Thirty Six Flashcards
(17 cards)
What are 6 classic symptoms of central myelin disorders?
- upper motor neuron type of weakness
- sensory loss
- visual loss
- oculomotor disturbances
- ataxia
- less commonly cognitive disturbances (usually with more widespread and confluent involvement)
What is the epidemiology and inheritance pattern of MS?
Perhaps the hallmark central white matter disorder, MS is the most common neurologic disease
among young adults, with highest incidence in the 20-40 age group, with presentations ranging
from childhood to the late adult years. There is a 7:3 female to male ratio, with prevalence
decreasing with proximity to the equator. Data from 2010 show a United States prevalence of
over 400,000 individuals, with over 8-10,000 new cases per years. There is likely a
multifactorial etiology, with a combination of environmental and genetic factors at play. The risk
in the general population rises from 0.1% to 4% with one affected first-degree relative, and to
20% if both parents are affected. There is an association with HLA-DR2 haplotypes. There is
also an increased risk of other autoimmune disorders in the family.
What is the pathophysiology of MS? What is it like histologically? What parts of the CNS are affected and in what order?
Pathophysiologically, it is believed that an MS “attack” is triggered by activation of autoreactive
CD4+ T cells in the peripheral immune system. A recent viral infection is suspected to initiate
this immunologic cascade, with agents such as Ebstein-Barr virus (EBV), human herpesvirus 6
(HHV6) and several others implicated though no one causative agent is consistently identified in
the serum. Once the cascade is initiated, there is migration of Th1 cells through the blood-brain
barrier into the central nervous system, with further activation of B cells and macrophages and
secretion of proinflammatory cytokines and antibodies. The resultant inflammatory damage to
myelin leads primarily to an initial round of demyelination. Remyelination can occur, though
over time there is also progressive axonal disruption and loss, over time leading to atrophy and
neurodegeneration. Recognized both radiographically and pathologically at gross examination,
the MS “plaque” represents these focal areas of inflammation and injury, and show a differential
microscopic appearance based on their age (early/acute versus active/nonacute versus chronic
inactive versus remyelinating). For some time this pathology was felt to lie exclusively in the
white matter of the brain, though it is becoming more clear over time that additional gray matter
involvement strongly contributes to the eventual neurodegeneration associated with the
disease.
What are clinically isolated syndromes? Name 3 examples.
A unique concept when discussing multiple sclerosis is that of the clinically isolated syndrome
(CIS). Often retrospectively seen as the first acute MS attack (once a recurrent clinical or
radiographic attack is noted), there is a subset of patients who will never go on to recurrent
episodes of clinically significant demyelination over time. There are other radiographic and
laboratory features (to be discussed below) identified during the first attack that help predict
conversion to a diagnosis of MS, though none with near 100% certainty. The most common
clinical presentations of a demyelinating attack that lead to consideration of a possible initial
presentation of MS include:
Optic Neuritis, Transverse Myelitis, and isolated brainstem syndrome.
How does optic neuritis present? What does physical exam reveal? Fundoscopy? MRI?
- optic neuritis- presenting with monocular or binocular acute/subacute vision loss. This is
frequently associated with orbital pain on eye movement. Physical exam reveals reduced
visual acuity and color vision on the affected side(s), and if unilateral, an afferent pupillary
defect. Optic disc edema (swelling at the optic nerve head) is visualized on fundoscopy in 1/3
of adult cases. MRI shows edema and inflammation of the optic nerve on T2-based
sequences, with abnormal contrast enhancement frequently present.
How does transverse myelitis present? What is Lhermitte’s phenomenon? What does the MRI reveal?
transverse myelitis, presenting with acute motor paralysis (paraparesis or quadriparesis)
based on level of cord involvement. There can be clinical findings consistent with a complete
“transected cord”, or smaller patchy areas of involvement. With dorsal column involvement, a
particularly useful clinical sign termed “Lhermitte’s phenomenon” is present, with electrical
paresthesias down the spine induced by neck flexion. MRI of the spine typically reveals a
discrete inflammatory lesion of the cord, with contrast enhancement, typically under 2-3
spinal segments in length.
What are 3 ways in which an isolated brainstem syndrome could present?
less commonly, an isolated brainstem syndrome with:
A) isolated CN nuclei involvement (may also have long tract involvement leading to contralateral motor or sensory findings on exam)
B) deficits of gaze to include horizontal or vertical gaze palsy or internuclear ophthalmoplegia (INO) from nuclear gaze center or medial longitudinal fascicular (MLF) lesions
C) unilateral ataxia (with or without other brainstem nuclear involvement) from lesions involving the cerebellar peduncles
What are two major clinical questions that should be asked when encountering a patient presenting with a CIS? What are 3 general features form the history or examination that should point you away from the diagnosis of MS? Give some examples. What are two disorders that are highly related to MS?
Two major clinical questions arise when encountering a patient presenting with a CIS. First,
what is the risk this patient will go on to have recurrent attacks consistent with multiple
sclerosis? Second, what other diagnostic entities enter into the differential diagnosis?
Features from the history or examination that should point the clinician away from a diagnosis of
multiple sclerosis include:
- signs of systemic illness such as fever, weight loss or meningismus or other organ systemic complaints outside of the nervous system
- neurologic features that are atypical for multiple sclerosis including peripheral neuropathy, myopathy, hearing loss, multiple cranial neuropathies, neuropsychiatric illness other than depression, prominent cognitive symptoms from the onset, extrapyramidal symptoms
- atypical radiographic features such as meningeal enhancement, unilateral lesions, longitudinally extensive spinal cord lesions (over three spinal segments), normal brain MRI, hemorrhagic lesions, simultaneous enhancement of all lesions\
- Acute Dissseminated Encephalomyelitis (ADEM)
- Neuromyelitis Optica (a.k.a. Devic Disease)
How is the diagnosis of MS made?
It is important to understand that there is no one definitive clinical, laboratory or radiographic
finding that, in isolation, can establish a formal diagnosis of multiple sclerosis. Instead, the
patient must present with a clinical “attack” or episode of neurologic disturbance for which
causative lesions are observed on imaging studies, and due to their appearance, or other
supportive clinical and ancillary studies are felt to be inflammatory or demyelinating in nature.
However, one attack, with a representative lesion on imaging is not enough to make a formal
diagnosis of multiple sclerosis. Classically, the diagnosis requires recurrent attacks over time,
affecting different parts of the central nervous system over time (the so-called dissemination in
time and space rule.)
What are 4 CSF findings that would point to MS? What are evoked potentials? Where are they done to help diagnose MS?
Prior to the advent of MRI, the patient was required to have recurrent clinical attacks, affecting different parts of the nervous system to be formally diagnosis with MS. Other ancillary tests were used frequently, such as lumbar puncture and evoked potentials. Examination of cerebrospinal fluid shows abnormalities in 85-90% of patients with MS. One of the hallmarks is intrathecal synthesis of gamma globulins, as measured by an elevated IgG synthesis ratio, or the presence of at least two oligoclonal bands in the spinal fluid that are not present in a paired serum sample. Both of these are markers of the inflammatory response in the central nervoussystem of the typical MS attack. There may also be a very mild increase in both CSF white blood count and protein, though extremely high results of either should suggest an alternative diagnosis (such as infection, neoplasm or collagen vascular disease.) Evoked potentials are electrophysiologic studies of the visual pathway (visual evoked potentials, or VEP’s) or somatosensory pathways in the dorsal column of the spinal cord (somatosensory evoked potentials or SSEP’s). These are useful in documenting involvement of these pathways when
imaging studies or physical findings do not support the clinical impression. In reality, with current MRI technology available, none of these ancillary studies may need to be performed with typical presenting clinical and radiographic features.
How is the MRI used to make a diagnosis of MS? Can it be made during a CIS? Explain. How does the presence of an asymptomatic white lesion during MRI for a CIS affect the likelihood of having a second MS related clinical attack in the next 14 years?
In fact, MRI of the brain and spine can fulfill both dissemination in space and time criteria for the diagnosis, even after the first clinical attack. The former is demonstrated by lesions in multiple different locations in the CNS (periventricular, infratentorial/spinal cord and juxtacortical) separate from the lesion causing the current clinical symptoms. Dissemination in time can be suggested by either new contrast enhancing (active lesions) or T2 lesions on follow up MRI OR the simultaneous presence of both enhancing and non-enhancing lesions on the same MRI study (suggesting different ages of the lesions.) This is a novel approach that has been used over the past 3-5 years an has enabled many more patients to be diagnosed with MS after one clinical attack, allowing perhaps earlier institution of “disease modifying therapies” as will be
discussed below. It is felt that prevention of as many future attacks (or even progressive accrual of asymptomatic CNS lesions) as possible, may slow down progression of disability with this syndrome. MRI during the first “clinically isolated” syndromic presentation is also a very powerful predictor risk of progression to MS. The presence of even one asymptomatic white matter lesion (in addition to the lesion responsible for the clinical symptoms) places the risk of having a second clinical attack over the next 14 years at 88%, whereas the risk plummets to only 19% if the brain is otherwise normal without any asymptomatic lesions.
What are 3 different categories of MS treatment?
In general, treatment can be grouped into three different categories:
- treatment of acute clinical attacks with corticosteroids
- suppression of chronic inflammation and demyelination with disease modifying agents
- symptomatic treatment of disabling features of MS such as spasticity, chronic pain, bladder dysfunction, fatigue, depression and cognitive impairment
Explain how acute clinical attacks are treated and how they work?
Corticosteroids are the mainstay of acute exacerbations, especially is associated with vision
loss, weakness or ataxia. Typically administered in an intravenous preparation at high doses for
3-5 days at a time (often followed by an oral tapering course of prednisone), corticosteroids are
potent anti-inflammatory drugs that reduce edema and help stabilize the blood-brain barrier.
They may also repair regulatory T-cell function during these acute attacks. Plasma exchange
may also be helpful for refractory patients, though the precise mechanism is not known.
How is chronic inflammation and demyelination treated? Explain how it works. Give 8 examples.
Disease modifying therapy for MS was ushered in during the 1990’s with the introduction of
several forms of interferon beta. Many different agents (table 1) have been developed with
multiple proposed mechanisms of action over the years, with each showing some effect
compared to placebo in reducing the number of acute exacerbations, and some showing
decreased MRI lesion burden and disability over a 2 year period. The long term benefit of most
of these agents is still under investigation. Mechanism of action of most injectable agents
involves shifting from a pro-inflammatory state (helper T cell type 1) to a more anti-inflammatory
(helper T cell type 2) profile. When using these agents, the goal is to initiate early in the disease
course (even after one clinical attack if MRI criteria are met for dissemination in space and
time), with the goal of preventing further clinical or radiographic relapses. Unfortunately, there is
a great degree of variability in treatment algorithms and definitions of treatment failure, and even
the best therapies, currently, have no good long-term efficacy data.
Avonex
Rebif
Betaseron
Glatiramer acetate
Mitoxantrone
Natalizumab
Fingolimod
Teriflunomide
How is spasticity treated in MS patients? How is neuropathic pain treated in MS patients? How is fatigue treated? How is bladder dysfunction treated? What other symptoms are there?
Eventually, most patients with multiple sclerosis with go on to benefit from symptomatic treatment of one of several disabling features of the diagnosis. Spasticity can be managed with several GABA agonists including baclofen or diazepam. Additionally, treatment with either an alpha-2 receptor agonist like tizanidine or dantrolene, which acts by inhibiting release of calcium from the sarcoplasmic reticulum, can be useful.
Neuropathic pain (centrally mediated) occurs in up to 80% of patients with MS and often require treatment with tricyclic antidepressants, certain anticonvulsants (gabapentin, carbamazepine and pregabalin) or an selective serotonin noradrenergic reuptake inhibitor like duloxetine. Narcotics can also be used for more disabling cases.
Fatigue severe enough to limit daily physical and intellectual functions occurs in 70-80% of patients with MS. Ensuring proper sleep habits and regular exercise are critical, though use of medications such as amantadine or stimulants (methamphetamine, methylphenidate and modafanil) may also be required to improving daytime
functioning.
Upper motor neuron type bladder dysfunction (usually initially due to disinhibited bladder contractions and failure to fill completely) may respond to anticholinergic medications like oxybutynin. Medical treatment of constipation is also quite often clinically indicated.
Cognitive and affective symptoms of this chronic illness can be extremely debilitating, and often require combined pharmacologic and non-pharmacologic therapies to prolong independent living.
How does the presentation of Acute disseminated Encephalomyelitis (ADEM) compare to MS? How do the MRI findings compare? CSF findings? How is it treated? What is the prognosis?
This is a traditionally monophasic illness (though relapsing and recurrent types rarely occur)
characterized by multifocal inflammation and demyelination. This disorder occurs much more
commonly in children than adults, and is much more closely linked to a recent immunization or
infection that the first presenting attack of MS. Onset is much more rapid and typically involves
some form of encephalopathy (with altered mentation and/or seizures). MRI reveals larger,
more confluent white matter lesions, compared to the discrete and radially organized
periventricular lesions in MS. Lesions can frequently be found in the deep grey nuclei as well.
CSF analysis tends to show higher CSF white blood count and protein levels than those seen in
MS. Elevated intrathecal gamma globulin synthesis is also noted (similar to MS). Due to
evidence of similar abnormal host immune response in the central nervous system, medications
used for acute symptoms are similar to those used in acute MS flares, including intravenous
corticosteroids, plasma exchange, and in the case of ADEM, intravenous immune globulin has
also shown benefit. Outcome is generally better for children than adults. Most children recover
nearly completely, though the risk of cognitive sequelae is higher to due a more likely
involvement of cortical grey matter in this disorder. A more fulminant acute hemorrhagic form
exists that is usually fatal.
How does neuromyelitis optica present? How does this compare to MS? How do the CSF findings compare to MS? What causes it? Where are lesions found in the brain? What is the prognosis? What is the treatment?
Clinically, patients present classically with unilateral or bilateral optic neuritis, sometimes
simultaneously, or often in close succession, with acute transverse myelitis. Although there is
nothing terribly unique about the optic nerve involvement when compared to MS, the spinal cord
involvement differs, with a higher likelihood of what is termed “longitudinally-extensive” lesions,
or lesions greater than 3 spinal segments in length. Lesions of the spinal cord in MS are
typically much more discrete, rarely exceeding one or two spinal segments. Examination of the
spinal fluid also typically shows distinct differences in patient’s with NMO, with much more
consistently elevated white blood counts (even into the hundreds) and protein levels.
Oligoclonal bands are present in only 20-30% of cases. Testing for the antibody (NMO-IgG) can
be performed on the serum or spinal fluid, with very high specificity for the disorder.
Sensitivities are improving with time and improved lab techniques, though occasionally repeat
testing is needed, and cases documenting positive antibodies only from the spinal fluid exist.
Aquaporin-4 is a osmotically driven bidirectional water channel located in astrocytic foot
processes in the CNS, and also in the kidney and stomach. Its purpose is to regulate water flux
between the blood and brain and CSF space. This protein is expressed at highest levels in the
spinal cord, optic nerve, brainstem (especially the area postrema), as well as periependymal
regions of the third and fourth ventricle and hypothalamus. The supraventricular white matter
does not contain a high concentration. For this reason, imaging studies in patients with NMO
show symptomatic and asymptomatic brain lesions in a much different pattern that in MS-
another feature in aiding the clinician in pursuing the diagnosis of NMO.
Relapsing disease, if untreated, is the rule rather than the exception for NMO. Sixty percent of
patients with relapse within one year of the initial clinical presentation, with a 90% relapse rate
within three years. Patients with NMO “attacks” are much less likely to completely recover
neurologic function than in patients with MS, and there may even be a greater need for early
diagnosis and institution of disease modifying treatment for this disorder. Acute attacks are still
treated with high dose corticosteroids (and occasionally plasma exchange). MS disease
modifying treatments have traditionally not been very effective in patients with NMO. More
aggressive general immune suppression with agents like azathioprine or mycophenolate mofetil
have been very helpful, and use of an agent called rituximab, which selectively depletes B-cell
responses have also shows clear efficacy in preventing relapses, though recurrent treatments
every six to twelve months are often needed. Long term data on prognosis and prevention of
progressive disability with prompt early treatment is not known, as this disorder has only been
firmly established over the past 10-15 years.
