, and VII are compressed by slowly expanding neuroma or meningioma.
  • Acute disseminated encephalomyelitis (ADEM) often follows an infection or vaccination (postinfectious or postvaccinal encephalomyelitis). ADEM is more likely to occur in children and to have a polysymptomatic or multifocal presentation, with systemic symptoms that are uncommon in multiple sclerosis. Patients develop sudden pyramidal symptoms, bilateral optic neuritis (unilateral optic neuritis is seldom or never seen and suggests multiple sclerosis). Importantly, there is also fever, headache, vomiting, shooting pains, meningismus, encephalopathy, altered consciousness, EEG changes, and blood and CSF pleocytosis. Oligoclonal bands in CSF are uncommon (0% to 30%), but protein is often greater than 100 mg/dl.

MRI lesions are large, “fluffy,” enhancing, often in ring patterns, often in a diffuse bilateral pattern, often in the corpus callosum and thalamus (thalamic T2 lesions are rare in multiple sclerosis), seldom in a Dawson finger shape, and less often periventricular and seldom cause T1 black holes (Dale et al 2000). Macrophages and sleeves of (later) demyelination surround venules in many small and large inflammatory lesions. Axons are relatively preserved. Myelin loss is more pronounced in multiple sclerosis than in acute disseminated encephalomyelitis and experimental allergic encephalomyelitis. All lesions are approximately the same age in the initial attack. A storm of many cytokines appears, with high granulocyte colony stimulating factor but no IL-17.

ADEM is usually monophasic, and MRI lesions are of similar age. This basic form lasts up to 3 months. Symptoms can fluctuate, and MRI may transiently show Gd-enhancing and nonenhancing lesions as ADEM evolves. If similar lesions reappear 3 months later, it is termed “recurrent ADEM.” In “multiphasic ADEM,” new brain areas are involved during a second episode. It is possible that abrupt discontinuation of steroid therapy allows recrudescent lesions. Therapy with high-dose glucocorticoids and then a prolonged taper is advised in ADEM.

There is more genetic linkage in multiple sclerosis. Multiple sclerosis eventually develops in 20% to 33% of ADEM patients. Thus, most patients with ADEM (66% to 80%) do not develop multiple sclerosis and should not be treated for multiple sclerosis when oligoclonal bands are negative.

  • Acute hemorrhagic leukoencephalitis appears to be a more severe form of ADEM but may have a distinct etiology.
  • Acute ischemic optic neuropathy has a sudden onset, may progress over several days with an unremitting course, and is typically seen in patients 60 to 100 years old. Pain is uncommon. Visual loss involves the central fixation area but is altitudinal, with sharp borders. Ischemic optic neuropathy is likely to cause disc swelling, pallor, arterial attenuation, hemorrhage, and permanent loss of vision.
  • Acute necrotizing encephalopathy of childhood, seen in Asian countries, follows several days of fever with a respiratory or gastrointestinal virus infection. Lesions are hypointense on T1 and hyperintense on T2 MRI in the bilateral thalami (classic for this condition) but are not present in the basal ganglia and cerebral cortex.
  • Aminoaciduria: 3-methylglutaconic aciduria type I causes adult onset leukoencephalopathy.
  • Amyloid angiopathy causes cerebral microhemorrhages but also a leukoencephalopathy that involves the U-fibers. Iron in lesions can be seen on T2-weighted MRI.
  • Aneurysm of intracranial blood vessels.
  • Atopic myelitis, idiopathic eosinophilic myelitis, hyperIgEaemic myelitis.
  • Autoimmune thyroid disease--often familial, causes tremor, seizures, and predominant cord involvement.
  • Balo concentric sclerosis has large concentric lesions with centrifugal waves of demyelination and remyelination. There is loss of myelin-associated glycoprotein and oligodendrocyte apoptosis. Demyelinated areas are high in nitric oxide synthetase (iNOS). Hypoxic conditioning may explain the rings, where sublethal hypoxia provides resistance to later injury. In the outer edge of preserved tissue, hypoxia-inducible factor1alpha (HIF) is increased (Stadelmann et al 2005), as it is in normal-appearing white matter in multiple sclerosis.
  • Behçet disease – CSF pleocytosis, large MRI lesions in upper brainstem and basal ganglia, occasional punctuate parenchymal enhancement. Behçet disease causes intermittent cranial nerve deficits, but it is associated with genital and oral ulcers, uveitis, and meningoencephalitis. Biopsies show polymorphonuclear cells and eosinophils surrounding arterioles. Optic neuropathy is relatively rare in Behçet disease.
  • CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), caused by a mutation of the Notch gene. Notch affects oligodendrocyte maturation and lymphocyte development. The intermittent strokes in midlife on a background of patchy MRI T1 holes plus diffuse increased white matter T2 signal can be confused with multiple sclerosis. T2 lesions are large and confluent and often significantly involve the anterior temporal lobes. It is diagnosed with skin biopsy (forearm) for granular osmiophilic material in arterioles, or with DNA analysis for the Notch mutation.
  • Cancer--primary and secondary brain tumors. Hemophagocytic lymphohistiocytosis, Langerhans cell histiocytosis, and neoplastic angioendotheliosis can be confused with multiple sclerosis.
  • Carcinomatous polyradiculopathy (typically with adenocarcinoma of breast and lung, lymphoma, or melanoma).
  • Cavernous sinus thrombosis affects cranial nerves III, IV, V, and VI.
  • Celiac antibodies are not increased in multiple sclerosis, but celiac disease can cause myelopathy and encephalopathy.
  • Cerebellar degeneration and Friedreich ataxia can mimic progressive cord symptoms.
  • Cerebrotendinous xanthomatosis (progressive myelopathy in a young patient, but with cataracts, diarrhea, ankle tendon xanthomas, and cerebellar dentate lesions on MRI).
  • Cervical compression (disc, spondylosis, or tumor) can cause a progressive paraparesis, gait disorder, and bladder dysfunction.
  • Charcot-Marie-Tooth disease (brain MRI lesions and progressive course).
  • Chemotherapy can cause a leukoencephalopathy (Ara-C, cisplatin, 5-fluorouracil, 5-florauracil+levamisol); neurotoxicity is worse with radiotherapy and progresses over time.
  • Chronic inflammatory demyelinating polyradiculoneuropathy with optic neuritis.
  • Cogan syndrome (vestibulo-auditory problems).
  • Congenital adrenal hyperplasia (diffuse brain white matter and corpus callosum abnormalities).
  • Connective tissue diseases can mimic multiple sclerosis. These diseases can cause vasculitis with neuropathy, cranial nerve damage, and CNS destruction. Systemic lupus erythematosus causes a severe, progressive thoracic myelopathy also called “lupoid sclerosis” or “acute lupus myelopathy.” It is acute or subacute with scattered white matter lesions in the cortical/subcortical junction but can affect gray and white matter. Twenty percent of patients have optic neuropathy in one or both eyes. When the cord is involved, the damage extends over many segments or the entire cord. Most patients with systemic lupus erythematosus, however, have no cord lesions. Treatment of connective tissue disorders diametrically differs from multiple sclerosis therapy, as interferons could cause worsening. (Sjögren syndrome is described below.) Craniofacial scleroderma is associated with bilateral-enhancing MRI lesions and oligoclonal bands.
  • Copper deficiency causes a progressive myelopathy and neuropathy, often related to gastrointestinal disorders, post-gastric bypass, and zinc excess (similar to the cuprizone model in rodents).
  • Cortical blindness must be discriminated from optic neuritis.
  • Cranial arteritis can affect the posterior optic nerve, without papilledema, in 70- to 80-year-old patients. It is associated with devastating visual loss; temporal pain, fever, weight loss, headache, fever, elevated sedimentation rate, and polymyalgia rheumatica.
  • Devic disease, or neuromyelitis optica, is a demyelinating, sometimes necrotic, inflammatory disease of the spinal cord and the optic nerves. Attacks are more severe and more frequent than in multiple sclerosis. In Asia and South America and in Native American Indians, Devic disease is more common than multiple sclerosis, and IL-17 may play a role in pathology (Ishizu et al 2005). In Europe and the United States, multiple sclerosis is far more common. Devic disease traditionally accounted for less than 1% of Occidental demyelinating disease, but a test (NMO-IgG) suggests that approximately 5% of “multiple sclerosis” cases with optic neuritis and longitudinal cord lesions are the Devic variant. This IgG1 neuromyelitis optica antibody recognizes aquaporin-4, a water transport channel that is localized in astrocyte foot processes over paranodal axons and near blood vessels. Aquaporin-4 is present in high levels in renal tubules, possibly explaining the low glomerular filtration rate in progressive multiple sclerosis (Calabresi et al 2002). Antibodies to aquaporin predict development of Devic disease and a more severe course. Devic disease is associated with connective tissue disease, rheumatoid arthritis, pernicious anemia, hypothyroidism and antibodies to thyroid antigen, and myasthenia gravis. The odds ratio of having another autoimmune disease is 10. Linkage of multiple sclerosis to these autoimmune disorders becomes unlikely when the Devic disease cases are eliminated from the “multiple sclerosis” pool. CNS Sjögren disease is similar to Devic disease (detailed below). Only 40% of CNS Sjögren patients are NMO-IgG positive, although 85% have positive minor salivary gland biopsies.

Devic disease is monophasic in one third of patients and relapsing in two thirds (Wingerchuk et al 1999). Devic disease has severe and frequent relapses and does not become progressive. The damage in the optic nerves and cord is diffuse, often total, and includes significant axonal loss. Lesions are sometimes cavitary and necrotic and are often hypointense on T1-weighted MRI scans. The spinal lesions extend over more than 2 vertebral segments and are usually cervical. Cervical MRI images in Devic disease are similar to CNS Sjögren disease. In the strict definition, MRI scans of the brain are normal; there is no demyelination in the brain, brainstem, or cerebellum (Mandler et al 1993). However, 20% later evince large brainstem and hypothalamic lesions, sometimes enhancing. CSF protein and neurofilament heavy chain levels are elevated. Seventy-five percent of patients have CSF pleocytosis, and 35% have greater than 50 cells/mm3; polymorphonuclear cells are often present. CSF IgG synthesis is usually normal, and CSF IgG1 is not elevated (it is elevated in multiple sclerosis). Oligoclonal bands are less common (40% or less) than in multiple sclerosis (97%) and can disappear over time.

Lesions in parenchyma and meninges have more IgM than IgG. There are few T cells but prominent eosinophils and granulocytes, likely related to excess IL-17. Aquaporin-4 is modulated off the astrocyte foot processes in Devic disease but not in multiple sclerosis. Although this antibody is present at all times, the attacks are intermittent.

Rituximab was therapeutic in a series of 8 patients (Cree et al 2005). Plasmapheresis may also reduce symptoms. Interferon therapy may cause worsening (Javed and Reder 2006; Wang et al 2006; Warabi et al 2007).

  • Eales disease, a syndrome of retinal perivasculitis and recurrent intraocular hemorrhages, is infrequently associated with neurologic abnormalities (7 of 17 patients).
  • Folate deficiency can cause encephalopathy and spastic paraparesis.
  • Gadolinium encephalopathy (MRI lesions).
  • Genetic—see storage disease.
  • Guillain-Barré Syndrome, Fisher variant, affects cranial nerves and eye movements. There are rare cases of this disorder and chronic inflammatory demyelinating polyneuropathy along with multiple sclerosis.
  • Hemophagocytic lymphohistiocytosis (associated with Epstein-Barr virus or a perforin mutation) loss of function prevents termination of immune response and inflammation of brain and peripheral nerves.
  • Hepatic encephalopathy, with symmetric high MRI T1 signal in the globi pallidi, likely from manganese deposition.
  • Hereditary spastic paraplegia (vs primary progressive multiple sclerosis).
  • Hypothyroidism--can cause constipation and fatigue even though the motivation to act remains. In multiple sclerosis, abulia is sometimes associated with fatigue.
  • Increased intracranial pressure and normal pressure hydrocephalus can cause visual and long tract findings.
  • Infection. Tuberculosis, tuberculomas, sarcoidosis, fungus such as Cryptococcus, syphilis, Lyme disease (Borrelia burgdorferi), chlamydia, mycoplasma, toxoplasmosis, brucellosis (abscesses, occasionally intramedullary, can involve spinal cord), familial Mediterranean fever, Listeria monocytogenes (cervical cord lesions), CNS Whipple disease, toxocariasis, purulent leptomeningitis, or intraocular inflammation. Inflammation of the paranasal sinuses seldom causes optic nerve inflammation.
  • Inflammatory bowel disease with brain lesions.
  • Leber hereditary optic neuropathy is a hereditary, maternally transmitted mitochondrial disease (base pair 11778 of mitochondrial DNA, causing loss of function of the reduced form of nicotinamide adenine dinucleotide dehydrogenase 4). It causes bilateral, often sequential, visual loss. In females, but not in males, it is sometimes indistinguishable from multiple sclerosis because of associated multiple sclerosis-like symptoms, destructive white mater lesions containing macrophages and CD8 T cells, widespread and periventricular white matter lesions on MRI, abnormal evoked potentials, and sometimes abnormal CSF (Harding et al 1992; Kovacs et al 2005). In men, diffuse white matter lesions are not present, but affected optic nerves show abnormalities on short-term inversion recovery MRI. The symptoms are often unilateral but eventually are bilateral. Visual loss is permanent and untreatable. Although neurons (third order retinal neurons) are the main targets in Leber disease, a parallel mitochondrial defect could theoretically also make oligodendroglia more susceptible to damage in multiple sclerosis. Other ocular disorders include Eales disease and retrobulbar vasculopathy of Susac (Weinshenker and Lucchinetti 1998; Susac et al 2003).
  • Leukoencephalopathy with vanishing white matter in adults causes slow neurologic deterioration and white matter lesions. Autosomal recessive mutation in eukaryotic initiation factor 2B (eIF2b) increases unfolded proteins.
  • Lyme disease is occasionally associated with unilateral or bilateral optic neuritis or ischemic optic neuropathy (in addition to retinal vasculitis), internuclear ophthalmoplegia, deafness, and multiple other neurologic signs.
  • Lymphoma can form white matter MRI lesions.
  • Maculopathy or macular degeneration.
  • The Marburg variant of multiple sclerosis has axonal loss and severe widespread diffuse or multifocal demyelination. Lesions can be of different ages and contain massive macrophage and CD8 cell infiltrates; in one case, inflammation preceded the demyelination. Death is within a year. Death in 1 month is frequent, often from brainstem or upper cord lesions. Steroids and chemotherapy prolong life to 3 months; plasmapheresis may be helpful.
  • Marchiafava-Bignami disease causes demyelination of the corpus callosum; lesions usually involve the medial corpus callosum, and there is clinical hemispheric disconnection.
  • Metastasis from cancer.
  • Metronidazole causes transient cerebellar dentate lesions.
  • Migraine can cause visual disturbances, vertebrobasilar symptoms, and disseminated T2 lesions on MRI. In women, when migraines are frequent and associated with aura, MRIs show small cerebellar infarcts—the location is more lateral than the cerebellar peduncle lesions of multiple sclerosis. Occasionally deep white matter lesions are seen in the centrum semiovale, likely from associated hypertensive disease (Kruit et al 2004).
  • Miller-Fisher syndrome (subacute ataxia and ophthalmoplegia from Guillain-Barré syndrome).
  • Mitochondrial disorders. Genetic mitochondrial syndromes can cause strokes, diffuse periventricular T1 holes and T2 white matter lesions, including the spinal cord. Non-syndromic mitochondrial disorders can cause scattered white matter lesions on FLAIR MRI.
  • Myasthenia gravis can cause diplopia and muscle weakness.
  • Myotonic dystrophy types 1 and 2 (brain white matter lesions on MRI).
  • Neoplastic (lymphoma, intravascular lymphoma, primary or metastatic central nervous system tumor; can involve eyes also).
  • Neuroretinitis. This is a form of papillitis with associated deposits of lipids and protein. These deposits radiate from the macula and form a stellate pattern at the macula or a half star between the macula and the disc. The "macular star" is formed as fluid from leaking disc capillaries accumulates within Henle layer around the fovea. The macular star may take up to 2 weeks to form after the onset of papillitis. The symptoms are similar to those in typical optic neuritis, but neuroretinitis seldom progresses to multiple sclerosis, suggesting that another etiology has been confused with multiple sclerosis.
  • Nutritional neuropathy includes Jamaican neuropathy and Cuban epidemic neuropathy.
  • Optic nerve glioma ("benign" glioma of childhood–a pilocytic astrocytoma; malignant glioblastoma is more common in adults).
  • Orbital pseudotumor with proptosis, pain, and ophthalmoplegia, but infrequent visual loss.
  • Paraneoplastic (anti-CV2 antibodies for optic neuritis. Also possible are limbic encephalitis, brainstem encephalitis, cerebellar degeneration, and lobar encephalopathy with large MRI lesions).
  • Parasites can migrate into the CNS and cause focal symptoms and must be excluded in patients from endemic areas, eg, cysticercosis.
  • Pelizaeus-Mertbacher disease (brain MRI lesions and progressive course), including proteolipid protein-1 mutation.
  • POLG-1 mutations (mitochondrial DNA polymerase gamma) can cause progressive CNS signs in childhood or late teens.
  • Porphyria. Hereditary coproporphyria can cause progressive CNS and PNS symptoms.
  • Posterior reversible leukoencephalopathy (PRES). There is increased T2 MRI signal in white > gray matter. Triggers include eclampsia, acute renal failure, hypertensive encephalopathy, and immunosuppressive drugs such as cyclosporin (high dose) and methotrexate.
  • Progressive multifocal leukoencephalopathy (PML). There are progressive symptoms such as cognitive loss, occipital visual loss, and hemiparesis. MRI lesions are usually large and rarely enhance. Optic neuritis or cord lesions are very likely.
  • Progressive necrotizing myelopathy provoked by mycoplasma pneumoniae, m Tb. In rats with experimental allergic encephalomyelitis, it is provoked by tilorone, an IFN-alpha/beta inducer.
  • Pseudotumor cerebri (visual loss).
  • Pseudoxanthoma elasticum (brain MRI lesions and vascular disease).
  • Radiation necrosis. Possibly treated with corticosteroids and hyperbaric oxygen.
  • Raeder paratrigeminal syndrome is unilateral facial pain in the V1 and V2 branches of the trigeminal nerve; it is associated with ptosis and miosis from a parasellar mass and must be differentiated from trigeminal neuralgia due to multiple sclerosis.
  • Sarcoidosis can involve single or multiple cranial and peripheral nerves, the brainstem, hypothalamus, and meninges.
  • Schilder disease (diffuse sclerosis) causes large hemispheral demyelinating lesions.
  • Sjögren syndrome. When associated with central and peripheral nervous system lesions, classic symptoms (sicca and rheumatic) are less common than in primary Sjögren disease. Serum antibodies to Sjögren syndrome A and B proteins (SSA and SSB) are positive in only one third of patients and are more often negative than in Sjögren disease without neurologic symptoms. A lip or parotid biopsy is needed to clinch the diagnosis (Alexander et al 1986; Sandberg-Wollheim et al 1992; Javed and Reder 2006).

In CNS Sjögren syndrome, one third have MRI, CSF, or evoked potential evidence of cerebral abnormalities; one third have longitudinal spinal cord lesions; the rest have optic neuritis and diffuse symptoms such as seizures, cognitive loss, and encephalopathy (Delalande et al 2003). In patients with CNS Sjögren lesions, there are small white matter MRI lesions in two thirds (occasionally in basal ganglia, infrequently in corpus callosum), oligoclonal bands in one third, and abnormal visual evoked potentials in about two thirds (de Seze et al 2003). PNS Sjögren disease can cause sensory ganglionitis, painful sensory neuropathy, and distal sensory-motor axonopathy.

Adil Javed has described a new Sjögren-related entity, seen predominantly in young black women. Patients with severe destruction from optic neuritis and longitudinal cervical cord lesions resemble patients with Devic disease, but NMO-IgG levels are negative in 60%. However, minor salivary gland biopsy is positive for Sjögren disease (inflammation grade 4+/4) in 85%, often when SSA and SSB serology is negative (Javed et al 2008). Other autoimmune diseases (myasthenia gravis, primary biliary cirrhosis) are often present. Treatment differs from multiple sclerosis therapy, as interferons may cause worsening. Mycophenolate mofetil provides some benefit, but the best responses are with rituximab (Javed personal communication 2007).

  • Storage disorders and genetic diseases versus childhood multiple sclerosis. Leukodystrophies are usually confluent and bilateral on MRI. Juvenile metachromatic leukodystrophy and late onset Tay Sachs disease have MRI signatures that could be confused with multiple sclerosis. Also to be considered are adult polyglucosan body disease (glycogen-branching enzyme mutation causes accumulation of polyglucosan bodies throughout the nervous system and cerebral myelin loss), Alexander disease (frontal, cerebellar, brainstem, and spinal cord T2 MRI lesions), childhood ataxia with cerebral hypomyelination (eIF2b mutation), late onset Canavan disease (mutations of aspartoacylase gene, restricted to oligodendrocytes, with accumulation of the substrate molecule N-acetyl-aspartate, NAA), Fabry disease (periventricular lesions, but non-multiple sclerosis clinical symptoms), Pelizaeus-Merzbacher disease (PLP mutation and dysmyelination; “jimpy” mouse is model), Refsum disease (ataxia and MRI lesions), and Wilson disease.
  • Subacute myelo-optic neuropathy (SMON) from halogenated hydroxyquinolines, including Entero-Vioform, diodoquin, and clioquinol.
  • Subacute sclerosing panencephalitis (SSPE)--T2 MRI lesions in periventricular and subcortical white matter, but this progressive disorder follows measles infection, with high titers of anti-measles antibodies.
  • Susac syndrome. Retrobulbar vasculopathy of Susac causes encephalopathy, branch (distal) retinal artery occlusions, and hearing loss (Weinshenker and Lucchinetti 1998). It affects 20- to 40-year-old women and is associated with headaches, hearing loss, tinnitus, pseudobulbar speech, and encephalopathy. There are microangiopathic infarcts in gray and white matter, and bilateral branch artery occlusions in the retina. MRI shows many multifocal white matter lesions of the central corpus callosum, plus lesions in deep gray, posterior fossa, brain parenchyma, and occasionally the leptomeninges. Acute large “snowballs” and multiple older small “punched-out” areas riddle the central corpus callosum (Susac et al 2003). Intravenous immunoglobulin and corticosteroids improve hearing and MRI.
  • Syphilis also has huge variety in its presentation.
  • Thyroid ophthalmopathy can cause diplopia.
  • Tobacco-alcohol amblyopia.
  • Tolosa-Hunt syndrome. Painful ophthalmoplegia with subacute boring eye pain, palsy of extraocular muscles, V1 sensory loss, sympathetic denervation of pupils, and rapid responses to 100 mg prednisone.
  • Trauma; direct or after anterofrontal deceleration.
  • Tuberculomas in the brain parenchyma.
  • Tuberous sclerosis can cause subcortical tubers that appear in white matter on MRI.
  • Tumor necrosis factor receptor-1-associated periodic syndrome (TRAPS; familial Hibernian fever) from a mutation in the p55 receptor for TNF occasionally has onset and MRI features of multiple sclerosis (Kumpfel et al 2008). It does not respond or have side effect with multiple sclerosis therapies, but improves with anti-TNF therapy.
  • Vaccination (polio and possibly influenza). Associations reported in a few papers are likely spurious, as the vast majority of studies find no link. Some find a 3-fold increase in the incidence of multiple sclerosis after vaccination with recombinant hepatitis B vaccine, but not with vaccines against other viruses (Hernan et al 2004), yet others report no increase. Confusion clouds this issue from statistical and reporting problems--combining data on recombinant and nonrecombinant vaccines, written versus computer records, and date of onset versus date of diagnosis. Most experts urge caution with live virus vaccines (measles, mumps, rubella, varicella/zoster, and yellow fever).
  • Vanishing white matter disease, from a defect in eukaryotic translation factor eIF2B, occurs rarely in adults, with progressive symptoms and white matter lesions on FLAIR MRI.
  • Vascular disease lesions are usually spherical and tend to be located in the centrum semiovale instead of “fingers” radiating outward from the corpus callosum. Some lesions in hypertensive elderly patients, however, are periventricular and are quite similar to multiple sclerosis lesions. Lacunes are common in the basal ganglia, but not in the corpus callosum. Vascular lesions with aging tend to be smaller and random but sometimes symmetrically involve the periventricular white matter in confluent posterior ischemic damage (Arnold and Matthews 2002). Vascular malformations and cavernous hemangiomas show persistent Gd enhancement.
  • Vasculitis (temporal arteritis, angiitis, cranial arteritis, Churg-Strauss syndrome).
  • Viruses or viral encephalitis (measles, mumps, rubella, chickenpox, cytomegalovirus, hepatitis A and B, herpes zoster vasculopathy, HHV-6 encephalomyelitis, acute HIV infection, HTLV-I (also associated with Sjögren syndrome), infectious mononucleosis, Japanese encephalitis (a flavivirus with bilateral thalamic lesions and polio-like flaccid paralysis), post-measles autoimmunity and subacute sclerosing panencephalitis, poliomyelitis (central cord lesions on MRI), West Nile virus (flavivirus) with a polio-like presentation.
  • Vitamin B12 deficiency causes subacute combined degeneration with centrocecal scotomata, optic atrophy, MRI lesions around the corpus callosum (not Dawson fingers), partially reversible leukoencephalopathy, and long tract signs from cord degeneration.
  • Vitamin E deficiency causes ataxia, myelopathy, and neuropathy.

In This Article

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited