7.1 Multiple Sclerosis
(Synonym: Disseminated sclerosis)
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of unknown etiology that involves demyelination of the central nervous system (CNS) with resultant neurologic dysfunction. The clinical manifestations are extremely variable in type and severity. Its onset is usually between 10 and 59 years (between 20 and 40 years approximately for 70% of patients). Prevalence is higher in Caucasians/Northern Europeans with female-to-male ratio of 2:1.
Most cases are sporadic; 25% concordance rate in monozygotic twin studies and studies of first-degree relatives (children of patients with MS have 30 to 50 times increased risk). Risk factors that are considered are the temperate latitudes, the family history, and the female preponderance.
MS is associated with conditions such as optic neuritis, trigeminal neuralgia, Bell’s palsy, uveitis, transverse myelitis, and Devic’s syndrome.
In 20% of patients with MS, the disease has a benign clinical course.
In 30% patients, the disease is relapsing (loss or deterioration of a neurologic function) and remitting (return to or toward normal function).
In other 50% patients, the disease is primarily progressive and secondarily progressive with relapse.
MS is sometimes classified as clinically definite, laboratory supported, probable, and possible depending on the history of attacks, signs on examination, and laboratory abnormalities (MRI, oligoclonal banding) supporting the diagnosis.
In the absence of a pathognomonic biomarker, MS remains a clinical diagnosis. An abnormal MRI without convincing clinical symptoms or signs cannot be used to make the diagnosis. Conversely, a normal MRI of the brain and spinal cord with a compatible history or examination does not exclude the diagnosis.
The laboratory tests are useful for diagnosing MS in the proper setting and with proper caution. The diagnosis of MD is seldom made without some laboratory support, especially in patients who do not quite meet all of the clinical criteria. However, no one test proves the diagnosis, and all laboratory data have sufficient problems with sensitivity and specificity to impair their usefulness.
Prospective studies have shown that two factors most reliably identify patients who do not have MS. The first is their lack of typical symptoms: no optic neuritis, Lhermitte’s sign, sensory level, neurogenic bladder, or other common deficits. The second is their lack of typical findings on MRI and cerebrospinal fluid (CSF) examination. Very few patients with MS have a normal MRI of the brain or normal CSF.
When to doubt the clinical diagnosis of MS:
7.1.1 Symptoms and signs of MS
Any symptom/sign appropriate to a lesion in more than one area of CNS (brain and spinal cord) may raise the suspicion for MS. Gray matter signs, such as seizures and altered mental state, occur rarely.
Common symptoms of MS are as follows:
Sensory (numbness, tingling, heaviness in an extremity, sensory level)
Visual (visual loss, color vision change, field defects)
Brain stem (diplopia, dizziness, difficulty swallowing or speaking)
Motor (weakness, spasticity, cramping)
Bowel and bladder dysfunction: urinary urgency and incontinence
The usual bladder dysfunction is sphincter dyssynergia: simultaneous contraction of the urinary bladder detrusor smooth muscle and the voluntary muscles of the pelvic floor.
cerebellar (ataxia of gait or of an extremity)
Fatigue (midday loss of energy unrelated to other MS signs or symptoms)
Following are the common signs:
Corticospinal tract (weakness, spasticity, hyperreflexia, asymmetric reflexes, Babinski sign)
Sensory (vibration loss, decreased pin sense, sensory level, Lhermitte’s sign which is an electric sensation descending the vertebrae with neck flexion. In addition to MS, another cause of this is cervical stenosis or other mechanical irritation to posterior column)
Brain stem (nystagmus, internuclear ophthalmoplegia. Internuclear ophthalmoplegia (INO) [Inability to adduct the eye with voluntary lateral gaze, but with preservation of adduction on convergence], facial weakness)
Optic nerve (loss of visual acuity, central scotomas, loss of color vision, optic nerve atrophy, afferent papillary defect/Marcus Gunn pupil, optic disc appearance: Pink, swollen with indistinct margin if papilla is involved; normal if involvement is retrobulbar. In optic atrophy pallor especially temporal area, distinct margin.)
Charcot’s triad (intention tremor, nystagmus, scanning speech)
Uhthoff’s phenomenon (worsening of symptoms and signs after exposure to heat or exercise)
7.1.2 Differential diagnosis
Postinfectious encephalomyelitis
This is a subacute syndrome caused by autoimmune response or a viral infection. Patients complain of acute or subacute onset of gait abnormalities, confusion, disorientation, problems with bladder or bowel control, muscle weakness, and other symptoms. Abnormalities consistent with demyelinating lesions can be seen on MRI. This condition may or may not be reversible. Typically, however, it presents itself as a monophasic illness, but chronic cases do occur and require long-term treatment.
Primary CNS vasculitis may result in syndromes resembling MS. Most notable symptoms include severe headaches, confusion, and sudden stroke-like episodes. High protein levels can be seen in CSF, as well as high erythrocyte sedimentation rate (ESR). Patients may have abnormal angiogram of cerebral vessels. Antinuclear or antiphospholipid antibodies may be present. Patients with vasculitis-related disorders, such as meningovascular syphilis, Sjogren’s syndrome, lupus erythematosus, Bechet’s disease, Wagener’s granulomatosis, and isolated CNS vasculitis, may present with an MS-like picture. Asking about the features of the systemic disease and watching for atypical MRI or clinical appearance are helpful in diagnosis.
Sometimes infections of the CNS may present like MS, but usually they have a different CSF and clinical picture. Lyme disease is known to cause intermittent neurologic events. Some of the most frequent problems include Bell’s palsy, nonspecific symptoms of numbness, fatigue, and amnesia. CSF findings may resemble those found in the MS and MRI may show a white matter disease. History of tick bites, rashes (erythema chronicum migrans), and arthralgia should be sought after. Screening for Lyme titer and/or a Lyme polymerase chain reaction (PCR) in the CSF or blood should help in diagnosis; predominantly axonal neuropathy on electromyography (EMG).
Systemic lupus erythematosus (SLE)
This condition may cause multiple neurologic pathology such as optic abnormalities, encephalopathy, transverse myelitis, and strokes. One needs to look for systemic abnormalities, such as elevated antinuclear antibody (ANA), leukopenia, hematuria, elevated ESR. On some occasions, lupus erythematosus and MS may be found in the same patient.
It is a retroviral disease caused by human T-cell leukemia virus (HTLV)-1 virus. It is uncommon in the continental United States, but may be seen infrequently in patients who reside for some time around the Caribbean Sea Basin. The major clinical manifestations are progressive spastic paraparesis or generalized white matter disease.
This syndrome can result in MRI findings that are very similar to MS. However, the main distinguishing features of this condition are oral and genital ulcers, and uveitis, as well as possible involvement of lungs, joints, intestines, and heart. This group of patients may present with either quadriparesis, pseudobulbar palsy, cranial neuropathy, cerebellar ataxia or cerebral venous thrombosis.
Sarcoidosis and Sjogren’s syndrome
Sarcoidosis and Sjogren’s syndrome may show lesions on MRI that resemble those found in MS. These are autoimmune conditions that affect multiple organ systems and should not be confused with MS. A chest X-ray may show granulomatous disease of the lungs, and meningeal enhancement is seen in patients with CNS involvement. Oligoclonal bands and IgG are raised in CSF of patients with sarcoidosis; peripheral facial palsy is common; reduced glucose is seen in CSF. CNS involvement and the course of the disease may show striking similarity to MS. Angiotensin-converting enzyme determination may be used for further differential diagnosis. It may be elevated in either serum or CSF but it is not reliably abnormal.
Vitamin B-12 deficiency and tertiary syphilis
Vitamin B-12 deficiency and tertiary syphilis may result in dorsal column abnormalities and dementia. These two conditions need to be ruled out when patients present with the abovementioned symptoms as their chief complaints. Serum and CSF VDRL test and the reflex loss in tabes dorsalis are discriminating features of neurosyphilis.
Leukodystrophies of adulthood (metachromatic leukodystrophy, Krabbe disease, and adrenal leukodystrophy) show large areas of involvement on the MRI scan where no normal white matter can be found.
These are hereditary degenerative disorders (olivopontocerebellar degeneration, spinocerebellar degeneration, etc.). Pedigree analysis; insidiously progressive course; progressive involvement; atrophy without demyelination. Initially may resemble chronic-progressive MS. However, characteristic white matter lesions on the MRI scan are usually absent and the CSF is normal in these patients.
Progressive multifocal leukoencephalopathy
CT and MRI lesions are nonenhancing; no oligoclonal banding; prominent dementia and aphasia; underlying immunosuppression always present (e.g., HIV, post-transplantation chemotherapy). HIV antibody positive; subcortical dementia; diffuse subcortical gray and white matter involvement on MRI.
Revealed by MRI of spinal cord and craniovertebral junction (e.g., cervical spondylosis, Chiari malformations). Lower motor neuron signs in upper limbs, lower cranial nerve palsies.
Intracranial tumors (gliomas, lymphomas)
Course gradually increasing in severity; recurrent seizures; normal evoked responses or lumbar puncture.
Craniocervical-junction anomalies
Dysarthria; dysphagia; ophthalmoparesis; quadriparesis; rapidly corrected hyponatremia.
Lower motor neuron signs; abnormal EMGs; cerebral, sensory, or sphincter involvement against this diagnosis.
Inborn errors of myelin metabolism
Usually presenting in childhood.
Metachromatic leukodystrophy, a deficiency of the enzyme aryl sulfatase
Adrenoleukodystrophy, a defect in metabolism of very-long-chain fatty acids
Krabbe globoid leukodystrophy, a deficiency of the enzyme galactosylceramidase
By far the most important disease confused with MS is psychiatric illness (45–76%). Most patients referred to a neurologist for a possible MS who do not have the disease instead suffer from some of psychiatric disorder: somatization, hypochondriasis, malingering, depression, anxiety or similar problems. There are seven conditions that account for almost all the alternative diagnoses at three MS centers in the United States as listed in the following table.
Conditions that account for almost all the alternative diagnoses at three MS centers in the United States | |||
Katzan I, Rudick RA. Guidelines to avoid errors in the diagnosis of multiple sclerosis Ann Neurol 1996;40:554
Rolak LA. The diagnosis of multiple sclerosis. Neurol Clin 1996;14(1):27–43
Rolak LA, Fleming JO. The differential diagnosis of multiple sclerosis. Neurologist 2007;13(2):57–72
7.1.3 Differential diagnosis based on the pathogenesis of MS
Progressive multifocal leukoencephalopathy (PML)
Postinfectious (postvaccination) encephalomyelitis
Subacute sclerosing panencephalitis
Leukodystrophies (metachromatic leukodystrophy, adrenoleukodystrophy and globoid cell (Krabbe’s disease), and Pelizaeus–Merzbacher disease)
Reversible posterior leukoencephalopathy
Paraneoplastic syndromes (limbic and brainstem encephalitis, progressive spasticity, and dementia associated with anti-amphiphysin antibodies)
Posterior fossa/foramen magnum neoplasms
CNS vasculitis (e.g., periarteritis nodosa, primary CNS angiitis, drug-induced and infection-associated vasculitis, retinocochlear vasculopathy of Susac)
Spinal and brainstem arteriovenous malformations
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
7.1.4 Laboratory diagnostic procedures for MS
There is no definitive laboratory test that is conclusive for MS.
Blood studies: (to exclude other disorders)
ANA (can be positive in low titer in up to 80% of MS patients)
Anti-SSA antibody (if sicca symptoms)
HLTV-1 antibody (if spastic paraparesis appears)
Fluorescent treponemal antibody absorption (FTA-ABS) test
CSF studies: If cranial MRI findings are not typical or diagnostic, CSF examination may provide additional support for diagnosis of MS.
WBC: normal or slight lymphocytosis (< 50 cell/mm)
Total protein should be normal or mildly increased in 25% of patients (> 54 mg/dl)
i. Two or more oligoclonal bands (OCBs) in CSF, in the absence of corresponding serum OCBs. OCBs are not directed against specific antigens and are not involved in pathogenesis of disease. They are present in 30–40% of possible and 90–97% of definitive MS patients. OCBs are also observed in other chronic inflammatory diseases of the CNS, in infectious disorders, and in 7% normal controls.
ii. Elevated IgG index (CSF IgG/CSF albumin)/(serum IgG/serum albumin) reflects activation of immune cells within CNS, present in 80% with definite MS (values > 0.68 support the diagnosis).
iii. Increased IgG synthesis rate (> 3 mg/day)
v. The sensitivity of these tests is improved during acute exacerbations
The appearance of the CSF and the opening pressure are normal
Differential diagnosis of increased CSF IgG:
Cranial CT scan is not sensitive enough to detect most MS lesions.
MRI is the most powerful diagnostic tool. It shows abnormalities in 90% of patients with clinically definite MS, 60–70% probable MS, 30–50% possible MS.
Cranial MRI: Common locations include periventricular white (Dawson’s fingers), corpus callosum, tapetum, brain stem, and spinal cord (especially posterior cervical cord). Active lesions tend to enhance with gadolinium. Characteristic lesions are ovoid, multifocal, and of varying ages (and intensities). Serial MRI scans can be useful to demonstrate dissemination in time by the appearance of new T2 (and proton density) or gadolinium-enhancing lesions at least 3 months after an initial scan without a second clinical exacerbation.
T2-weighted lesions are nonspecific and can be related to edema, inflammation, demyelination, gliosis, remyelination, or axonal loss. T1-weighted lesions without gadolinium enhancement (“black holes”) are more specifically indicative of axonal loss or gliosis and correlate better with physical disability measures. (+)
Spinal MRI (cervical and/or thoracic levels): It is useful to rule out compressive lesions in cases of myelopathic presentation and may show either cord hypersensitivities when cranial MRI is not diagnostic, or cord atrophy in chronic cases. Fluid-attenuated inversion recovery (FLAIR) images enhance T2 lesion resolution, especially in the spinal cord. The contribution of myelin loss versus axonal loss to brain atrophy in MS is not differentiated by current MRI measures.
Evoked potentials identify clinically silent white matter lesions and document dissemination in space (e.g., whether different parts of the CNS are affected). Patients may have significant defects along visual evoked response (VER), somatosensory evoked response (SSER), and brainstem auditory evoked response (BAERs) pathways without clinical symptoms or signs. In uncooperative patients and patients in whom MRI cannot be performed (e.g., due to pacemaker), measuring evoked potentials is an alternative. The sensitivity of evoked potential testing is high but its specificity is low.
Visual evoked potentials (VEP) are the most helpful; these record the electrical response from the visual cortex in the occipital lobe. Normally, a response appears approximately 100 milliseconds after the stimulus is presented to the eye, and a delay implies demyelination in the visual pathways.
VEPs are abnormal in approximately 40, 60, and 85% of possible, probable, and definite MS patients, respectively. Somatosensory evoked potentials (SSEPs) are abnormal in approximately 50, 70, and 80% of possible, probable, and definite MS patients, respectively. BAERs are abnormal in approximately 30, 40, and 70% of possible, probable, and definite MS patients, respectively (see the following table).
Wallace CJ, Sevick RJ. Multifocal white matter lesions. Semin Ultrasound CT MR 1996;17(3):251–264
Francis GS, Evans AC, Arnold DL. Neuroimaging in multiple sclerosis. Neurol Clin 1995;13(1):147–171
Gronseth GS, Ashman EJ. Practice parameter: the usefulness of evoked potentials in identifying clinically silent lesions in patients with suspected multiple sclerosis (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;54(9): 1720–1725
Lee KH, Hashimoto SA, Hodge JP, et al. MRI of the head in the diagnosis of multiple sclerosis. A prospective 2-year follow-up with comparison with clinical evaluation, evoked potentials, oligoclonal banding, and CT. Neurology 1991;41:657–660
7.1.5 Diagnostic criteria for MS
McDonald criteria for definite MS
The McDonald criteria make use of the clinical presentation and the advances of MRI.
When a patient presents with two or more attacks with clinical evidence of two or more neurological deficits, there is no need for additional requirements to make the diagnosis of MS, because there is dissemination in place and time (▶Fig. 7.1).
Fig. 7.1 Multiple sclerosis in a 22-year-old woman with a 6-week history of sensory disturbances in her right arm. No other symptoms were present. CSF was positive for oligoclonal bands. (a) Axial FLAIR sequence of the brain demonstrates multiple hyperintense lesions. (b) Axial DIR sequence of the brain. The lesions are depicted in higher contrast. (c) Sagittal T2w image of the cervical spine demonstrates multiple hyperintense lesions. Each of the lesions spans no more than one vertebral body height. (d) Sagittal T1w sequence after contrast administration. Individual lesions show marked enhancement. (Reproduced from Intramedullary Space. In: Forsting M, Jansen O, ed. MR Neuroimaging: Brain, Spine, Peripheral Nerves. 1st edition. Thieme; 2016.) Multifocal large confluent lesions demonstrating T2-hyperintensity (e), T1-hypointensity (f), and heterogeneous enhancement (g) in the periventricular white matter bilaterally. (h) The susceptibility-weighted image demonstrates the normal periventricular white matter venules (arrows) crossing through these confluent active MS plaques, a finding not usually seen with brain neoplasms. (Reproduced from Case 86. In: Tsiouris A, Sanelli P, Comunale J, ed. Case-Based Brain Imaging. 2nd edition. Thieme; 2013.) Tumefactive demyelinating lesions (TDLs). TDLs are demyelinating lesions > 2 cm in diameter, frequently showing mass effect and surrounding edema. (i) Axial fluid-attenuated inversion recovery image show two examples (arrows). (j) Axial enhanced T1-weighted image shows the enhancing edges that represent areas of increased inflammatory activity. (k) The lesion periphery frequently shows restricted water diffusion, with hyperintensity on diffusion weighted imaging (l) and hypointensity on the apparent diffusion coefficient map. (Reproduced from Diffusion Weighted Imaging and Diffusion Tensor Imaging in Demyelinating Diseases. In: Leite C, Castillo M, ed. Diffusion Weighted and Diffusion Tensor Imaging. A Clinical Guide. 1st edition. Thieme; 2015.) (l) Sagittal T1-weighted MRI of the cervical spinal cord following the administration of gadolinium-DTPA in a patient with acute multiple sclerosis showing slight enhancement at the C2-C3 level. There is virtually no widening of the spinal cord. (m) Axial T1-weighted MRI following the administration of gadolinium-DTPA shows characteristic quadrantic location of enhancement in the dorsolateral region of the cervical spinal cord. (Reproduced from Diagnostic Imaging Studies. In: Dickman C, Fehlings M, Gokaslan Z, ed. Spinal Cord and Spinal Column Tumors. 1st edition. Thieme; 2006.)
In all other cases (less than two attacks or less than two clinical lesions), there is a role for MRI to fulfil the diagnostic criteria be demonstrating dissemination in space (DIS), in time, or both.
The McDonald criteria are very specific, because if you want to use MRI for the diagnosis of MS, you have to make sure that the patient really has MS.
For dissemination in space (DIS), lesions in two out of four typical areas of the CNS are required:
For dissemination in time (DIT), there are two possibilities:
Schumacher criteria for definite MS
Two separate attacks—onset of symptoms is separated by at least 1 month
Symptoms must involve the white matter
Age 10–50 (although usually 20–40)
Objective deficits are present on the neurologic examination
No other medical problem can be found to explain the patient’s condition
The key to the Schumacher criteria for the clinical diagnosis of MS is the first two features, i.e., two separate symptoms at two separate times or lesions disseminated in space and in time.
Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med 2000;343(13): 938–952
Lucchinetti C, Brück W, Noseworthy J. Multiple sclerosis: recent developments in neuropathology, pathogenesis, magnetic resonance imaging studies and treatment. Curr Opin Neurol 2001;14(3):259–269
7.2 Isolated Idiopathic Optic Neuritis
(Synonyms: retrobulbar optic neuritis, optic papillitis, inflammatory optic neuropathy)
Optic neuritis is a common disorder, the pathogenesis of which refers to inflammation of the optic nerve with variable demyelination affecting individuals between the ages of 15 and 45, with a white (85%) predominance. Women are affected approximately three times more frequently than men. Optic neuritis occurs as the initial symptom of MS in 35–62% patients and is likely a forme fruste of MS in its isolated form. In pregnant women with MS, there is a diminished risk of new exacerbations including optic neuritis, especially during the third trimester.
Optic neuritis may be classified as follows:
Anatomically (retrobulbar optic neuritis, papillitis, neuroretinitis)
By incidence (retrobulbar being the most common, followed by papillitis, and neuroretinitis)
Patients with known MS are at significant risk of optic neuritis. It is the first symptom in 20% of MS patients and occurs in 70% of patients sometimes during the course of the illness. In patients presenting with isolated optic neuritis, the risk of developing MS is approximately 30% after 5–7 years. In long term follow-up studies, 75% of women and 34% of men developed clinically definite MS.
Viral and parainfectious causes
Adenovirus, coxsackie, cytomegalovirus, HIV, hepatitis A, Epstein–Barr virus, measles, mumps, rubella, varicella zoster, herpes zoster
Vasculitides (SLE, Wegener’s granulomatosis)
7.2.1 Clinical features
Isolated idiopathic optic neuritis is characterized by the following:
Acute onset of orbital pain, particularly eye pain on an eye movement test
Central or paracentral scotoma
Color desaturation (dyschromatopsia)
Progressive, often unilateral vision loss over hours or days
Diminished contrast sensitivity (98%); photopsia (30%)
On examination, a patient with isolated idiopathic optic neuritis will exhibit:
Impaired visual field. Central visual scotoma is the hallmark of optic neuritis, accounting for over 90% of the visual field defects, whereas the optic disc may appear normal in retrobulbar neuritis (two-thirds of patients), inspiring the adage “the patient sees nothing and the physician sees nothing.” In anterior optic neuritis (or papillitis), the disc may be swollen, and in less than 6% of patients hemorrhage may occur at the disc margin. The optic disc may become pale weeks after the initial episode.
7.2.2 Differential diagnosis
Acute optic neuritis can usually be distinguished from other conditions on clinical grounds. History is usually suggestive with compressive optic neuropathy from intracranial tumors, anterior ischemic optic neuropathy, sinus disease, autoimmune optic neuropathies, radiation-induced optic neuropathies, and central serous choroidopathy.
Optic nerve diseases that may be confused with optic neuritis/papillitis include:
7.2.3 Investigations
Special testing
A complete neuro-ophthalmologic examination emphasizing visual acuity at near and far distances, a search for the relative afferent pupillary defect (Marcus Gunn pupil), color vision testing, and careful perimetry are essential in evaluating optic neuritis.
Optic neuritis typically causes prolongation of the latency and decreased amplitude of the P100 of the VEPs, the first large positive peak occurring approximately 100 milliseconds after stimulus. Pattern reversal stimulus presentation yields more reproducible results. Abnormalities of the VEP indicate dysfunction at any point along the visual pathways from the retina to the striate cortex, and are not pathognomonic for demyelinating optic neuropathy. Other disorders, such as compressive lesions, glaucoma, hereditary and toxic optic neuropathy, and papilledema, can also cause VEP disturbances.
Imaging studies
Gadolinium enhancement on MRI is demonstrated in the optic nerves of the majority of patients with acute optic neuritis and correlates with recovery of visual acuity and improvement of VEP amplitudes. The incidence of white matter lesions found with MRI was 48.7%. However, more recent information showed that 36% of placebo-group patients with two or more periventricular lesions of at least 3 mm in size, identified by MRI developed definite MS within 2 years, compared with only 3% of those in whom MRI was normal (▶Fig. 7.2).
Fig. 7.2(a–c) Idiopathic optic neuritis or Devic’s disease. The optic nerves and the spinal cord are usually involved. Often there are few T2 lesions in the brain (thick arrow). There are extensive spinal cord lesions (> 3 vertebral segments) involving most of the cord with low T1 and high T2 signal intensity and swelling of the cord. Unlikely in MS the lesions are usually smaller and peripherally located.
Blood testing
Initial analysis of the Optic Neuritis Treatment Trial led to the conclusion that the use of the ancillary studies, (e.g., ANA, fluorescent treponemal antibody absorption test, Lyme titer, serum and/or CSF angiotensin-converting enzyme level, CSF studies including IgG index and synthesis rate, oligoclonal bands, cryptococcal antigen, cytology, and hypercoagulable studies in selected patients, such as anticardiolipin antibodies, protein C & S, antithrombin III, activated CRP, factor V Leiden, plasma viscosity, fibrinogen, and homocysteine) was limited for defining a cause for visual loss other than optic neuritis associated with demyelinating disease.
Optic Neuritis Study Group. The five-year risk of multiple sclerosis after optic neuritis; experience of the Optic Neuritis Treatment Trial. Neurology 1997;49:1404–1413
Beck RW. Optic neuritis. In MIller NR, ed. Walsh and Hoyt’s Clinical Neuro-ophthalmology. 5th ed. Baltimore: Williams & Wilkins;1998
7.3 Acute Disseminated Encephalomyelitis
Acute disseminated encephalomyelitis (ADEM) is an acute, monophasic postinfectious or parainfectious (occurs after a viral illness or vaccination) encephalitis. In 50–75% of cases, the beginning of the disease is preceded by a viral or bacterial infection, usually a sore throat or cough (upper respiratory tract infection 7–14 days prior). Occasionally, ADEC occurs 3 months after a vaccination (most commonly after measles, mumps, and rubella vaccination). It is more common in children than in adults (more than 80% of childhood cases occur in patients younger than 10 years, the ratio of boys to girls is 1.3:1) and is believed to be caused by an immune response triggered by an antigen (viral or vaccine). ADEM is found in all ethnic groups and races. The prognosis for recovery is generally good; recovery is usually spontaneous. Mortality has been estimated as high as 10–20% and as low as less than 2%). Morbidity usually involves visual, motor, autonomic, or intellectual deficits, and epilepsy if grey matter is affected. Deficits may persist for several weeks; however, most deficits resolve within 1 year. Mental retardation is possible, especially in children younger than 2 years of age at disease onset.
7.3.1 Signs and symptoms
Early physical manifestations:
Irritability and lethargy are common first signs.
Fever returns nearly in half of cases.
Headache is reported in 45–65% of the cases.
May occur over hours to 6 weeks from onset of early symptoms.
7.3.2 Diagnosis
Criteria that facilitate diagnosis include:
History of recent infection (although it may have been clinically silent)
Disseminated CNS disease with neurologic findings
The history of events is the single most important part of the diagnostic criteria. In many cases, especially in the absence of preceding illness or recent vaccination, ADEM is a diagnosis of exclusion. ADEM tends to have neurologic signs and symptoms not typically present in MS, such as headache, nausea, vomiting, drowsiness, and meningismus.
Neither MRI nor CSF results alone are adequate for diagnosing ADEM. MRI is useful in highlighting the disseminated involvement of the white matter and identifying extend and location. MRI findings are virtually impossible to distinguish from MS lesions.
MRI of the brain typically shows multiple high-signal intensity lesions involving white matter. The lesions usually are symmetric, and occipital head regions are predominantly involved. The lesions can affect gray matter and basal ganglia as well. In contrast to MS plaques, the lesions are usually of the same age (i.e., they show more uniform enhancement). If the spinal cord is involved, ADEM lesions are continuous affecting multiple levels, whereas a typical MS lesion is confined to one spinal cord level. The typical MS lesions are also posterior in location on axial, cross-sectional views of the spinal cord, whereas in the ADEM lesions tend to be more diffused throughout the entire cord.
In regard to ADEM, the CSF can be normal or, more likely, show nonspecific changes including an elevated protein and pleocytosis with lymphocytic predominance, a normal glucose, and negative cultures. Electroencephalogram (EEG) is also often performed, eliciting abnormal, yet nonspecific results including generalized and focal slowing and epileptiform discharges (▶Fig. 7.3).
Fig. 7.3 (a–d) Young patient with acute disseminated encephalomyelitis (ADEM). On MRI, there are often diffuse and relatively symmetrical lesions in the supra and infratentorial white matter which may enhance simultaneously. There almost always is preferential involvement of the cortical gray matter and the deep gray matter of the basal ganglia and thalami.
7.3.3 Differential diagnosis
There is a close diagnostic association between MS and ADEM that is difficult to differentiate on the basis of a single clinical encounter or radiographic image alone. See the following table.
It is also important to differentiate between ADEM and viral encephalitis. The striking feature of ADEM is the prodromal illness or history of recent vaccination, the visual loss in one or both eyes, and spinal cord involvement which are uncommon in encephalitis. A history of recent travel abroad or to areas of high risk for arboviruses is useful information for the diagnosis of encephalitis.
List of differentials
Acute inflammatory demyelinating polyradiculoneuropathy
Toxic/metabolic encephalopathy
Infectious encephalitis (herpes simplex, Lyme disease)
Vasculitis (polyarteritis nodosa)
Post-malarial neurological syndrome
HIV-1-associated CNS complications
Antiphospholipid antibody syndrome
Cerebral venous sinus thrombosis
Gabis LV, Panasci DJ, Andriola MR, Huang W. Acute disseminated encephalomyelitis: an MRI/MRS longitudinal study. Pediatr Neurol 2004;30(5):324–329
Höllinger P, Sturzenegger M, Mathis J, Schroth G, Hess CW. Acute disseminated encephalomyelitis in adults: a reappraisal of clinical, CSF, EEG, and MRI findings. J Neurol 2002;249(3):320–329
Petzold GC, Stiepani H, Klingebiel R, Zschenderlein R. Diffusion-weighted magnetic resonance imaging of acute disseminated encephalomyelitis. Eur J Neurol 2005;12(9):735–736
7.4 Transverse Myelitis
(Transverse myelopathy: The term doesn’t imply any etiological factor, whereas “myelitis” refers to inflammatory diseases of spinal cord)
This is a neurologic syndrome caused by inflammation of the spinal cord that is localized over several segments of the cord and functionally transects one level of the cord. Transverse myelitis (TM) is uncommon with an incidence of 1–5 cases per million. It occurs in both adults and children. TM is generally a monophasic illness (one-time occurrence), but a small percentage of patients with a predisposing underlying illness may suffer a recurrence.
7.4.1 Etiology
TM may occur in isolation or in the setting of another illness. When it occurs without apparent underlying cause, it is referred to as idiopathic. Idiopathic TM is assumed to be a result of abnormal activation of the immune system against the spinal cord which causes inflammation and tissue damage. TM often develops in the setting of viral and bacterial infections, especially those which may be associated with a rash (e.g., rubeola, varicella, variola, rubella, influenza, mycoplasma, Epstein–Barr virus, cytomegalovirus, and mumps). Approximately one-third of patients with TM report a febrile illness (flu-like illness with fever) in close temporal relationship to the onset of neurologic symptoms. In some cases, there is evidence that there is a direct invasion and injury to the cord by the infectious agent (especially poliomyelitis, herpes zoster, and AIDS). A bacterial abscess can also develop around the spinal cord and injure the cord through compression, bacterial invasion, and inflammation.
7.4.2 List of illnesses associated with transverse myelitis
Parainfectious: occurring at the time of and in association with an acute infection or an episode of infection.
Viral: herpes simplex, herpes zoster, cytomegalovirus, Epstein–Barr virus, enteroviruses (poliomyelitis, coxsackie virus, echovirus), human T cell leukemia virus, human immunodeficiency virus, influenza, rabies
Bacterial: Mycoplasma pneumoniae, Lyme borreliosis, syphilis, tuberculosis
Paraneoplastic syndrome (uncommon; the immune system produces an antibody to fight off the cancer and this cross-reacts with the molecules in the spinal cord neurons)
Vascular (primarily due to inadequate blood flow to the spinal cord instead of actual inflammation)
7.4.3 Signs and symptoms
Signs and symptoms of TM may develop rapidly over several hours to several days or more slowly over 1–2 weeks. Typical symptoms include:
TM-associated pain often begins in the neck or back. Sharp, shooting sensations may also move down the legs or arms or around the abdomen.
Some patients with TM report numbness, tingling, coldness, or burning sensations below the affected area of the spinal cord. These patients are especially sensitive to the light touch of clothing, or the extreme heat or cold.
Some patients with mild weakness notice that they are stumbling, dragging one foot, or that their legs feel heavy as they move, where others may develop severe paralysis.
Increased urinary urgency, difficult micturition and constipation.
Muscle spasms (e.g., especially in the legs)
7.4.4 Screening and diagnosis
The general history and physical examination do not give clues about the cause of spinal cord injury. The first step concerning a patient with complaints and examination suggestive of a spinal cord disorder, is to rule out a mass lesion which might be compressing the spinal cord (e.g., tumor, herniated disc, spinal stenosis, and abscess). This is important because early surgery to remove the compression may sometimes reverse neurologic injury to the spinal cord. The easiest test to rule out such a compressive lesion is an MRI of the cord. If MRI is not available or the images are equivocal, myelography must be performed.
T2-weighted MRI and contrast enhancement should be performed for complete spinal cord urgently. MRI also gives information about inflammation of the spinal cord and may suggest MS, intramedullary tumor, or abscess. Lesions with hyperintense signal on T2-weighted images over several cord segments are often found in TM. Sometimes the cord is swollen. An MRI of the brain is often performed to screen for lesions suggestive of MS (▶Fig. 7.4).
Some patients with TM may have abnormally high numbers of white blood cells (lymphocytic pleocytosis) with normal or elevated total protein level suggesting an infection or an inflammation. Oligoclonal bands are present in 20–40% of patients with TM.
There are no specific blood tests to diagnose TM. The following work-up should be done to identify potential underlying causes: complete blood count (CBC)/differential, rapid plasma regain (RPR), ANA, double-stranded DNA, anti-SSA and anti-SSB antibodies, serum vitamin B12 level, HTLV-1 antibody, and serum angiotensin-converting enzyme.
