Multiple sclerosis differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Fahimeh Shojaei, M.D.

## Overview

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Multiple sclerosis must be differentiated from other diseases that can mimic this disease clinically or radiologically such as systemic lupus erythematosis, Sjögren’s syndrome, vasculitis, neuro-behçet’s disease, sarcoidosis, antiphospholipid (Hughes) syndrome , susac syndrome, lyme disease, syphilis, HTLV-1 infection, HIV-Related Disorders of the CNS, migraine, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, leber’s hereditary optic neuropathy, vitamin B12 deficiency, metachromatic leukodystrophy, Fabry’s disease, Krabbe’s disease, adrenoleukodystrophy, mitochondrial encephalopathy epilepsy lactic acidosis and stroke like episode, stroke, primary CNS lymphoma , and dural arteriovenous fistula and true malformations.

## Differentiating multiple sclerosis from other diseases

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Multiple sclerosis must be differentiated from other diseases that can mimic this disease clinically or radiologically such as:

#### Inflammatory/autoimmune conditions:

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* systemic lupus erythematosus: Systemic lupus erythromatosus can cause neurological manifestations such as seizures, movement disorders, transverse myelitis, cranial and peripheral neuropathies, and optic nerve involvement. In the brain MRI of SLE patients, there are pieces of evidence of atrophy and subcortical white matter lesions. SLE is diagnosed based on systemic manifestations, present of oligoclonal bands and IgG in CSF and high titer of antinuclear antibodies.
* Sjögren’s syndrome: Sjogren disease can cause neurological manifestations including cerebral vasculitis, myopathy, transverse myelitis and acute optic neuropathy. There are evidence of oligoclonal band and increased IgG in CSF and white matter lesions in MRI. Sicca syndrome, rheumatic manifestation and high titers of ANA. SSRo and SS-La will confirm the diagnosis.
* Vasculitis: Wegener’s granulomatosis and polyarteritis nodosa are sometimes categorized as a differential diagnosis of MS, but the most common vasculitis which can mimic MS, is isolated angitis of the central nervous system (IACNS). IACNS is an inflammatory disease with an unknown cause. It affects small and medium sized arteries in the brain parenchyma and meninges. Neurological manifestation of this disease is headache, personality change, paresis, seizures, cranial neuropathy and intracerebral /subarachnoid hemorrhages. There are monoclonal bands and increased protein and lymphocytic pleocytosis and IgG levels in the CSF of this patients. MRI may show patchy or diffuse increased signal in periventricular and subcortical white matter. diagnosis is made by evidences of vasculitis changes in angiography or biopsy.
* Neuro-behçet’s disease: Behcet’s disease is an idiopathic inflammatory disorder and can manifest as a triad of oral and genital ulcers and anterior uveitis. Lungs, gastrointestinal tract, joint, and skin can be involved too. Rarely, neurological signs can be the first manifestation of the disease. The most common neurological manifestation of behcet’s disease is psychiatric symptoms, intranuclear ophthalmoplegia, headache and sensory/motor deficits. The course of the disease can be relapsing remitting or progresive. In the CSF specimen we can see high levels of protein, pleocytosis (granulocytic, unlike MS) and oligoclonal bands (which can be suppressed by corticosteroid treatment). In MRI the most common involvement can be seen in brain stem and basal ganglia.
* sarcoidosis: Sarcoidosis is an inflammatory disease with formation of non caseating epitheloid granulomata. It’s a multisystem disease but affects lungs more than other organs. There is a 5-10% change of neurological involvement and in 50 % of these patients neurological involvement can be the first sign or symptoms. It usually affects cranial nerves, hypothalamus and pituitary gland. involvement of optic nerve, brain stem and spinal cord can mimic MS symptoms. In MRI we can see an isolated or diffuse lesion in brain parenchyma or even periventricular white matter lesion like MS. CSF analysis can be very same to MS but in sarcoidosis we have elevated amount of angiotensin converting enzyme.

* Antiphospholipid (Hughes) syndrome: In antiphospholipid syndrome, the presence of anticardiolipin and/or lupus anticoagulant can cause arterial and venous thrombosis. It can cause neurological manifestations like transient ischemic attack, ischemic encephalopathy, thrombosis of cerebral veins, seizure, headache, guillain barre syndrome, dementia, chorea and optic nerve neuropathy. In MRI there is evidence of white matter T2 hyperintense and/or cortical lesions. The latter is in favor of APS. In CSF analysis lack of oligoclonal bands is against the MS diagnosis. Differentiating MS from APS is so difficult that it’s recommended to treat MS patients for APS too.
* Susac syndrome: Susac syndrome is an idiopathic disease that causes microangiopathy of brain, retina, and cochlea arterioles. Involvement of this arterioles leads to visual disturbance, hearing loss, and encephalopathy. In MRI there is white and gray matter lesions and leptomeningeal involvement. CSF analysis shows elevated protein level and pleocytosis.

#### Infections:

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* Lyme disease: Borrelia burgdorferi is transmitted through a tick bite and can cause rash (erythema chronica migrans) typical for lyme disease. This disease can affect cranial nerves especially seventh nerve. It is usually easily differentiated from MS because of meningitis involvement in MRI and pleocytosis as well as high lyme titer in CSF.
* syphilis: Neurosyphilis, more commonly seen in HIV+ patients can be in two forms. One can be seen in late secondary or early tertiary stages as meningovascular involvement and the other one can be seen in later stages as parenchymal involvement. Meningovascular lesions can present like a stroke while the other one cause gummas (contrast enhancing lesions). In CSF, there are pieces of evidence of oligoclonal bands, pleocytosis, and elevated gammaglobulin.
* Progressive multifocal leukoencephalopathy: Progressive multifocal leukoencephalopathy (PML) is cause by activation of JC virus and is more commonly seen in immunocompromised patients. Some evidences shows the relation between PML and drug natalizumab. In MRI of PML patients we see multiple white matter lesions that can become confluent with no enhancement in T1. Diagnosis of PML is based on detecting JC virus in CSF.
* HTLV-1 infection: Human T lymphotrophic virus, transmitted through sexual activity, can cause tropical spastic paraparesis. The involvement of spinal cord and MRI pattern of Tropical spastic paraparesis can mimic MS disease. In CSF we have positive HTLV-1 titer, lymphocytic pleocytosis, oligoclonal bands and high level of proteins.
* HIV-Related Disorders of the CNS: HIV infection frequently involves CNS and can be the initial manifestation of the disease. In an MRI, there are white matter lesions. In a CSF analysis, there are high levels of proteins and cell counts but oligoclonal bands are rarely seen.

#### Metabolic and Genetic/Heriditary Disorders:

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* Migraine: Migraine is a throbbing headache, which worsens by sound and light. It can cause a variety of transient neurological manifestation including sensory loss, visual loss, ophtalmoparesis, and vertigo. These manifestations can occur before or with the migraine headache but in some cases, which we call “amigrainous migraine”, we have neurological problems without headache. In an MRI of these patients, we can see small areas of deep frontal white matter lesions.
* Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy:
* Leber’s hereditary optic neuropathy: Leber’s hereditary optic neuropathy is caused by mitochondirial DNA mutation. It presents as acute bilateral blindness. The MRI finding of MS and LHON are alike and make it difficult to differentiate them.

* Vitamin B12 deficiency: B12 deficiency can cause neurological manifestation including peripheral neuropathy, optic neuropathy, cervical myelopathy, and fatigue. MRI findings include contrast enhancement of posterior and lateral spinal cord columns preferably in cervical and thoracic levels.
* Lysosomal disorders:

1. Metachromatic leukodystrophy: MLD is an autosomal recessive lysosomal storage disease that leads to accumulation of galactosyl sulfatide.
2. Fabry’s disease: X-linked disease with impaired activity of a-galactosidase leading to accommodation of globotriaosylceramide in many organs including ganglion cells of the autonomic nervous system.
3. Krabbe’s disease: Autosomal recessive disease with impaired activity of galactocerebrosidase leading to destruction of CNS and PNS myelin and axonal degeneration.

* Adrenoleukodystrophy: ALD disease causes accumulation of long chain fatty acids. X-linked type of this disease (adrenomyeloneuropathy) will cause spinal cord disease and peripheral neuropathy and can be considered as a differential diagnosis of MS disease.
* mitochondrial encephalopathy epilepsy lactic acidosis and stroke: One of the mitochondrial diseases that can categorized as a MS differential diagnosis in mitochondrial encephalopathy epilepsy lactic acidosis and stroke (MELAS). The manifestations include: Seizures, exercise intolerance, limb weakness, stroke like episodes, hemiparesis and hemianopia. There are evidences of calcium deposition in caudate nucleus and globus pallidus in CT scan and cortical involvement in MRI imaging.

#### CNS lymphoma

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Primary CNS lymphoma is mostly diffuse large B-cell lymphoma (DLBCL). These patients more commonly present with neurological manifestation rather than B symptoms. In MRI evaluation, because of high cell count and scant cytoplasm lesions become isotense to hypointense on T2. In CSF analysis, there are increased number of WBC and proteins, low levels of glucose and positive cytology for cells with enlarged nucleus and course chromatin.

#### spinal diseases

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Dural arteriovenous fistula and true malformations can be mistaken with MS since they can all cause thoracic myelopathy.

## References

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