Multiple Sclerosis-1

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Multiple sclerosis
Neurology
Neuroimmunology
Demyelinating dis
Contributors Multiple sclerosis
Anthony T Reder MD, contributing editor. Dr. Reder of the University of Chicago has served sclerosis

on advisory boards and as a consultant for Bayer, Berlex Laboratories, BioMS Medical Corp,
Quick Referenc
Biogen Idec, Caremark Rx, Lilly, Neurocrine Biosciences, Novartis, Pfizer, Schering, Serono,
Sections of Sum
and Teva Marion.
- Historical note a
nomenclature
Publication dates - Clinical manifest
Originally released June 27, 1994; last updated August 4, 2011; expires August 4, 2014 - Clinical vignette
- Etiology
Synonyms - Pathogenesis an
Disseminated sclerosis pathophysiology
- Epidemiology
- Prevention
Key points - Differential diag
- Diagnostic work
• Multiple sclerosis is caused by immune attack against brain cells.
- Prognosis and
• The primary damage is oligodendroglia destruction and demyelination, but axons and complications
neurons are also damaged. - Management
• The incidence of multiple sclerosis is increasing around the world. - Pregnancy
• Multiple sclerosis lesions cause focal neurologic deficits, but also generalized problems - Anesthesia
with fatigue, cognition, and bladder control. - ICD codes
• Diagnosis is complex and requires neurologic history, clinical and MRI exam, and - OMIM
sometimes spinal fluid analysis. Supplemental C
• New therapies have dramatically changed the course of multiple sclerosis and survival - Associated disor
from the disease, but therapies are still only partially effective. - Related summar
- Differential diag
- Demographics
Historical note and nomenclature
References
Greek and Roman physicians did not document multiple sclerosis, but it may have been - References cited
mentioned in 13th century Icelandic sagas. Saint Lidwina of Holland appears to have
Related Items
developed multiple sclerosis in 1396 (Medaer 1979). The court physician was not optimistic
after examining Lidwina, stating, "Believe me, there is no cure for this illness; it comes
- Cervical spinal c
directly from God. Even Hippocrates and Gallenus would not be of any help here." The multiple sclerosi
clinical description and prognosis of multiple sclerosis have improved in the intervening 500 - Cervical spinal c
years, but progress in understanding its etiology is debatable. multiple sclerosi
Multiple sclerosis was clearly described in 1822 in the diary of Sir Augustus D' Este, - Immune cell pro
grandson of King George III of England (Firth 1948). One of his relapses is described as electrical stimula
synergize to exh
follows: in multiple scler
- Multiple sclerosis
At Florence, I began to suffer from a confusion of sight. About the 6th of (MRI)
November, the malady increased to the extent of my seeing all objects double. - Multiple sclerosis
Each eye had its separate visions. Dr. Kissock supposed bile to be the cause. I to Therapy A
was twice blooded from the temple by leeches. Purges were administered. One - Multiple sclerosis
to Therapy B
Vomit and twice I lost blood from the arm. The Malady in my eyes abated,
- Oligoclonal band
again I saw all object naturally in their single state. I was able to go out and multiple sclerosi
walk (Murray 2005). - Periventricular lo
plaques in multi
Cruveilhier in Paris and Carswell in London published detailed illustrations of central (MRI)
nervous system plaques and sclerosis in the 1840s. Charcot published detailed clinical

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descriptions and detailed the demyelination in plaques, and Rindfleisch described the - Multiple sclerosis
vascular disease
perivascular inflammatory CNS lesions in the 1860s (Cook 1998). These observers
symptoms
documented the intermittent and seemingly random neurologic symptoms and the variable
- Pathological sub
evolution of the disease. The history of multiple sclerosis is extensively reviewed in Murray multiple sclerosi
(Murray 2005). - WBC pause betw
endothelial cells
basement memb
Clinical manifestations natalizumab, the
effects

Multiple sclerosis lesions in the brain and spinal cord can damage every function of the
central nervous system. The clinical presentation varies from mild to aggressive symptoms - Intention tremor
titubation, and d
and from relapsing-remitting to progressive disease, and the presentation changes in type of
- Internuclear
evolution over time. The protean symptoms include fatigue as well as disturbed function in ophthalmoplegia
sensory, motor, bladder, bowel, sexual, cerebellar, brainstem, optic nerve, and cognitive sclerosis
realms. Multiple sclerosis symptoms, especially fatigue, limit activity in three fourths of Patient Hando
patients. The neuroanatomical location of plaques is not completely random. Lesions have a - Esclerosis múltip
predilection for the periventricular white matter, so certain symptoms and signs are (Spanish)
common. For instance, the medial longitudinal fasciculus has a periaqueductal location. - Mielitis transver
(Spanish)
Damage to the medial longitudinal fasciculus causes internuclear ophthalmoplegia, a
- Multiple sclerosis
frequent sign of multiple sclerosis.
- Neuralgia del tri
In most patients, symptoms of an exacerbation arise over hours to days, typically last 2 to (Spanish)
6 weeks, and then remit, sometimes completely. Forty percent of these attacks cause long- - Pain
lasting deficits (Lublin et al 2003; 2008), but 20% improve. Resolved symptoms can - Transverse mye
reappear transiently with infections or heat (“ghost symptoms,” Uhthoff phenomenon). - Tremor
Fatigue from central lesions. Generalized physical and mental fatigue is the number one - Trigeminal neura
problem in two thirds of patients (Reder and Antel 1983; Noseworthy et al 2000). Patients
describe fatigue as “profound”; it “disrupts life” and it is “different from any other Web Resources
experiences.” They say that because of the fatigue, “each day of the week at work is Alerts and Advis
cumulatively harder,” and it gets “worse with heat.” The motor fatigue that normally follows - FDA: Avoiding
muscular exertion is magnified (“fatigability,” in 75%) after sustained or repetitive muscle Cardiotoxicity W
Mitoxantrone (2
contractions and after walking; the fatigue often develops rapidly after minimal activity. It is
- FDA: Natalizuma
distinct from weakness and may not correlate with weakness in individual muscles (Schwid
- FDA: Natalizuma
et al 1999). Another type of fatigue is sometimes unprovoked (“lassitude,” “asthenia,” or of Healthcare Pr
“overwhelming tiredness,” in 20%). Fatigue limits prolonged neuropsychological testing. Information (20
Rating scales of multiple sclerosis fatigue are difficult to design and correlate poorly with - FDA: Update on
function because these symptoms are multidimensional. Self-reports often do not correlate Associated with
Natalizumab (20
with clinical measurements of muscle and cognitive fatigue.
Fatigue is an essential part of the neurologic history. Fatigue can be the only symptom of Guidelines
an exacerbation, or one of many. It is least common in primary progressive multiple - AAN: Multiple Sc
- AAN: Neutralizin
sclerosis. Thirty percent of multiple sclerosis patients report fatigue before the diagnosis of Antibodies to In
multiple sclerosis (Berger personal communication 2011). Fatigue does not correlate with beta: Clinical an
MRI plaque load, Gd enhancement, depression, or inflammatory markers. Fatigue, however, Radiographic Im
defined by the Sickness Impact Profile Sleep and Rest Scale (SIPSR), predicts later brain - NGC: EFNS Guid
atrophy (Marrie et al 2005). It is associated with low prefrontal activity on PET, with reduced the Use of Neuro
the Managemen
event-related potentials, and with low N-acetylaspartate in frontal lobes and basal ganglia Multiple Sclerosi
on magnetic resonance spectroscopy. - NICE: Multiple S
Fatigue usually is worse in heat, in high humidity, and in the afternoon; body temperature (U.K.)
is slightly higher in all these situations. This extreme sensitivity to heat is termed “Uhthoff Google Scholar
phenomenon,” wherein a minimal elevation of body temperature interferes with impulse - Other articles on
conduction by demyelinated axons because of their lower “safety factor.” Spasticity amplifies PubMed
fatigue by creating resistance to movement, complicating routine actions. Central fatigue - Other articles on
has been attributed to decreased Na+/K+ ATPase in multiple sclerosis plaques, disruption of Other Related Li
the Kv 1.3 potassium channel in mitochondria, serum and spinal fluid neuroelectric blocking - European Charc
factors, neuronal dysfunction and exhaustion, axonal injury and poor axonal conduction, Foundation

impaired glial function, poor perfusion of deep gray matter area, and the need to use wide - Multiple Sclerosi
Association of A
areas of the cortex. Functional MRI for physical and cognitive tasks shows compensatory



(inefficient) reorganization of the damaged CNS, with increased demand on remaining - Multiple Sclerosi
International Fe
neurons. “Primary fatigue” is worst at midday.
- MS Society of Ca
In “non-primary fatigue,” contributors to fatigue and central conduction block are acidosis;
- MS Society of G
lactate; heat after exercise; the rise in body temperature in the afternoon; and a half-
and Northern Ire
degree centigrade rise in body temperature during the luteal phase post-ovulation; pain;
- National MS Soc
poor sleep (daytime fatigue with waking at night, “middle insomnia,” often caused by need Professional Res
to urinate, and also spasms and itching and high incidence of sleep-related movement Center
disorders); depression; low levels of dehydroepiandrosterone (DHEA) and its sulphated - Video: Patient G
Managing MS (A
conjugate (DHEAS); inflammatory cytokines in the central nervous system [prostaglandins,
Foundation)
tumor necrosis factor-alpha, and interferon-gamma (IFN-gamma)]. Insula lesions in stroke
- Video: Multiple S
can cause underactivity and tiredness; the insular cortex atrophies in secondary progressive Histopathology S
multiple sclerosis. Fatigue is associated with restless leg syndrome, circadian rhythm About Links
disruption, periodic limb movements, and hypersomnolence on sleep studies. A report of a - About Web Reso
specific brain sodium channel blocker (Brinkmeier et al 2000) could not be confirmed
(Cummins et al 2003). Medications, hypothyroidism, anemia, and muscle deconditioning can
contribute to fatigue.
Sleep disorders in multiple sclerosis are heterogeneous, often profound, and unexplained.
Patients often complain of insomnia yet still have severe daytime fatigue. In small studies,
CSF hypocretin (orexin) is normal in multiple sclerosis, unlike the low levels in narcolepsy.
However, the frequent hypothalamic plaques in corticotrophin-releasing factor pathways
could damage orexin-containing neurons. This would reduce input to the suprachiasmatic
nucleus and disrupt circadian clock genes.
Autonomic problems. The hypothalamus controls autonomic functions, temperature,
sleep, and sexual activity. Cortical, brainstem, and spinal cord lesions often interrupt the
sympathetic nervous system. This causes slow colonic transit, bladder hyperreflexia, and
sexual dysfunction. Other less-recognized phenomena from sympathetic nervous system
disruption are vasomotor dysregulation (cold, purple feet), cardiovascular changes
(orthostatic changes in blood pressure, poor variation of the EKG R-R interval on Valsalva
maneuver, possibly increasing risk of surgery), poor pilocarpine-induced sweating, poor
sympathetic skin responses—especially in progressive multiple sclerosis (Karaszewski et al
1990; Acevedo et al 2000), pupillary abnormalities, and possibly fatigue. Rarely, plaques in
brainstem autonomic pathways cause atrial fibrillation or neurogenic pulmonary edema,
sometimes preceded by lesion-induced cardiomyopathy. Sixty percent of patients have
pupillary reactions that are abnormal in rate and degree of constriction (de Seze et al 2001).
Pupillary defects do not correlate with visual-evoked potentials or history of optic neuritis.
Autonomic dysfunction does correlate with axonal loss and spinal cord atrophy yet not with
cord MRI lesions. It is possible that plaques in the insular cortex, hypothalamus, and cord all
disrupt sympathetic pathways. Parasympathetic and sympathetic dysfunction correlates with
duration of multiple sclerosis but not with disability (Gunal et al 2002). Parasympathetic
dysfunction (eg, heart rate variation with respiration, abnormal pupillary reactions) is most
pronounced in primary progressive disease. Sympathetic dysfunction (blood pressure
response to straining) can worsen during exacerbations, and it is possibly tied to
dysregulated immunity (Flachenecker et al 2001), less response to the beta-adrenergic
agonist, isoproterenol (Giorelli et al 2004), and conversion to progressive multiple sclerosis.
Periodic hyperthermia and profound hypothermia (to 28C/79F, author's observation) are
occasionally seen. Cognition is surprisingly preserved with hypothermia. These patients are
at high risk for infection because immunity is compromised at low temperature. Conversely,
worsening hypothermia can forecast an infection. Abnormal temperature regulation is
presumably from hypothalamic or thalamic plaques.
Cognitive function. Higher cortical functions, language skills, and intellectual function
usually appear normal to a casual observer. However, careful clinical observation and
sensitive neuropsychological tests find slight to moderate cognitive slowing, slow information
processing, word-finding difficulties, poor recent “explicit” memory, poor clock-drawing, and
decline in effortful measures of attention in 50% of patients (Rao et al 1991; Beatty 1999;
Arnason 2005). Up to half of patients with clinically isolated syndromes are significantly



impaired on some tests. Complaints range from “I always forget where I put my keys” and
“the lights are off in the factory” to “I am no longer able to perform cube roots in my head.”
These subcortical signs often appear during complex tasks (especially with use of affected
limbs), with speeded responses, during working memory, and when multiple visual and
sensory stimuli confront the patient: “I feel like I live in an IMAX theater.” The simple
question, “Do you have trouble walking through a shopping mall?" is often met with an
anguished, "Yes, it's too overwhelming.”
Patients should be screened for cognitive problems at the first exam. Patients with normal
cognition tend to maintain cognitive levels, but mild cognitive deterioration predicts
progressive decline in cognition over 3 years. The best measure of cognitive slowing
(information processing speed, sustained and complex attention, and working memory)
appears to be the symbol digit modalities test (SDMT). Mood swings, irritability, and
frustration from slow cognition are common. The family may notice impairment before the
patient does. When disputed by the family, complaints of cognitive decline suggest
depression. Cognitive deficits are most pronounced in secondary progressive disease, but
often do not correlate with physical disability. Cognitive decline leads to difficulty with
employment and daily life. Patients have more difficulty walking while performing cognitive
tasks. Neuropsychological evaluation can review residual strengths and weaknesses for
employment, social function, and driving ability; evaluation can also investigate depression
and lead to therapy.
Decision making is compromised from slower learning plus impaired emotional reactivity.
Occasionally, patients go through a phase of wildly illogical thinking that later resolves as
the disease progresses. “Low anxiety” leads to inconsistent, risky decisions in a Gambling
Task and predominates in early multiple sclerosis (Kleeberg et al 2004). Impulsivity
correlates with loss of anterior corpus callosum integrity in cocaine-dependent subjects and
possibly also in multiple sclerosis.
Some patients have nearly normal neurologic exams yet are unable to walk from poor
patterning of leg movement and gait. Electrophysiological tests confirm this apraxia and
show impaired input to the motor cortex and to pathways involved in motor planning. Spinal
learning may also be impaired (Arnason 2005).
Patients with mild cognitive impairment have cortical thinning on MRI. Chronic cases have
extensive hippocampal demyelination (Geurts et al 2007), although cognition is less affected
in primary progressive multiple sclerosis. T1 brain and corpus callosum atrophy, third
ventricular width, and T2 lesion load correlate modestly with poor cognition. Basal ganglia
hypointensity and atrophy (brain parenchymal fraction) correlate modestly with decreased
memory. Retinal nerve fiber layer thickness, however, correlates quite well with symbol digit
modality tests (r=0.754) (Toledo et al 2008). Global N-acetyl aspartate has a moderate
correlation with cognitive loss. Decreased attention correlates with lower N-acetylaspartate
in the locus ceruleus in relapsing-remitting patients.
On functional MRI, decreased activation of the cerebellum correlates with poor motor
learning. Excessive activation (poorly focused) in the supramarginal gyrus, insula, and
anterior cingulum correlates with poor episodic memory (Rao personal communication
2005). Excess activation also links to less hand dexterity, suggesting greater allocation of
cognitive resources. Conventional MRI and functional MRI (fMRI) abnormalities correlate
with slow psychomotor speed and increased risk of driving accidents. Positron emission
tomography (PET) shows cortical hypometabolism above subcortical plaques. Cognitive
impairment in rats with experimental allergic encephalomyelitis lasts long after inflammatory
lesions have resolved.
Low bone density is associated with cognitive impairment (Weinstock-Guttman personal
communication 2011). This may be a consequence of loss in CNS input to bone or to an
underlying cytokine abnormality.
Exacerbations can reduce cognition, sometimes as the sole symptom. B Arnason argues
that memory problems appear during exacerbations in early multiple sclerosis, coincident
with T cell inflammation in the CNS. Later in the disease, cognition is increasingly impaired,
coincident with greater monocyte and microglial activation and monokine secretion (Arnason



2005).
Visual memory declines in multiple sclerosis. Visual pathways course from optic nerves,
around the ventricles to the occipital cortex, and back around the ventricles to temporal
memory areas. Visual pathways are likely to be interrupted by periventricular plaques and
inflammatory cytokines. IFN-beta therapy benefits visual memory (below).
Aphasia is rare in multiple sclerosis but can arise in acute disseminated encephalomyelitis.
Depression. This topic is extensively reviewed by Arnason (Arnason 2005). The incidence
of depression is increased 2- to 3-fold in multiple sclerosis patients (>50%) and their
families. Severe, short-duration multiple sclerosis is associated with more depression, but
primary progression is associated with less depression. Plaques and hypometabolism in the
left arcuate fasciculus (supra-insular white matter) (Pujol et al 1997), right temporal (Berg
et al 2000), and left temporal and inferior prefrontal areas (Feinstein et al 2004) are
associated with depression. However, depression does not correlate with MRI burden of
disease or atrophy, disability, or cognitive deficits.
The dexamethasone suppression test is a marker of neuroendocrine function in depression.
It is abnormal during active multiple sclerosis (Reder et al 1987; Fassbender et al 1998),
possibly from chronic inflammation, cytokine stress, and induction of CRH/AVP in
hypothalamic neurons. During attacks, depression and cytokine levels are strongly
correlated [tumor necrosis factor-alpha, IFN-gamma, and interleukin 10 (IL-10) all rise]
(Kahl et al 2002), possibly because IFN-gamma increases serotonin transporter and
indoleamine dioxygenase levels, lowering serotonin.
Therapy with IFN-beta can occasionally trigger depression, probably because interferon
elevates indolamine-2,3-dioxygenase, which lowers levels of tryptophan and serotonin.
However, IFN-beta therapy as well as antidepressants could elevate brain serotonin by
decreasing IFN-gamma levels. Both agents induce brain-derived neurotrophic factor.
Surprisingly, patients taking anti-depressants have lower BDNF levels in circulating immune
cells (Hamamcioglu and Reder 2007), possibly because depressed multiple sclerosis patients
have low BDNF levels before antidepressant therapy.
Suicide is elevated 7-fold in multiple sclerosis. Suicidal patients are more likely to have a
family history of mental illness, to abuse alcohol, to be under social stress or be depressed,
and to live alone. Confused thoughts and occasionally psychosis can be seen with
exacerbations.
Pseudobulbar affect (pathological laughing and crying, involuntary emotional expression
disorder) can be disabling. Disinhibition is from multiple supratentorial plaques and is
occasionally associated with hiccups and paroxysmal dystonia. Euphoria, despite concurrent
neurologic problems, was described by Charcot. It is possible the euphoria is cytokine-
mediated, akin to “spes phthisica”—a feeling of hopefulness for recovery seen in patients
with tuberculosis.
Optic neuritis. The optic nerves are frequently involved (approximately 2/3 clinically),
especially in younger patients. Thirty-one percent of army recruits with multiple sclerosis
have optic signs. “Asymptomatic” patients, free of optic neuritis, frequently have abnormal
visual evoked potentials or perimetry.
Optic neuritis typically begins with subacute loss of vision in 1 eye. The central scotoma is
described as blurring or a dark patch. Color perception and contrast sensitivity are also
disturbed. Subjective reduction of light intensity is often associated with an ipsilateral
Marcus Gunn hypoactive pupillary response. Ninety-two percent have retro-orbital pain with
eye movement.
With acute lesions, there may be blurring of the disc margin or florid papillitis. With
papillitis (in 5%), inflammation near the nerve head can cause disc-swelling, cells in the
vitreous, and deep retinal exudates. When the inflammation is retrobulbar, the fundus is
initially normal. After the neuritis resolves, the disc is usually pale ("optic pallor"), commonly
in its temporal aspect. Slit-like defects in the peripapillary nerve fiber layer can be seen with
red-free (green) light using an ophthalmoscope. This axonal damage in the retina, an area
free of central nervous system myelin, suggests that optic nerve pathology extends beyond
central nervous system plaques. Retinal nerve fiber layer atrophy and thinning is obvious on



optical coherence tomography (OCT). On OCT, the fellow eye is often abnormal, though not
as severe.
Bilateral simultaneous optic neuritis led to multiple sclerosis in 1 of 11 adults after an
interval of up to 30 years. Sequential optic neuritis led to multiple sclerosis in 8 of 20 (Parkin
et al 1984). In children, 1 of 17 developed multiple sclerosis after bilateral onset.
Visual function usually begins to improve several weeks after the onset of optic neuritis,
and resolution continues over several months. Complete recovery of visual acuity is the rule,
even after near blindness. Other disturbances of vision, however, often persist, such as
visual "blurring" and red or blue desaturation that causes colors to appear drab (“not as
vivid”). There is progressive loss of color discrimination with longer duration multiple
sclerosis. Bright lights cause a prolonged afterimage, a "flight of colors." Depth perception is
impaired and is worse with moving objects (“Pulfrich phenomenon”). Eye movements
sometimes cause fleeting flashes of light (“movement phosphenes”). The mechanism
corresponds to the fleeting cervical sensory changes of Lhermitte sign (Lhermitte of the
eye). Increased body temperature can amplify all of these symptoms and diminish visual
acuity (“Uhthoff phenomenon”).
Uveitis and pars planitis (peripheral uveitis) are present in 1% of multiple sclerosis
patients. Conversely, 20% of patients with pars planitis develop multiple sclerosis or optic
neuritis. Some of these patients will develop macular edema, vitreous opacities, papillitis,
vasculitis and vitreous hemorrhage, and cataracts. Perivenous sheathing is an inflammatory
change of the retina seen in one fourth of multiple sclerosis patients. Cortical lesions can
distort vision, eg, visual inversion.
Brainstem abnormalities, including diplopia. Lesions in the brainstem disrupt intra-
axial nerves, nerve nuclei, internuclear connections, plus autonomic, motor, and sensory
long tracts. Sixth or third nerve and rarely fourth nerve lesions cause diplopia. Cerebellar
and brainstem lesions cause eye movement abnormalities, usually coinciding with more
severe disability. Proton density MRI is the best way to image abnormalities in the
brainstem, including plaques in the median longitudinal fasciculus. There are reports of high
T2 signal MRI lesions in peripheral third, fifth (in 2% of patients, with two thirds bilateral),
and eighth nerves.
Medial rectus weakness is usually part of an “internuclear ophthalmoplegia” (INO). In a
young patient, INO is nearly pathognomonic of multiple sclerosis. Infarcts, trauma, and
disparate other causes are possible, especially in older patients (Keane 2005). Internuclear
ophthalmoplegia is paresis or weakness of adduction ipsilateral to a medial longitudinal
fasciculus lesion, along with dissociated nystagmus of the abducting eye. Lesions, usually in
the pons or midbrain, cause internuclear ophthalmoplegia when they interrupt connections
between the pontine paramedian reticular formation that innervates the ipsilateral abducens
nucleus and the contralateral third nerve nucleus. This illustrates an important principle:
plaques predominate in periventricular regions and cause characteristic signs.
Internuclear ophthalmoplegia is subclinical or “latent” in 80% of patients (in this case, it
would be termed “internuclear ophthalmoparesis”). Rapid eye movements can bring out this
hidden, minimal oculomotor weakness, causing slowing of the early adducting saccades—an
adduction lag.
demonstrate ataxic eye movements from cerebellar lesions. Convergence may be normal
despite an affected medial rectus. Medial longitudinal fasciculus lesions are seen best with
proton density MRI but are even more apparent with the clinical exam. Internuclear
ophthalmoplegia is often worse with heat and better with cooling (Frohman et al 2008).
Nystagmus is common in multiple sclerosis. It is usually inconsequential, but nystagmus
and oscillopsia can be severe enough to prevent reading or driving a car.
Seventh nerve lesions mimic Bell palsy. Because the lesions are intra-axial, the sixth nerve
is often simultaneously disturbed. Facial myokymia is from pontine tegmentum lesions of the
facial nerve and can be revered with carbamazepine and possibly botulinum toxin.
Hearing loss is relatively rare, but auditory processing could be slowed by brainstem and
deep white matter lesions. Central hearing defects could be supported by brainstem auditory
evoked potentials. They could also differentiate multiple sclerosis from benign positional



vertigo, which has no central defect. Vertigo is common and sometimes so incapacitating
that patients are bed-bound. Isolated autoimmune disease of the auditory nerve can also
cause hearing loss and vertigo. The relation to multiple sclerosis is unclear.
Up to one fourth of patients have problems swallowing. Horner syndrome is occasionally
present.
Transverse myelitis. The cord symptoms in idiopathic transverse myelitis are generally
more severe than in multiple sclerosis. In multiple sclerosis, a complete transverse lesion is
less common than a partial cord lesion (ie, a Brown-Séquard syndrome).
Cerebellar dysfunction and tremor. The cerebellum or its pathways are damaged in
50% of patients. "Charcot's triad" of cerebellar signs is nystagmus, intention tremor, and
“scanning” speech (in the sense of examining words carefully, “scandés” from Charcot). In
3% of patients, intention tremor of the limbs, ataxia, head or trunk titubation, and
dysarthria can be totally disabling.
Surprisingly, patients with severe ataxia are often strong and thin and would otherwise be
fully functional. The Stewart-Holmes rebound maneuver to detect cerebellar dyssynergia
does not correlate well with kinetic tremor (flex or extend at elbow) and intention tremor
(finger-to-nose). This suggests damage to different anatomic pathways (Waubant et al
2003). Poor cerebellar function correlates with loss of cerebellar volume on MRI.
Dystonia and parkinsonian symptoms are occasionally caused by a multiple sclerosis
plaque. Severe cerebellar signs correlate with poor pulmonary function.
Weakness. The long course of axons traveling from the motor cortex through the cord to
the lumbar motor neurons increases the likelihood that a random plaque will interrupt motor
neuron conduction. Legs are usually affected more than arms. Patients complain of a foot-
drop, tripping, or poor stair climbing. The hip flexors are often weak and out of proportion to
other leg muscles, likely from multiple cervical cord lesions (D Garwacki). Patients can walk
backwards more easily than they walk forward because gluteal muscles are stronger than
the iliopsoas. Hyperreflexia, spasticity, and a Babinski sign are common. Rarely, plaques
interrupt intra-axial nerve roots, and the deep tendon reflexes disappear and muscles
atrophy. Radicular symptoms arising from a posterior cord lesion are often painful, but
anterior plaques are not. Some muscle weakness and fatigue can be explained by a shift in
myosin heavy chain isoforms and less contractile force, a result of muscle inactivity and
deconditioning (Garner and Widrick 2003). Walking ability can be measured with a timed 25-
foot walk or the 6 spot step test, which incorporates coordination and balance.
Spasticity. Spasticity increases with a full bladder or bowels, pain, exposure to cold, and
sometimes on the day after IFN-beta injections (an effect of cytokines or direct modification
of neuronal excitability). There is often transient stiffness after physical inactivity. On
arising, the first few steps are difficult. Similarly, internuclear ophthalmoplegia is most
obvious with the first eye movements of the exam. Painful tonic spasms are common in
patients with severe spasticity and are sometimes provoked by exertion or hyperventilation.
Extrapyramidal symptoms disappear when the causative plaque resolves (Maimone et al
1991b).
Bladder and sexual dysfunction. Bladder dysfunction is common and markedly reduces
quality of life. It is the initial symptom in 5% of patients and eventually develops in 90%.
Two thirds of patients have bladder hyperreflexia with urgency and frequency. This is
complicated by sphincter dyssynergia in half of the patients (Schoenberg 1983; Andrews and
Husmann 1997; Betts 1999). Some of these patients are initially areflexic. The other third of
symptomatic patients have hyporeflexic bladders. Patients' description of residual volume is
often unreliable, so volume should be measured with office sonography or catheterization.
Detrusor hyporeflexia is linked to pontine lesions; detrusor-sphincter dyssynergia is linked to
cervical spinal cord lesions. Both are more common in Japanese populations than in Western
populations.
Glomerular filtration rate is reduced by 20% (Calabresi et al 2002). This could be from
chronic neurogenic bladder, urinary tract infections, antibiotics, ionic contrast agents, non-
steroidal anti-inflammatory drug use, and chronic dehydration.
Seventy percent of patients complain of sexual problems—orgasmic difficulty, poor



erections or lubrication, low pleasure, low libido, poor movement, and genital numbness.
Impotence develops in 40% to 70% of male patients. Fifty percent of women with multiple
sclerosis have significant sexual problems and complain of loss of libido, orgasms, and
genital sensation. Orgasmic dysfunction correlates with loss of clitoral vibratory sensation
and cerebellar deficits (Gruenwald et al 2007). Difficult or no orgasm was associated with
abnormal or absent (26/28) pudendal somatosensory evoked potential, although desire was
normal (Yang et al 2000). Occasionally, women have diffusely felt orgasmic spasms, not in
skeletal muscle, that last for up to 5 minutes. Others mention increased vaginal sensation
and orgasmic intensity.
Sexual problems often follow or coincide with bladder dysfunction. They are often
associated with loss of sweating below the waist from lesions of the sympathetic pathway
and also with disruption of genital somatosensory pathways. MRI T1 lesions in the pons
correlate with sexual dysfunction, far better than other MRI measures, urodynamics, or
pudendal and tibial evoked potentials. Other literature varies on anatomical links to plaque
location.
Constipation. Constipation is experienced by 50% of clinic patients and is more prevalent
in progressive than in relapsing forms. Poor voluntary squeeze pressure on manometric
testing, combined with little sensation of “fullness” is typical. Insensitivity to rectal filling
causes incontinence. This is uncommon but not rare and is usually associated with
constipation. Disruption of autonomic pathways in the cord may underlie the constipation.
Gut neurons have not been studied as direct targets of the immune system in multiple
sclerosis, but enteric glia have more antigenic resemblance to glia in the central nervous
system than glia in the peripheral nervous system (Gershon et al 1994).
Sensory symptoms. Sensory symptoms are common. Sensations are characteristically
hard to describe because they are spontaneous or distorted perceptions of everyday stimuli
caused by areas of demyelination and ephaptic connections unique to each patient. Sensory
loss ranges from decreased olfaction to marked loss of pain perception in small spots or over
the entire body. Poor perception of vibration in the feet, but spared position sense, is
present in more than 90% of multiple sclerosis patients. Vibratory loss can be quantified
with a tuning fork and sometimes improves with drug therapy. Sensory paths are unable to
transmit impulses from the rapidly oscillating tuning fork, a combination of demyelination
and cytokines that interfere with axonal conduction (Smith et al 2001).
symptoms are also common. Tingling, numbness, a tight band (usually at T6-T10, the
“multiple sclerosis hug”), pins and needles, a dead feeling, “ice” inside the leg, standing on
broken glass, and something "not right" are common descriptions. Paresthesias typically
begin in a band (a “multiple sclerosis hug”) around the trunk at T6-T9 (often from a cervical
plaque). They sometimes start in a hand or foot and progress over several days to involve
the entire limb. The sensations then resolve over several weeks.
Lhermitte sign. In 1924, Lhermitte described an electric discharge following flexion of the
neck in multiple sclerosis. Forty percent of multiple sclerosis patients have Lhermitte sign
(symptom, phenomenon). This is rapid, brief "electric shock" or "vibration" running from the
neck down the spine, similar to when trauma to the ulnar nerve triggers the “funny bone.”
The intensity of the pain is directly related to the amplitude and rapidity of neck flexion. In
an instinctive protective reflex, the patient may straighten her neck. This sign is from
mechanical stimulation of irritable demyelinated axons. Ninety-five percent of patients with
this sign have cervical cord MRI lesions. Cord compression can also generate the sign and
must be ruled out.
Pain. Up to two thirds of patients with multiple sclerosis have pain at some time during the
course of their disease (Clifford and Trotter 1984; Moulin et al 1988; Stenager et al 1991),
although pain was regarded as rare in much of the older literature. The pain is chronic most
of the time, but acute or intermittent pain also occurs. Legs are affected in 90%, and arms
in 31%, of patients complaining of pain. Pain is more common in older women with
spasticity or myelopathy, and in multiple sclerosis of long duration (Moulin et al 1988;
Stenager et al 1991). It is often worse at night and when the ambient temperature changes
suddenly.



The spectrum of pain includes central neuropathic pain from focal demyelination (eg,
trigeminal neuralgia, dysesthesias, and nonspecific pain) to pain and dysesthesias from
ephaptic transmission (Lhermitte symptom, radicular pain, tonic seizures), inflammation or
swelling (optic neuritis, headaches), visceral pain from chronic constipation or painful
bladder spasms, abnormal motor activity (tonic seizures, spasms, clonus), or simple
orthopedic musculoskeletal pain. Lesions in pain inhibitory pathways, abnormal sodium
channel redistribution, or maladaptive neural plasticity during plaque repair may cause the
central pain. Chronic back pain can arise as a consequence of multiple sclerosis, causing
unilateral weakness or spasticity, poor posture, and accelerated degenerative disc disease.
Pain is common in optic neuritis. A swollen, inflamed optic nerve puts pressure on the dural
sheath. Pain in or behind the eye sometimes precedes the visual loss. The pain in optic
neuritis can be present at rest, on voluntary eye movement, and with pressure on the globe.
Vasoactive amines, prostaglandins, and kinins released by inflammatory cells may magnify
the pain in optic neuritis and in trigeminal neuralgia.
Trigeminal neuralgia. Trigeminal neuralgia is relatively rare in multiple sclerosis
(occurring in 0.5% to 1% of patients) (Rushton and Olafson 1965). Bilateral trigeminal
neuralgia has been described as pathognomonic of multiple sclerosis (Jensen et al 1982).
However, it can be caused by vascular lesions (Meaney et al 1995) when arteries compress
the trigeminal nerve at the junction of the central and peripheral nervous system (root entry
zone). Vascular compression causes demyelination and remyelination, sometimes aberrant,
allowing ephaptic conduction between active and silent nerve fibers, and between light touch
and pain fibers (Love and Coakham 2001).
The trigeminal neuralgia of multiple sclerosis is from a plaque in the fifth nerve nucleus
(Olafson et al 1966) or the brainstem entry zone of nerve fibers (Gass et al 1997). After
facial nerve injury, IFN-gamma increases, but pituitary adenylyl cyclase-activating
polypeptide recruits anti-inflammatory Th2 cells. Radicular pains in multiple sclerosis,
especially if lancinating, may have a similar mechanism. The cisternal (peripheral) fifth
nerve enhances on MRI in 3% of patients, but this is usually clinically silent.
Brainstem plaques can cause glossopharyngeal neuralgia.
Headaches. Headaches are more common in multiple sclerosis (27%) than in matched
controls (12%) (Watkins and Espir 1969). They can herald exacerbations.
Seizures and paroxysmal symptoms. Epileptic seizures double in incidence in multiple
sclerosis and are more common in later stages. They seem to result from new or enhancing
lesions in the cortex or subcortical areas. They can be triggered by 4-amino pyridine or rapid
reductions in baclofen.
Other paroxysmal symptoms last seconds to minutes and are triggered by hyperventilation
(eg, 20 deep breaths), stress, cold, touch, metabolic abnormalities, exercise, or acute
exacerbations. Paroxysms include visual complaints, diplopia, vertigo, dysarthria, facial and
limb myokymia, tonic motor seizures, spasms, dystonia, restless legs, akinesia, kinesigenic
choreoathetosis, hyperekplexia, rapid eye movement sleep disorders, ataxia, itching, and
pain and paresthesias (eg, trigeminal neuralgia, Lhermitte sign). Transverse spread between
demyelinated axons (ephaptic transmission) is a likely cause. It is probably amplified by
cytokines, extracellular potassium, dysfunction of ion channels, and heterogeneity of new
sodium channels.
Associated diseases. In multiple sclerosis, there are links between inflammatory bowel
disease and thyroiditis, and bone mass is low. Other autoimmune diseases are not
associated with multiple sclerosis—and may be less prevalent than in the general population.
Many reported associations are likely from the strong autoimmune proclivity in Devic disease
or CNS Sjögren disease, variants that comprise 5% of “multiple sclerosis” patients. Cancer
incidence is likely reduced.
Natural history. The course of multiple sclerosis varies. Heterogeneity over time
complicates the use of stage-specific therapies. Classification is important because no
therapies are effective in the primary progressive forms.
At onset, at an average of 28 years old, multiple sclerosis is relapsing-remitting 85% of the
time. This form predominates in young women. Attacks typically occur once every 2 years.



Survival is decreased by 10 years.
Fifty percent of relapsing-remitting patients become progressive after 10 years, and 89%
by 26 years; this is termed "secondary progressive” multiple sclerosis. The number of
neurologic systems in the initial attack, and not recovery from the attacks, predicts the
chance of developing progressive disease. Once progression appears, the rate of decline is
constant.
About 10% to 15% are progressive from onset, at an average of 38 years old, with
continuing deterioration for a year or more, without obvious exacerbations or remissions,
although the rate of decline fluctuates. Compared to age 10 to 19 years, the relative risk of
primary progression is 2.3 at age 25, 8.1 at 35, 19 at 45, and 47-fold higher at age 50 to 59
years (Stankoff et al 2007). These categories are not immutable; patients frequently drift
from one type of multiple sclerosis to another, become stable, or suddenly develop active
disease (Goodkin et al 1989). Primary progression is considered a unique form of multiple
sclerosis, but 28% of these patients will eventually have exacerbations (Kremenchutzky et al
1999), sometimes after 20 years of pure progression.
The progressive form affects the spinal cord predominantly (in 90%), begins at a later age
(40 years) than the relapsing form, and is approximately as common in men as in women.
These patients have progressive paraparesis and loss of vibration and pinprick sensation in
the legs, and they typically develop a small, spastic neurogenic bladder. Cerebral MRI
lesions are 6 times less frequent in the primary progressive group compared to relapsing-
remitting patients who become progressive later on (Thompson et al 1991). However, in
white matter that appears normal on conventional MRI, low N-acetyl aspartate levels are low
(reflecting widespread neuronal loss or dysfunction), and the magnetization transfer ratio is
low (Filippi et al 1999). Relapses in the first 2 years predict earlier onset of progression.
Relapses after the first 2 years are linked to lower chance of becoming progressive (Scalfari
et al 2010), suggesting that evolution of immune dysregulation modifies the course of
multiple sclerosis. Progression has features of an age-dependent degenerative process
(Kremenchutzky et al 2006). Age at onset of multiple sclerosis is 30 years for secondary
progressive disease but 39 years for primary progressive multiple sclerosis. Age at beginning
of progression is 39 in both groups.
Exacerbations contribute to disability. Forty-two percent to 49% have residual loss of 0.5
EDSS points at 2 to 4 months, and 28% to 33% have a loss of 1 or more EDSS point (Lublin
et al 2003; Hirst et al 2008). Some improve; however, 19% have a 0.5 point decrease and
10% have a 1 point decrease (Lublin et al 2003). In 700 placebo-treated patients from 11
clinical trials, worsening after exacerbations was nearly equivalent to improvement (Ebers et
al 2008). The authors conclude that disability could not be used as an outcome measure in
most (short-term) clinical trials.
Occasionally, patients have acute fulminant multiple sclerosis (Marburg variant). This
malignant form of multiple sclerosis is possibly associated with developmentally immature
myelin basic protein (Wood et al 1996).
Twenty percent of patients have “benign multiple sclerosis,” defined as a Kurtzke disability
score of 3/10 or lower. After 20 years, 6% of the overall population is still benign—largely
comprised of those who scored 2 or lower at 10 years (Hawkins and McDonnell 1999). Some
patients with benign multiple sclerosis have surprisingly large lesion loads on MRI (Strasser-
Fuchs et al 2008). Clinical/MRI dissociation is also seen in correlating MRI with clinical
activity (r is only 0.25). Predictors include young onset, monosymptomatic, no cord
symptoms, and few attacks or MRI lesions. Cognitive function, fatigue, and pain should be
included in assessment of a propitious course. Autopsy studies indicate that there is a large
reservoir of undetected and, therefore, benign multiple sclerosis.
Unsuspected and asymptomatic cases. Multiple sclerosis is sometimes unsuspected
during life, yet found at autopsy. Twelve unsuspected cases of multiple sclerosis were found
in 15,644 autopsies in Switzerland. Only 2 had no reported neurologic signs during life
(Georgi 1961). There were 5 diagnosed cases of multiple sclerosis in 2450 autopsies in
London and Ontario (Gilbert and Sadler 1983). In autopsy studies, the calculated prevalence
of unsuspected multiple sclerosis would be about 31 in 100,000 in Paris (3 in 9300)



(Castaigne et al 1981); 90 to 128 in 100,000 in Switzerland (Georgi 1961); and 204 in
100,000 in Ontario (Gilbert and Sadler 1983). This suggests that the number of undiagnosed
"normal" people with multiple sclerosis approximates the number of patients diagnosed with
multiple sclerosis. Of asymptomatic “normal” first degree relatives, 4% to 10% have MRI
lesions indistinguishable from multiple sclerosis (De Stefano et al 2006). This suggests that
“benign” multiple sclerosis is itself a spectrum, and sometimes should not be treated with
immunomodulators.
Clinically isolated syndromes. “Clinically isolated syndromes” include optic neuritis,
transverse myelitis, and solitary brainstem lesions. They evolve into multiple sclerosis most
often when the MRI T2 lesion load is high and when the CSF reflects inflammation. When
clinically isolated symptoms appear in parallel with non-enhancing MRI lesions plus at least 1
enhancing lesion, 70% to 80% of patients will have another gadolinium-positive lesion
within 6 months. A positive spinal tap further increases the chance that multiple sclerosis
will develop. Partial cervical myelopathy, without brain MRI lesions, often evolves into
clinically definite multiple sclerosis if evoked potentials and CSF are abnormal (Bashir and
Whitaker 2000).
Childhood multiple sclerosis. An attack before the age of 16 happens in 3% to 5% of all
patients. A family history (8%) is more common than in adult forms. Sensory symptoms and
optic neuritis are common (approximately 50%, even though these symptoms may
sometimes not be reported by children). Brainstem and cerebellar symptoms,
polysymptomatic disease, and seizures are more frequent than in adult onset multiple
sclerosis, but recovery from exacerbations is better (Duquette et al 1987; Selcen et al 1996;
Ghezzi et al 1999; Ruggieri et al 1999). One third of patients have cognitive problems. As in
adult forms, sphincter involvement and a progressive course have a poor prognosis. Boys
predominate over girls between 8 and 10 years of age, but the girl-to-boy ratio is 2:1 after
10 years. Relapses are a bit more frequent in childhood (every 1.6 years versus every 2
years in adults) but are only 4 weeks long versus 7 weeks in adults (Ness et al 2007). The
course is slower than in adult-onset multiple sclerosis (Simone et al 2002), and the median
time from onset to secondary progression is 28 years. Nonetheless, with continuous
exacerbations they become disabled at a younger age than adult-onset patients. Primary
progression is exceptionally rare (2% of an already uncommon event).
MRI, EEG, and visual-evoked potentials are each abnormal in 80% of patients, and CSF is
abnormal in 66% of patients (CSF IgG levels are lower in children, so this is probably an
underestimate) (Duquette et al 1987; Banwell 2004). Oligoclonal bands are uncommon in
acute disseminated encephalomyelitis, a disorder sometimes difficult to separate from the
first attack of multiple sclerosis. Bands are positive in 29% of acute disseminated
encephalomyelitis, 64% of acute multiple sclerosis, and 82% of multiple sclerosis at later
times in a medium-sized series (Dale et al 2000). Serum antibodies to myelin
oligodendrocyte glycoprotein are increased in frequency in children versus adults. The
prolonged relapsing-remitting course suggests therapies may be more effective in children
than in adults. [Neurology 2007;68(16, Suppl 2) is devoted to pediatric multiple sclerosis.]
Geographic variation. The incidence and symptoms of multiple sclerosis are different
around the globe. It is uncommon at the equator (prevalence 2 to 10 per 100,000), and
increases with distance from the equator (up to 200 per 100,000). This suggests
environmental factors influence the incidence, but emigrating northern Europeans tended to
stay in temperate climates, suggesting genetic influence. Multiple sclerosis is rare in Asia (4
per 100,000) (Kurtzke 1975). Multiple sclerosis in Japan, China, Malaysia, in black Africans,
and in some groups of Canadian Aboriginals often resembles Devic disease because it
typically affects the optic nerves and spinal cord and occurs at an earlier age than the
Western form of multiple sclerosis (Cosnett 1981; Phadke 1990).
Quality of Life (QOL) and clinical scales. Responses by 433 patients were used to
generate the 59-question Functional Assessment of Multiple Sclerosis quality of life scale
(Cella et al 1996). A factor analysis demonstrated that multiple sclerosis had independent
effects on several important factors that impact patients' lives.
Separate axes with little overlap included the following:



(1) Mobility. This correlated highly with the neurologic exam (Kurtzke Expanded Disability
Status Score, Scripps Numerical Rating Scale, and Ambulation Index) but not with the other
subscales.
(2) “Emotional well-being” and “general contentment,” which negatively correlated with
psychiatric measures of anxiety and depression.
(3) “Symptoms.”
(4) Family and social well-being.
(5) “Fatigue” plus “thinking,” an indicator of cognitive function. Fatigue is highly prevalent;
cognitive loss has the most important impact on quality of life.
Neurologic and social function, fatigue, mood, and cognition are important components of
clinical multiple sclerosis that are often more disabling than inability to walk. Because these
factors do not correlate, different pathogenic mechanisms are likely. For example, difficulty
walking could arise from damage to long tracts or oligodendroglia, and fatigue may be
caused by inflammatory cytokines in the CNS. Different pathological causes may also vary in
responses to drugs; they should all be evaluated in therapeutic trials.
Patient-rated scales provide important information about independent factors that are
missed when exams are limited to assessment of mobility. Telephone and self-administered
scales correlate well (r=0.9) with physician exams.
The Kurtzke Extended Disability Status Score (EDSS) is a central clinical measure in most
trials. It is based on the neurologic exam and ranges from 0 to 10, where 0 = normal, 4 =
walks unaided for greater than 500 meters, 5 = walks unaided for greater than 100 meters,
6 = needs a cane to walk 100 meters, 7 = walks less than 20 meters with aid, 8 =
perambulated in wheelchair, and 10 = death. Cognitive problems, fatigue, sexual function,
job capabilities, and social factors do not weigh heavily in this scale. This scale is not linear,
and transition between stages 4 and 6 is fastest.
The Multiple Sclerosis Functional Composite Scale (MSFC) evaluates motor function of legs
and arms and cognition. It adds information to the Kurtzke Expanded Disability Status Score
and was used in a phase 3 clinical trial of intramuscular IFN-beta-1a (Cohen et al 2001).
Correlation between the Kurtzke scale and the Multiple Sclerosis Functional Composite scale
is only r = -0.15.
The global Multiple Sclerosis Severity Scale (MSSS) combines disease duration with the
Kurtzke score to combine rate and severity (Roxburgh et al 2005). Many of the patients who
defined the MSSS were on therapy, so untreated progression rates are probably even higher
than the table indicates.

Clinical vignette
A 28-year-old woman began to stumble when walking. Her right leg was slightly stiff and
weak, especially after exercise and hot showers. These symptoms developed over 3 days
and gradually disappeared over 4 weeks.
She was on the college swim team before these symptoms arose. There, when she was 21
years old, she developed a unique and extreme type of fatigue that differed from the usual
fatigue after intense swimming workouts. This disappeared after several weeks, but
reappeared again when she was 28 years of age. One maternal aunt had multiple sclerosis.
An MRI scan showed multiple periventricular lesions. Her spinal fluid had elevated IgG
levels and 3 oligoclonal bands (normal, less than 2).
One year later, 10 days after a “cold,” she developed blurred vision in her right eye and
her visual acuity dropped to 20/200. She had moderate pain behind her eye when she
looked to either side. The pain and visual loss gradually disappeared over 6 weeks. Two
years later, she noticed that both legs were becoming gradually weaker and spastic and she
needed to run to the bathroom nearly every hour to urinate. These symptoms slowly
progressed over the next 10 years, with occasional exacerbations affecting other areas of
the brain. IFN-beta was begun in the middle of the relapsing and progressive phase and the
frequency of attacks and rate of progression slowed. She is now walking with the help of
bilateral ankle and foot orthoses. She has been aided by minor modifications of her



workplace and by treatment of multiple sclerosis symptoms, and she continues to work as a
business executive.

Etiology
Although there appears to be an "autoimmune" attack against myelin and myelin-forming
cells in the brain and spinal cord, multiple sclerosis cannot be called a true autoimmune
disease. T cell and antibody reactivity have been tested against numerous virus and brain
antigens, but no target antigen has been clearly demonstrated. The antigen-induced animal
model, experimental allergic encephalomyelitis, does not appear spontaneously in wild mice.
HLA types are associated, but the mechanism is unclear. There are surprisingly few links to
autoimmune disease, except Crohn disease and possibly thyroid disease. Systemic lupus
erythematosus is underrepresented in multiple sclerosis and is linked to opposite responses
to type I interferons (Javed and Reder 2006).
Specific antigenic targets for inflammation in multiple sclerosis. Candidate central
nervous system antigens and targets include:
• Proteins from infectious agents (viruses, chlamydia) that match brain antigens.
• Proteins from neurons (synapsin).
• Myelin (eg, myelin oligodendrocyte glycoprotein, myelin basic protein, proteolipid protein,
and myelin-associated glycoprotein) and glycolipids (ganglioside GD1a). Antibodies to MOG
may cross react with Epstein-Barr virus nuclear antigen. Heat shock protein-65 is highly
conserved between bacteria and man, and it is cross-reactive with the myelin antigen cyclic
nucleotide phosphohydrolase (Birnbaum et al 1996).
• Proteins from glia (astrocyte alpha-B crystallin, S100-beta, and arrestin; plus
oligodendroglial 2',3' cyclic nucleotide 3' phosphodiesterase, alpha-B crystallin, and
transaldolase) (Schmidt 1998) and oligodendrocyte-specific protein (Cross et al 2001).
Alpha-B crystallin may bind immunoglobulin and not vice versa, but these proteins could
trigger antigen-specific responses or be involved in a gradual evolution in immune reactivity
over time, ie, "epitope spreading" to related antigens.
The antibody response to central nervous system antigens varies between patients. Anti-
myelin basic protein responses are weak in multiple sclerosis, differing from the strong
responses in animal models. However, pro-inflammatory cells recognizing myelin basic
protein are increased when low concentrations of myelin basic protein are used to detect
high avidity human T cell clones (Bielekova et al 2004). Anti-proteolipid antibodies in CSF
are more common in women than men, in patients with later onset of multiple sclerosis, in
patients without a family history of multiple sclerosis, and in those who have low levels of
CSF immunoglobulin and oligoclonal bands (Warren et al 1994). Antibodies to myelin
oligodendrocyte protein are debatably elevated in all forms of multiple sclerosis (and other
inflammatory brain diseases). Antibodies to myelin basic protein are low in early multiple
sclerosis and increase over time (Reindl et al 1999), but detection is erratic between
laboratories. Even if antibodies to brain antigens do not cause multiple sclerosis, they could
modify disease course.
Arguments are made against the presence of a “multiple sclerosis antigen.” For instance, 1
in 220 people vaccinated with the Semple rabies vaccine—which contains central nervous
system tissue—develop autoimmune encephalitis (similar to EAE). Patients susceptible to
this encephalitis, however, have a human leukocyte antigen (HLA) makeup that is distinct
from multiple sclerosis patients (Piyasirisilp et al 1999).
The lack of a causative antigen suggests that fundamental control of immune responses
may be abnormal and that oligodendroglia are innocent bystanders damaged by unregulated
inflammation. Activated lymphocytes and monocytes might enter the central nervous system
because of nonspecific adhesion to endothelial cells, become activated within the central
nervous system, stay longer during trafficking through the central nervous system, and
escape from the normal CNS suppression of the immune response. Putative antigen-specific
responses are described below.
Non-antigen-specific immunity for inflammation in multiple sclerosis. Etiologies



that do not invoke specific target antigens are possible in multiple sclerosis.
Viruses. Through direct damage to oligodendroglia, by retrovirus incorporation into
oligodendroglia and T cells, and from immune reactivity to shared determinants between
oligodendroglia and viruses. The role of human herpes virus-6 and endogenous retroviruses
awaits confirmation in multiple sclerosis. Human endogenous retroviruses, HERV, which
make up 10% to 30% of the human genome correlate with a more progressive course.
However, detection of these viruses is possibly a byproduct of immune activation of viruses
and not the cause of the disease. Activated astrocytes produce retrovirus-encoded syncytin,
which is toxic to oligodendrocytes.
Antibodies to Epstein-Barr virus correlate with brain atrophy and are elevated early in the
course of multiple sclerosis. This may simply reflect multiple sclerosis-characteristic high
titers to many antigens and many viruses, possible because HLA-DR2 is over-represented in
multiple sclerosis and because DR2-positive people have higher antibody titers to Epstein-
Barr virus, measles, and rubella (Compston et al 1986). Anti-Epstein-Barr virus antibodies
could arise from persistent infection of astrocytes or B cells, causing costimulatory molecule
expression, IL-6 secretion, and immune activation. Epstein-Barr virus infects B cells and
could generate an autoreactive B cell population resistant to apoptosis and immune control.
Antibodies to cytomegalovirus, in contrast, correlate with better outcome (Zivadinov et al
2006). Varicella-zoster virus DNA increases briefly in mononuclear cells during relapses, but
this virus does not increase the risk of multiple sclerosis. Report of varicella-zoster virus
particles in multiple sclerosis brains has not been confirmed (Burgoon et al 2009).
In children, Epstein-Barr virus NA-1 seropositivity increases the risk of multiple sclerosis
3.8-fold. Cytomegalovirus positive serum confers a lower risk of multiple sclerosis in children
0.27-fold (Waubant et al 2011).
Bacteria and chlamydia. Through cross-reactive antigens, superantigen activation of
pathogenic T cells, responses to induced heat shock proteins (all trigger cytokine release),
and release of bacterial toxins, possibly from posterior sinuses and submucosa (Gay 2007).
Conversely, parasite infestation could be protective.
Oligodendroglia. Defective function or repair.
Diet. Affects immunity through oral tolerance and shapes the microbiome. Diet can modify
macrophage function, membrane composition of immune cells, and prostaglandin synthesis.
Genetic. Predisposition to respond to brain antigens, altered control of the immune
response to brain antigens, lack of neurotrophic proteins, or poor ability to repair CNS
damage.
Other mechanisms. Toxins, microchimerism of circulating blood cells, and endocrine,
catecholamine, and stress interrelations with immunity have been proposed.
In the 1950s, anticoagulants failed to significantly impact the course of multiple sclerosis
based on a theory that CNS microvessels had poor blood flow. Recent use of venous stenting
to reverse putative cerebral venous outflow problems (CCSVI) has not been beneficial in
controlled studies, although anecdotes of benefit are common. Tens of millions of dollars in
research money and medical costs, huge amounts of investigators' intellectual energy, and
misplaced hope by patients are being directed at this questionable therapy.

Pathogenesis and pathophysiology
Multiple sclerosis is a demyelinating disease, but brain parenchymal and meningeal
inflammation and chronic cytokine exposure also affect neuronal metabolism and survival.
This leads to brain atrophy, fatigue, cognitive loss, and neurologic abnormalities. The course
of multiple sclerosis can be broken down into 3 phases:
(1) The initiating event (inflammation, viruses, hypothalamic damage).
(2) Recovery from relapses.
(3) Chronic progression.
Immunity underlying the CNS pathology. The initiating event for the first attack of
multiple sclerosis is unknown. Genetics and environment both play a role (Page et al 1993).
Multiple sclerosis plaques are formed after invasion of inflammatory T cells and monocytes.



Immune activation is a multi-step process. Primed T cells may be alerted to a CNS antigen
and then “licensed” by the innate immune system exposed to viral or microbial antigens
through CpG oligonucleotides and toll receptor-9 (TLR-9) or pertussis toxin in experimental
allergic encephalomyelitis (Darabi et al 2004) before they are activated by brain antigens.
During development, it is possible that thymic presentation of alternately-spliced golli-
myelin basic protein in the context of abnormal costimulatory molecules (Maimone and
Reder 1991), or later exposure to a viral antigen, starts an autoimmune cascade. Following
peripheral activation, circulating T cells adhere to post-capillary venules in the brain and
spinal cord. The T cells pass through the endothelial cells and migrate into perivascular brain
parenchyma. Note that an equivalent number of monocytes and T cells are present in
plaques at early stages. Brain dendritic cells can emigrate to the periphery and educate T
cells, and these T cells may then home back to the brain.
In the plaque, the cellular infiltrate is associated with destruction of the inner myelin
lamellae and dysfunction of oligodendroglia, possibly with diffuse effects such as fatigue and
slowed cognition. Early on, gemistocytic astrocytes have high levels of GFAP and also trophic
factors, BDNF, TrK receptors, and VEGF (Ludwin 2006). Astrocytes stimulated by IL-9
produce CCL20, which attracts Th17 cells.
Inflammation, based on the presence of Gd-enhancing MRI lesions, resolves in 2 to 8
weeks. However, immune cells in plaques are poised for activation, and there is continued
low-grade inflammation as well as chronic axonal loss and demyelination.
Immune activation and dysregulation. Immune activation in peripheral blood precedes
neurologic problems and MRI activity. Several weeks before attacks, there are increases in
Concanavalin A-stimulated IFN-gamma and tumor necrosis factor-alpha production (Beck et
al 1988), IFN-gamma levels in serum (Dettke et al 1997), IFN-gamma-induced [Ca++]
influx in T cells (Martino et al 1995), and secretion of prostaglandins by monocytes (Dore-
Duffy et al 1986). Excessive numbers of cytokine-secreting cells are seen early in multiple
sclerosis, even in acute monosymptomatic optic neuritis. Cytokines such as IFN-gamma,
osteopontin, and IL-2 activate immune cells, Th17 cells, and endothelial cells, and induce
costimulatory molecules that further enhance T cell proliferation and activation (Prat et al
2000a).
During active multiple sclerosis, Th1 cell-mediated inflammation increases. Lymphocytes
express excessive levels of the activating zeta chain of the T cell receptor on CD4 T cells
(Khatibi and Reder 2008), activation proteins (HLA-DR and CD71), costimulatory molecules
on B cells (CD80, also called B7-1) (Genc et al 1997a), and Th1 cell chemokine receptors
(CCR5 and CXCR3) (Balashov et al 1999). Inflammatory cytokines and cytokine-secreting
cells (eg, IL-2, IL-15, IL-17, IL-23, and IFN-gamma) are elevated (Trotter et al 1991; Lu et
al 1993). Messenger ribonucleic acid for inflammatory cytokines is elevated in white blood
cells (Rieckmann et al 1994; Byskosh and Reder 1996). IL-1, IL-6, and IL-15 and tumor
necrosis factor-alpha are present in the CSF (Maimone et al 1991a; Kivisakk 1998). These
Th1-like cytokines and monokines amplify immune responses. In support, IFN-gamma
"therapy" and granulocyte colony-stimulating factor (G-CSF) infusions trigger attacks of
multiple sclerosis, though they both prevent experimental allergic encephalomyelitis. IFN-
gamma, a proinflammatory cytokine, is toxic to actively remyelinating oligodendroglia, and
it activates monocytes and microglia. However, it inhibits proliferation of Th1 cells (it
downregulates the IFN-gamma receptor-beta chain), can cause apoptosis of activated T cells
(Ahn et al 2004), and is protective for mature oligodendroglia (Lin et al 2007). Thus, timing,
location, and degree of inflammation are all affected by cytokines.
During attacks of multiple sclerosis, concanavalin A-induced suppressor cell function drops
(Antel et al 1986). During progressive multiple sclerosis, excessive IL-12 production induces
IFN-gamma (Balashov et al 1997). Low production of IL-10 removes another brake on Th1
cells (Soldan et al 2004). IL-15 (related to IL-2) levels rise in blood > CSF monocytes,
especially during attacks and progression. These changes could lead to delayed-type
hypersensitivity (Th1-type) immune reactions.
The Th1/Th2 dichotomy is too simplistic, however:
(1) Both types of cytokines rise in blood cells before attacks—a “cytokine storm” (Link



1998). Both Th1 and Th2 cytokines are present in CNS immune cells (Cannella and Raine
1995) and also in peripheral immune cells following IFN-beta therapy (Byskosh and Reder
1996; Wandinger et al 2001).
(2) Therapy with anti-CD52 (alemtuzumab) depletes Th1 cells, potentially causing a Th1 to
Th2 shift, but does not stop progression or MRI activity.
(3) Th2 cytokines can potentially cause damage. A Th2-driven form of myelin-
oligodendrocyte-glycoprotein-induced experimental allergic encephalomyelitis causes lethal
demyelination.
(4) Monokines are increased in CSF (Maimone et al 1991a). Families with high IL-1/IL-1Ra
plus high TNF-alpha/IL-10 ratios have a 6-fold increased risk of having a family member
with multiple sclerosis (de Jong et al 2002).
(5) Microarrays of immune cell RNA show the IFN-alpha/beta pathway is more
dysregulated than the Th1 and Th2 pathways in untreated patients (Yamaguchi et al 2008).
Interferon dysregulation is discussed with IFN-beta therapy in “Interferon immunology” in
the Management section.
Th17 cells are a subset of CD4 cells that amplify autoimmune CNS inflammation and may
be important in multiple sclerosis. IL-6 plus transforming growth factor-beta generate IL-17-
producing cells from naïve CD4 cells. IL-23 maintains this population and also induces IL-17
in memory CD4 cells. The inflamed blood-brain barrier and monocytes, which have
transformed into dendritic cells, help polarize naïve T cells into Th17 cells (Ifergan et al
2008). IL-4, IL-27, IFN-gamma, and IFN-beta all inhibit IL-17 production.
Th17 and regulatory T cells (Tregs) are induced by the aryl hydrocarbon receptor (AhR),
which is bound by dioxin, breakdown products of aromatic amino acids (eg, tryptophan),
and prostaglandins. Dioxin inhibits hematopoietic stem cell expansion. Effects on multiple
immune cell populations and culture conditions could explain published differences in Th17
function. The commonly-used RPMI culture media has low levels of AhR ligands, but Iscove's
media has high levels and is much more conducive to Th17 cell induction (Veldhoen et al
2009).
IL-17-expressing cells increase during exacerbations and are higher in plaques and CSF
than serum in multiple sclerosis (Matusevicius et al 1999; Durelli et al 2009), in optico-
spinal multiple sclerosis (Ishizu et al 2005), and likely in some Devic variants of multiple
sclerosis. IL-17 is produced by CD4 and CD8 cells and oligodendrocytes in perivascular areas
of active lesions (Tzartos et al 2008). Cells simultaneously secreting IFN-gamma plus IL-17
are also increased in multiple sclerosis. CSF IL-17 and IL-8 levels correlate with the length of
spinal cord lesions.
CD2 is a costimulatory T cell molecule that binds CD58 (LFA-1). Although expression of the
usually measured epitope of CD2 is normal on CD4 and CD8 cells, stimulation through CD2
is reduced in progressive multiple sclerosis. The conformation of CD2 is altered because
there is a marked fall in avid rosette-forming cells (CD2 on T cells binds CD58 on RBC) and
other antibodies do not bind normally (Reder et al 1991). An allele of CD58 that increases
CD58 mRNA is protective against multiple sclerosis (odds ratio = 0.82), and CD58 mRNA is
1.2 times normal in exacerbations and 1.7 times normal in remissions (De Jager et al 2009).
Activation through CD2 increases regulatory CD4 cells and CD4 suppressor function; effects
on CD8 cells are unknown. Thus, there may be a reciprocal relation between multiple
sclerosis state-specific low CD2 function and CD58 expression.
Cytolytic CD8 cells and monocytes in plaques directly damage neurons and axons more
than CD4 cells do. CD8 cells that produce Th1-like cytokines are elevated in optico-spinal
multiple sclerosis (Ochi et al 2001). Expanded CD8, but not CD4, clones appear in blood,
CSF, and multiple sclerosis plaques. Multiple sclerosis therapies tend not to target these
cells.
CD8+,CD28- suppressor cell function may be the most important form of immune
suppression in multiple sclerosis. The antigen that induces these suppressor cells is
unknown. When induced by concanavalin A, suppressor function drops during attacks of
multiple sclerosis (Antel et al 1986; Karaszewski et al 1991; Correale and Villa 2008). In an
extensive series of experiments, Antel and colleagues showed that the T cell population in



multiple sclerosis that suppresses immune reactions is predominantly CD8+CD28-, but is
CD4-negative (Antel et al 1979; Crucian et al 1995). Thus, CD8 cells had much more potent
suppressor effects than CD4 cells. CD8 suppressor cells form a 3-way bridge with monocytes
and destroy HLA-E (mouse Qa-1)-expressing pathogenic CD4 cells (Tennakoon et al 2006;
Correale and Villa 2008). CD8+,CD28-,FoxP3+ suppressor cells also induce tolerogenic ILT3
and ILT4 molecules on endothelial cells (Manavalan et al 2004) and on antigen-presenting
cells. During exacerbations, high levels of IL-15 and likely IFN-gamma induce expression of
the inhibitory NG2A protein on CD8 cells, and CD8 suppressor function falls (Correale and
Villa 2008). In mice, similar CD8,CD122 regulatory cells produce IL-10 to inhibit proliferation
and IFN-gamma production by CD8 cytotoxic cells. IL-10 also induces more of these
suppressor cells, as does glatiramer therapy in humans.
Transfer of neuroantigen-reactive CD8 cells inhibits experimental allergic encephalomyelitis
(York et al 2010). In CD8 knockout mice, attacks resolve, but later relapses still occur. This
would suggest that CD8 cells do not terminate the inflammation in mice but do prevent
recurrent attacks. Generalizations across species are suspect, however. The major
suppressor cell subpopulation in mice consists of CD4+CD25+ T regulatory cells, but in man
and likely in multiple sclerosis, the more potent subset is CD8+CCD28-.
The fall in mitogen-induced CD8 suppressor cell function is unexplained, but it correlates
highly with clinical activity (r = 0.79) (Antel et al 1979), far better than MRI correlates with
clinical disease (r = 0.25). MRI also correlates poorly with serum cytokine levels (Kraus et al
2002). This suppressor defect is corrected with IFN-beta, glatiramer acetate, beta2-
adrenergic agonists, and Fc receptor ligands. Monitoring of CD8 expression, suppressor cell
function, CD80 expression, or specific Th1, Th2, and Th17 markers could predict impending
attacks of multiple sclerosis, could differentiate between multiple sclerosis attacks and
transient worsening from fever, and reflect early therapeutic responses to drugs.
Tr1 CD4 suppressor cells secrete 6 times less inhibitory IL-10 in multiple sclerosis; plus,
target multiple sclerosis cells are resistant to IL-10 compared to normal controls (Martinez-
Forero et al 2008). CD56bright NK suppressor cells (Takahashi et al 2004) and
CD4+,CD25++,(CD39+),FoxP3+ T regulatory cells (Treg) may also be involved in immune
regulation in multiple sclerosis, and the latter have reduced function in multiple sclerosis.
Memory Tregs return to normal levels in progressive disease (Venken et al 2008). Treg
development requires IL-2, IL7, vitamin A, TGF-beta, and indoleamine dioxygenase (induced
by IFN-beta). The environment in the eye generates suppression; very small amounts of
retinal antigens create CD4,CD25+ cells that inhibit immunity in mice. The CNS may behave
similarly.
Thymic export of new T cells is reduced in multiple sclerosis, so T cells have fewer T-cell
receptor excision circles (Trec). Recent thymic emigrant cells, including Tregs, are reduced
in relapsing-remitting multiple sclerosis (Haas et al 2007). The immune system in multiple
sclerosis shows premature aging using this measure, and it is 30 years older than in healthy
controls (Hug et al 2003). Trec numbers do not change with IFN-beta therapy.
B cells reflect the abnormal T cell immunity. They also have direct effects on immune
regulation and brain destruction (Meinl et al 2006). B cells secrete IL-6, IL-10, TNF-alpha,
and chemokines. IL-6 can enhance generation of IL-17 T cells. Lipopolysaccharide-activated
B cells produce nerve growth factor and brain-derived neurotrophic factor. Nerve growth
factor is a survival factor for memory B cells.
In multiple sclerosis, B cells secrete half as much inhibitory IL-10 after stimulation with
anti-CD40 (a model of bystander T cell activation) and B cell receptor plus anti-CD40 (a
model of B cell plus T cell activation) compared to healthy controls (Duddy et al 2007). B
cells in multiple sclerosis blood express high levels of costimulatory molecules (CD80). As a
result, they are potent antigen-presenting cells because they are exquisitely focused against
specific antigens (Genc et al 1997b). B cells are activated by B-cell activating factor (BAFF),
made by myeloid cells. CSF BAFF and the B-cell attracting chemokine, CXCL13, are
increased during relapses and in secondary progressive multiple sclerosis (Ragheb et al
2011). CSF BAFF levels correlate with IL-6 and IL-10, suggesting that all of these factors
amplify B cell function and CSF antibody production.



High CSF immunoglobulin synthesis and antibody titers to measles virus were reported in
the 1950s. CSF IgG and oligoclonal bands are present in more than 95% of patients. High
levels of IgG predict a worse prognosis and faster progression. In clinically isolated
syndromes, clonal expansion is reflected by rearranged mRNA and certain heavy chains
(VH4 or VH2) and is more likely to lead to multiple sclerosis, but these antibodies do not
predominantly react against myelin (Bennett et al 2008). There are CSF and serum
antibodies to unknown antigens, viruses, myelin proteins, axons (triose-phosphate
isomerase), and DNA (ANA). Over 50% of brain plaques contain antibodies plus
complement, although the antibodies and oligoclonal bands have not been shown to cause
demyelination (Lucchinetti et al 1999). Some anti-brain antibodies can enhance
remyelination in mice. In progressive multiple sclerosis, B cells have continued to clonally
expand and are present in germinal center-like areas in the meninges.
Chemokines attract immune cells. Monocytes secrete excessive CXCL8 (IL-8) in multiple
sclerosis serum, and presumably CNS, to attract other monocytes and potentially
polymorphonuclear neutrophils. However, polymorphonuclear neutrophils are not seen in
multiple sclerosis CSF. In contrast, in Japanese optico-spinal multiple sclerosis, increased IL-
8 and IL-17 as well as both Th1 (IFN-gamma) and Th2 (IL-4 and IL-5) cytokines are seen.
In a subset of patients with this Japanese Devic-like variant, IL-8 in CSF and neutrophils in
lesions correlate with spinal cord lesion formation (Ishizu et al 2005). IFN-beta decreases IL-
8.
Multiple sclerosis CSF and plaques contain CCR7+ dendritic cells; T cells express CCR7 only
in the CSF. T cells in plaques have downregulated CCR7, a receptor needed for migration,
and are then unable to leave the CNS (Kivisakk et al 2004).
Monocytes and microglia present antigens and amplify immune responses. They
communicate with cells hundreds of microns away through tunneling nanotubes that
transmit calcium ions and antigens. They over-express receptors for immunoglobulins and
are activated by low levels of serum receptor for advanced glycation end-products (RAGE).
Inhibitory molecules expressed by monocytes (HLA-G, ILT3) are reduced in multiple
sclerosis, but are upregulated by IFN-beta (Mitsdoerffer et al 2005; Jensen et al 2010).
Peripheral monocytes produce excessive nitric oxide, which is neurotoxic and damages
oligodendroglia but also destroys activated T cells. Microglia in the brain release nitric oxide,
oxygen radicals, complement, protease, and cytokines. CSF nitric oxide metabolites
correlate with gadolinium-enhanced MRI lesions, clinical activity, and progression of multiple
sclerosis. Nitric oxide also modifies brain proteins to form nitrotyrosine. This creates
neoantigens in the brain and generates antibodies to S-nitrosocysteine in the CNS (Boullerne
et al 2002). Even though activated macrophages are generally toxic to CNS cells, they may
have positive effects too. (See Recovery from relapses, below.)
IFN-alpha-secreting plasmacytoid dendritic cells are more frequent in early multiple
sclerosis in some studies. However, they produce less IFN-alpha and are defective as
antigen-presenting cells (Stasiolek et al 2006). In contrast, myeloid dendritic cells in
secondary progressive multiple sclerosis are activated and proinflammatory (Karni et al
2006).
Trauma and stress have been implicated as causing multiple sclerosis or triggering
exacerbations (McAlpine et al 1972; Poser 1986; Buljevac et al 2003; Li et al 2004). Stress
and exacerbations are sometimes difficult to define, and studies conflict. Stress at home and
physical abuse during childhood appear to prevent multiple sclerosis. Links of exacerbations
to stress and trauma are nonexistent when stress, trauma, and concomitant clinical
manifestations of multiple sclerosis are carefully analyzed (Sibley 1988; 1993; Siva et al
1993), even though there is a slight increase in new MRI lesions (Mohr et al 2000). Gunshot
wounds and SCUD missile attacks actually seem to protect against exacerbations according
to some reports (Sibley 1988; Nisipeanu and Korczyn 1993), but another war report
suggests increased exacerbations (Golan et al 2008). Local irradiation of the brain can
increase lesions of multiple sclerosis within the radiation field, possibly by disruption of the
blood-brain barrier (Murphy et al 2003).
The hypothalamus regulates autonomic functions, body temperature, sleep, and sexual



activity. It controls an endocrine cascade from corticotrophin releasing hormone (CRH), to
adrenocorticotropic hormone, to cortisol. Serum cortisol and exogenous steroids turn down
corticotrophin secretion. This endocrine activity has consequences for immune regulation.
Hypothalamic plaques are common in multiple sclerosis and disrupt endocrine regulation
(Huitinga et al 2004). Surviving myelin bundles are next to HLA class II positive microglia.
Inflammation in the hypothalamus may explain the high number of corticotrophin and
arginine-vasopressin double-positive neurons that are unique to multiple sclerosis, especially
in disease of long duration. Arginine-vasopressin potentiates the action of corticotrophin on
adrenocorticotropic hormone release. The resultant elevation in cortisol could be beneficial
because high numbers of corticotrophin-releasing factor/arginine-vasopressin neurons
correlate with low hypothalamic lesion load. Similarly, rats with high corticosterone are
protected against experimental allergic encephalomyelitis.
The hypothalamic-pituitary-adrenal (HPA) axis is hyper-responsive to corticotrophin-
releasing hormone, especially in primary progressive multiple sclerosis (Then Bergh et al
1999). Chronic HPA axis overactivity may render cells insensitive to glucocorticoids and
allow them to escape from immune restraint. Levels of cortisol, adrenocorticotropic
hormone, dehydroepiandrosterone, and cells secreting corticotropin releasing hormone are
increased most in progressive and active forms of multiple sclerosis (Ysrraelit et al 2008).
Glucocorticoids plus antidepressants normalize the HPA axis in multiple sclerosis.
Acute and chronic inflammation induces high serum cortisol levels that cause systemic and
local steroid resistance. IL-1alpha, produced by activated macrophages, inhibits
glucocorticoid receptor translocation to the cell nucleus (Pariante and Miller 2001). High
levels of tumor necrosis factor and IL-1 and IL-6 correlate with hypothalamic-pituitary-
adrenal axis (HPA) activation and with fatigue. In parallel, the hypothalamic-pituitary-
adrenal axis is hyporesponsive to dexamethasone feedback during active multiple sclerosis,
and so are immune cells ex vivo (Reder et al 1987). Conversely, cyclic adenosine
monophosphate (cAMP) agonists (prostaglandins, beta-adrenergic agonists, and some
antidepressants) enhance steroid receptor translocation and could potentiate glucocorticoids.
The weak response to steroids correlates with high CSF white blood counts and enhancing
lesions on MRI (Fassbender et al 1998). Mechanisms for this resistance include (1)
downregulation from chronic high cortisol (mildly increased in multiple sclerosis), possibly
from adrenocorticotropic hormone released by immune cells (Reder 1992; Reder et al 1994;
Lyons and Blalock 1997); (2) a mutation in the steroid receptors; and (3) interaction with
other signaling pathways.
Recovery from relapses. Immune regulation causes the inflammation to wane. As clinical
symptoms resolve, there is a rise in inhibitory Th2 cytokines, immunoglobulins, and
glucocorticoids (Reder et al 1994a). There is suppression of inflammation, redistribution of
axonal sodium channels in surviving axons, remyelination, and rewiring of the brain
(compensatory adaptation or functional reorganization of neurons and synapses).
Inflammation is turned off by apoptosis and suppression of activated immune cells.
Apoptosis of Th1 cells is mediated by steroids (endogenous or therapeutic), IFN-gamma
(Furlan et al 2001; Ahn et al 2004), tumor necrosis factor-alpha, and nitric oxide. IFN-beta
causes apoptosis of Th17 cells, which express high levels of the type I interferon receptor
(Durelli et al 2009). Toxic effects on neurons and oligodendroglia are caused by some of
these same compounds: TNF-alpha, glutamate, nitric oxide, and other T-cell and monocyte
products. Finally, as described above, subnormal suppressor T-cell function in clinically
active multiple sclerosis may prolong inflammation.
Macrophages secrete some compounds that are neuroprotective, suggesting there is a
balance between destruction and repair during inflammation. Macrophages also produce
trophic factors such as platelet-derived growth factor (PDGF), epidermal growth factor
(EGF), transforming growth factor beta (TGF-beta), insulin-like growth factor 1 (IGF-1),
neural growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3
(NT3). BDNF is expressed in lesions by T cells, macrophages and microglia, and astrocytes.
Immune cells secrete more BDNF during relapse, but levels fall with progression. After
relapses, other neurotrophic factors rise, including glial cell-line derived neurotrophic factor


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