The Differential Diagnosis of Multiple Sclerosis: Loren A. Rolak, MD, and John O. Fleming, MD

REVIEW
The Differential Diagnosis of Multiple Sclerosis

Loren A. Rolak, MD,* and John O. Fleming, MD
Objective: This article will discuss the diagnosis of multiple scle-
rosis (MS), with particular attention to differentiating it from other
diseases that can mimic it.
Methods: We reviewed our own data, as well as the published
experience on the differential diagnosis of MS and the most com-
mon errors leading to misdiagnosis.
Results: Psychiatric diseases are mistaken for multiple sclerosis
more often than any other conditions. Other multifocal illnesses or
white-matter diseases are seldom confused with multiple sclerosis.
Conclusion: Neurologists are most likely to misdiagnose multiple
sclerosis in patients who have psychiatric problems or who have
uncommon presentations of common diseases such as migraine,
stroke, or neuropathies.
Key Words: multiple sclerosis, differential diagnosis, optic
neuritis, Lyme disease, lupus, vitamin B12 deciency, psychiatric
disease
(The Neurologist 2007;13: 5772)
N
eurologists must often diagnose diseases for which there
are no denitive tests: migraine headaches, Parkinson
disease, and amyotrophic lateral sclerosis (ALS) are just
some examples. For these patients, neurologists can never-
theless integrate features of the history, physical examination,
and laboratory tests to achieve such accuracy that they rarely
doubt their diagnosis. Yet with multiple sclerosis (MS), this
same process seems more difcult, the diagnosis less certain,
and the doubt much greater. The reputation of MS as a
challenging disease to diagnose is well earned. Yet it is
important to conrm MS, if possible, because the stakes can
be high. When given a diagnosis of MS, a patient may lose
his or her present job and his or her future employability.
Peace of mind is also lost as the diagnosis of a chronic,
relapsing, possibly disabling but unpredictable disease can
crumble even the sturdiest psychologic defenses. The diag-
nosis may commit patients to medical treatments that could
continue for years. In some settings, initiation of treatment
early might result in later medical benets. When faced with
a patient who might have MS, neurologists thus feel many
pressures to get it right.
THE DIAGNOSIS OF MULTIPLE SCLEROSIS
Diagnostic Principles
The goal of this article is to review the diseases often
confused with MS, rather than to discuss the proper way to
diagnose MS. Nevertheless, while analyzing the differential
diagnoses, a few words are appropriate about recognizing the
disease itself to distinguish it from its mimics.
Although ofcial requirements have been proposed
for diagnosing MS,
1
these are of limited value for clinicians.
Conrming or refuting MS is not done by following any
cookbook or algorithm of the same tests on each and every
patient. Instead, the diagnosis must be reached by careful
examination of all the evidence both for and against the
disease, and through questioning, examining, and testing; the
neurologist must assemble this evidence until it is sufciently
compelling to nd the patient guilty or not guilty of
having MS. Even when great care is used, the diagnosis may
be made in error (innocent people found guilty) or inappro-
priately dismissed (guilty people found innocent), and expert
neurologists may disagree among themselves (hung juries).
The inability to sometimes prove the diagnosis beyond a
shadow of a doubt, combined with the many nuances and
pitfalls in the history, physical examination, and testing for
MS, create the challenges of diagnosing MS.
2
Ultimately, the
diagnosis will depend upon the extent to which the patients
overall picture has the expected ndings typical of MS.
3,4
Red Flags and the Differential Diagnosis of MS
The diagnosis of MS should be questioned when clin-
ical or laboratory ndings are unexpected or atypical. These
unusual features or red ags should raise suspicion that MS
is not present.
5,6
Rare patients with these red ags do have
MS. However, most patients with other diseases will be
identied by the presence of one or more of these atypical
From the *Marsheld Multiple Sclerosis Center, Marsheld Clinic, Marsh-
eld, Wisconsin; and Neurology, University of Wisconsin, Madison,
Wisconsin.
The authors declare no conicts of interest.
Reprints: Loren A. Rolak, MD, Marsheld Clinic, 1000 N. Oak Avenue,
Marsheld, WI 54449. E-mail: [email protected].
Copyright 2007 by Lippincott Williams & Wilkins
ISSN: 1074-7931/07/1302-0057
DOI: 10.1097/01.nrl.0000254705.39956.34
Ultimately, the diagnosis will depend upon the
extent to which the patients overall picture
has the expected findings typical of
multiple sclerosis.
The Neurologist Volume 13, Number 2, March 2007 57
features. Table 1 is a summary of the ndings which should
alert the clinician to consider alternative diagnoses.
Prospective studies have shown that 2 factors most
reliably identify patients who do not have MS.
6
The rst is
their lack of typical symptoms: no optic neuritis, Lhermitte
sign, sensory level, neurogenic bladder, or other common
decits. The second is their lack of typical ndings on
magnetic resonance imaging (MRI) and CSF examination.
Very few patients with MS have a normal MRI of the brain
or normal CSF.
The Abnormal MRI
It has often been said that MS is a clinical diagnosis.
This is not entirely true. It is unlikely a patient would be
diagnosed with MS today (at least in Europe or North
America) without undergoing MRI scanning. The introduc-
tion and renement of MRI has changed the diagnostic
process in MS, and most diagnostic criteria for MS rely
heavily on interpretation of MRI.
1
This has also changed the misdiagnosis of MS. The
most common reason for falsely attributing a patients symp-
toms to MS is faulty interpretation of the MRI.
7
Signal
abnormalities of one sort or another are so common on MRI
as to be ubiquitous. Over-interpretation of such scans, falsely
assuming the signal changes are MS, is the most common reason
for misdiagnosing MS (Table 2). The MRI, like other clinical
features or laboratory tests, is simply one piece of evidence that
must be placed in context to arrive at a correct diagnosis.
THE DIFFERENTIAL DIAGNOSIS OF
MULTIPLE SCLEROSIS
Diagnostic Principles
MS is a disease disseminated in time and in space. Yet
the differential of MS is almost never other diseases dissem-
inated in time and in space. MS is a white-matter disease. Yet
the differential of MS is almost never other white-matter
diseases. Instead, the mimics of MS are the mundane condi-
tions that most commonly affect the nervous system, such as
migraine, stroke, and neuropathies. Of these, psychiatric
illnesses dominate. Tables 3, 4, and 5 list many of the
diseases disseminated in time and in space that most standard
texts present as the differential diagnoses of MS.
4,8,9
In fact,
most of these are rare conditions seldom, if ever, seen in
clinical practice. They are presented here for the sake of
completeness, but their occurrence is so unusual that a pos-
itive test for these diseases may be more often a false positive
than a true one. The misinterpretation of false-positive tests in
MS is such a hazard that it deserves special caution.
The Hazards of Routine Screening: Beware of
False Positives
The majority of patients presenting with a clinical
picture typical of MS do in fact have MS. Mindlessly screen-
ing these patients with an unvarying battery of tests seldom
generates a different diagnosis and more often leads to
confusing false-positive results.
10
This is especially true of
many tests ordered for the evaluation of other white-matter
TABLE 1. Red Flags for the Misdiagnosis of MS
I. Red ags in the history and examination
1. Normal neurologic examination
2. Abnormality in a single location; no dissemination in space
3. Progressive from onset; no dissemination in time
4. Onset in childhood or over age 50
5. Psychiatric disease present, ie, another explanation for ndings
6. Systemic disease present, ie, another explanation for ndings
7. Prominent family history; consider genetic disease
8. Gray matter symptoms: dementia, seizures, aphasia
9. Peripheral symptoms: peripheral neuropathy, fasciculations
10. Acute hemiparesis
11. Lack of typical symptoms: no optic neuritis, bladder problems,
Lhermitte sign, sensory level, etc
12. Prolonged benign course, ie, diagnosis made years ago with few
ndings now
II. Red ags in the laboratory tests
1. Normal or atypical MRI
2. Normal CSF
3. Abnormal blood tests, though many are false positives
TABLE 2. Partial Differential Diagnosis of MS on MRI
1. Age-related changes
2. Acute disseminated encephalomyelitis
3. CNS vasculitis
4. Behet disease
5. Sjgren syndrome
6. Sarcoidosis
7. Metastatic neoplasm
8. CADASIL (cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy)
9. Binswanger disease
10. Migrainous ischemia
11. Cerebrovascular disease
12. Progressive multifocal leukoencephalopathy
13. Inherited white matter diseases
14. Effects of radiation therapy or drugs
15. CNS lymphoma
16. Lyme disease
17. HTLV-1 infection
18. CNS lupus
19. Mitochondrial encephalopathies
20. Antiphospholipid antibody syndrome
The most common reason for falsely
attributing a patients symptoms to multiple
sclerosis is faulty interpretation of the magnetic
resonance imaging.
Rolak and Fleming The Neurologist Volume 13, Number 2, March 2007
2007 Lippincott Williams & Wilkins 58
diseases disseminated in time and in space (Tables 35). For
many of these, the normal test ranges, sensitivities, and
specicities are poorly established. (For example, when is a
sedimentation rate abnormal? Or an ANA?)
The Optic Neuritis Treatment Trial
The Optic Neuritis Treatment Trial (ONTT) is an in-
structive example of the pitfalls of screening tests in demy-
elinating disease. This study enrolled 457 patients with optic
neuritis to determine the effectiveness of treatment and nat-
ural history of the disease. Patients were diagnosed with optic
neuritis on clinical grounds: acute monocular visual loss with
a eld defect and an APD in an otherwise healthy young
person. All patients were screened for other diseases that
could mimic optic neuritis by having an MRI scan of the
brain, CBC, metabolic prole, chest x-ray (to exclude sar-
coid), FTA, and ANA. Thirty-one percent had a spinal tap.
Only 2 out of the 457 patients proved to have a disease other
than optic neuritis (1 with a pituitary tumor and 1 with an
aneurysm). There were no patients whose diagnosis was
changed by CSF or chest x-ray. Six had a positive FTA and
15 had an elevated ANA, but all of these were false positive.
These screening tests thus confused the management of a
number of patients, but none ever led to a different diagnosis.
This was true whether patients came from rural or urban
settings, the North or the South, academic centers or else-
where.
11,12
Lyme Disease
Many authorities list Lyme disease high on the differ-
ential diagnosis of MS as a disease of young people capable
of causing white-matter symptoms, sometimes relapsing and
remitting, occasionally with MRI changes mimicking MS. In
fact, the classic clinical and MRI picture of MS is almost
never produced by Lyme disease, and routine screening in the
absence of a specic indication will produce more false
positives than true positives. In a study of MS patients in a
Lyme-endemic area in New York, 283 consecutive patients
with MS were screened for Lyme disease and 19 had positive
Lyme serology. On further testing, including spinal tap with
measurement of intrathecal antiborrelia antibodies, none of
these 19 patients had Lyme disease.
13,14
Vitamin B12 Deciency
A deciency in vitamin B12 can lead to myelin dam-
age, including a myelopathy, which can mimic MS. So
vitamin B12 deciency is commonly listed in the differential
diagnosis of MS. Clinicians can again be led astray by
screening tests, with studies showing decreased levels in up
to 19% of MS patients. The reason for low serum vitamin
B12 levels in MS patients is not clear, but these are usually
false-positive values. Most MS patients labeled instead as
decient in B12 actually do have MS.
1517
TABLE 3. Diseases Sometimes Disseminated in Space but
Not in Time
1. Shower of cerebral emboli
2. Thrombocytopenic purpura
3. CNS vasculitis
4. Mitochondrial encephalopathies
5. Drugs and toxins
6. Acute disseminated encephalomyelitis
7. PML (progressive multifocal leukoencephalopathy)
8. Mycoplasma encephalopathy
9. Lyme disease
10. Vitamin B12 deciency
11. Behet disease
12. Sarcoidosis
13. Paraneoplastic syndromes
14. Periventricular leukomalacia
15. Psychiatric syndromes
TABLE 4. Diseases Sometimes Disseminated in Time but
Not in Space
1. Tumor (brain or spinal cord)
2. Arteriovenous malformation (brain or spinal cord)
3. Familial cavernous hemangiomata
4. Cervical spondylosis
5. Chiari malformation
6. Foramen magnum lesions
7. Peripheral neuropathy
8. Leber optic atrophy
9. Familial spastic paraplegia
10. Adult-onset leukodystrophies
11. Migraine
12. Sjgren disease
13. HTLV-1
14. Cerebellar degeneration
15. Syringomyelia
TABLE 5. Diseases Often Disseminated in Both Time and
Space
1. Cerebrovascular disease, including emboli
2. Familial cavernous hemangiomata
3. CNS lymphoma
4. SMON (Subacute myelo-opticoneuropathy)
5. CNS vasculitis
6. Migratory sensory neuritis
7. Myasthenia gravis
8. Mitochondrial disease
9. Sjgren disease
10. HIV
11. Eale disease
12. Systemic lupus erythematosus
13. Lyme disease
14. Porphyria
15. Sarcoidosis
16. Antiphospholipid antibody syndrome
17. Spinocerebellar degeneration
18. CADASIL
19. Psychiatric syndromes
20. Devic disease
The Neurologist Volume 13, Number 2, March 2007 Differential Diagnosis of MS
Lupus, Inammatory Diseases, ANA,
and Autoantibodies
The various causes of vasculitis gure prominently in
most lists of MS mimics. For example, systemic lupus ery-
thematosus affects the central nervous system in approxi-
mately 40% of patients and can cause optic neuritis, myelop-
athy, and even INOs. In the CSF, IgG and oligoclonal bands
can occur in 50%-70% of patients with CNS lupus, and MRI
changes may be indistinguishable from those of MS. How-
ever, CNS involvement almost always occurs in the setting of
unmistakable systemic disease so that lupus should seldom be
confused with MS. Patients with CNS lupus usually have
joint disease, rashes, alopecia, fevers, renal failure, and other
stigmata of systemic lupus. Their spinal uid usually also
shows much higher protein and polymorphonuclear cell
counts, more closely mimicking meningitis than MS. What is
true of lupus holds for most other connective tissue inam-
matory diseases as well, such as Sjogren syndrome, Behcet
syndrome, and sarcoid.
18
Screening for these systemic, inammatory, autoimmune,
collagen vascular diseases is complicated by the presence of
many immune-system changes in MS patients, including a high
incidence of autoantibodies. But these are usually of no clinical
signicance. In one study, a positive ANA was found in 81% of
MS patients.
19
Screening all suspected MS patients with an
ANA will therefore yield too many false positives and too few
cases of other inammatory diseases.
Note that the same can be said for the lupus anticoag-
ulant or antiphospholipid antibodies. These are also found in
a high percentage of MS patients. Although their signicance
is still being debated, they are often of no clinical importance
and merely confuse the diagnosis.
20
An abnormal screening laboratory test is simply one piece
of evidence, and it must be combined with additional data and
seasoned with clinical judgment before arriving at a denite
diagnosis. Beware of diagnosing rare diseases (Lyme, vitamin
deciency, vasculitis, etc) even when their tests are positive.
Psychiatric Disease and Normal People
By far the most important disease confused with MS is
psychiatric illness.
21,22
Most patients referred to a neurologist
for consideration of possible MS who do not have the disease
instead suffer from some form of psychiatric disorder: som-
atization, hypochondriasis, malingering, depression, anxiety,
or similar problems. In the few instances where the differen-
tial diagnosis of MS patients has been documented (as sum-
marized in Table 6), psychiatric diseases emerged as the
foremost problem. At the University of Colorado Multiple
Sclerosis Center, 67% of patients referred for possible MS
had some other condition, of which psychiatric disease was
the most common.
22
Among patients referred to Dalhousie
Universitys MS Unit from 19791983 (before the availabil-
ity of MRI), 13% did not have MS; most had psychiatric
problems.
21
Prospective data from the Marsheld Multiple
Sclerosis Center, a private, nonuniversity referral clinic,
shows that 49% of the 142 patients evaluated for possible MS
since May 2004 had other diseases. Seventy-ve percent of
these had psychiatric diagnoses. As shown in Table 6, there
are 7 conditions that accounted for almost all the alternative
diagnoses at these 3 MS centers. None of these are other
white-matter or inammatory diseases disseminated in time
or in space. Across diverse settings and referral patterns, over
3 decades, with or without MRI, the most common conditions
mistaken for MS were psychiatric.
The second largest diagnostic category of non-MS
patients is normal people describing everyday sensations that
are misconstrued as abnormal. In one study, 32% of normal
people between the ages of 20 and 45 reported transient
neurologic symptoms, such as visual changes, loss of power,
poor balance and coordination, and speech difculty.
23
Care
thus must be taken not to overemphasize the multitude of
transient disturbances that plague all normal people: itches,
twitches, falling asleep limbs, and eeting visual obscurations.
Two useful features in distinguishing MS symptoms
from normal or psychiatric problems are their anatomy and
their time course. Psychiatric symptoms tend to be diffuse
and difcult to explain anatomically, such as tingling in both
hands and both feet simultaneously, numbness over the entire
face, or generalized symptoms such as feeling weak all
over. In contrast, MS symptoms usually have a clear ana-
tomic location. Even if an MS attack affects different foci in
the nervous system, there will be distinct lesions (such as
optic nerve plus spinal cord) rather than diffuse and general-
TABLE 6. Most Common Diagnoses for Patients
Without MS
Colorado
(N 139)
Dalhousie
(N 52)
Marsheld
(N 70)
Psychiatric disease 63 (45%) 14 (27%) 53 (76%)
Migraine headaches 29 (21%) 7 (14%) 2 (3%)
Stroke or TIA 7 (5%) 3 (6%) 2 (3%)
Peripheral neuropathy 6 (4%) 3 (6%) 1 (1%)
Cervical stenosis 4 (3%) 1 (2%) 1 (1%)
Benign sensory symptoms 0 11 (22%) 8 (11%)
Vertigo 0 3 (6%) 0
Screening for systemic, inflammatory,
autoimmune, collagen vascular diseases is
complicated by the presence of many
immune-system changes in multiple sclerosis
patients, including a high incidence
of autoantibodies.
By far the most important disease confused
with multiple sclerosis is psychiatric illness.
ized symptoms. True MS relapses also have a nite time
course; they occur abruptly, evolve over minutes to days, and
then slowly resolve within days to weeks. Normal transient
symptoms in contrast tend to be quite brief, lasting seconds to
minutes. Psychiatric symptoms may uctuate, but usually
without the pattern of sudden onset followed by gradual
resolution. The persistence of symptoms can be another clue
to their psychiatric origin. The average person with MS
generally has 1 distinct neurologic episode per yearin many
studies actually closer to every 24 monthsand they are then
free of symptoms until their next relapse. Patients with a
psychiatric disease generally have multiple symptoms that
come and go all the time. They are seldom free of symptoms.
They seldom feel well.
The coexistence of known psychiatric problems is ob-
viously another clue that a patients neurologic symptoms
might be psychiatric in origin. If a patient is known to be
anxious or depressed or has a history of other psychosomatic
problems, their current symptoms must be viewed with more
suspicion. Studies have shown that when experienced clini-
cians conclude (after appropriate investigations) that a pa-
tients symptoms are nonorganic, they are seldom wrong.
24
Most of us correctly identify psychiatric ndings. Neverthe-
less, people with psychiatric illness can also develop MS, and
clinicians must guard against too supercial an evaluation of
such patients.
HOW TO INFORM PATIENTS THAT THEY DO
NOT HAVE MS
After a complete workup, often a diagnosis of MS, or
any serious neurologic disorder, will not be established. The
manner in which patients should be informed of this conclu-
sion largely depends on their psychologic status. At one end
of the spectrum are patients who, apart from understandable
concern about the possibility of a disabling illness, are essen-
tially normal psychologically. For these patients, the neurol-
ogist may explain the circumstances that led to the initial
suspicion of MS (eg, over-reading of an MRI scan or mis-
placed concern about benign paresthesias) and the objective
ndings which have shown that MS is not present.
An intermediate class of patients consists of persons
who have mild but persistent anxiety or mood disorder (the
worried well), either constitutionally or because of the
lingering suspicions on their part or the part of their neurol-
ogist that organic disease might be present. These patients
will benet from infrequent but regularly scheduled (eg, q.
36 months) return visits to the neurologist for reassurance
and reevaluation. Eventually, these patients usually reach a
point where they can be returned to the long-term supervision
of their primary physician, always with the offer of a repeated
neurologic assessment if needed.
At the other end of the psychologic spectrum are
patients who have severe underlying mental disturbance and
whose symptoms frequently evoke very negative emotions in
physicians. For example, in an analysis of 300 new outpatient
visits, Carson and colleagues
25
found that patients whose
symptoms were not explained by organic disease were con-
sistently rated as most difcult to help by neurologists. In this
regard, ODowd
26
coined the term heartsink patients for
persons who exasperate, defeat, and overwhelm their doctors
by their behavior. Patients presenting with psychogenic
symptoms often suffer from somatization disorder, anxiety
disorder, hypochondriasis, depressive disorder, or an attach-
ment to illness as a way of life.
Very few neurologists have the resources and skills to
effectively manage patients with chronic psychogenic disor-
ders. A major mistake for the neurologist in this circumstance
is to attempt too much; for example, to try to cure the
incurable by endeavoring to reverse an ingrained pattern of
psychogenicity in one brief conversation. So if most patients
with psychogenic symptoms reject immediate referral to a
mental health professional and if the neurologist is usually
not the best person to provide continued management, who
is? The medical literature provides a consistent and positive
answer to this question, namely, that the primary care phy-
sician, who deals with a high percentage of nonorganic or
embellished complaints during each practice day,
27,28
is usu-
ally well qualied by experience and training to help these
patients. Several authoritative guidelines endorse short, fre-
quent visits to a primary care physician for a program based
on reassurance and support; limiting of testing and subspe-
cialty referrals to those that truly are necessary; rst-line
treatment of depression and anxiety; and a gradual, nonthreat-
ening shift of focus to consideration of stress and other
psychologic factors.
29,30
Eventually, psychogenic patients of-
ten reach the point that they will accept expert psychiatric
referral. In summary, while the best hope for fundamental
change over the long term lies with psychiatric treatment, in
the short term, optimal management is usually based on
supportive care with a primary care physician. Obvious
exceptions to the recommendation for delayed psychiatric
management are the rare patients who are psychotic or who
are a danger to themselves or others.
CONCLUSION
The determination of MS is not made by following any
set of diagnostic criteria. Rather, it depends upon the extent to
which a patients clinical and laboratory evidence is typical of
MS. Other diseases usually have atypical features signaling
they are not MS. Over-interpretation of the false-positive
MRI is the most common mistake in misdiagnosing MS. The
differential diagnosis of MS is not other white-matter dis-
eases nor other diseases disseminated in time and space.
Instead, the great mimicker of MS is psychiatric disease. On
the rare occasions when another neurologic problem presents
as MS, it will be a common condition such as migraine or stroke.
Diagnoses of uncommon conditions are usually false posi-
tives. Neurologists must learn to deal with psychiatric patients
in a compassionate but rm manner and rely on primary care
providers to help the well-being of those patients.
ADDENDUM
Table 7 is a comprehensive list of 100 conditions that
might mimic MS. While we believe this can be a valuable
resource, most of these are rare conditions that will seldom be
encountered.
TABLE 7. One Hundred Conditions Sometimes Mistaken for Multiple Sclerosis
Disease What It Is How It Mimics MS How to Tell It From MS
1. Clinically isolated
syndrome or
monosymptomatic
demyelination
A single attack of optic neuritis, transverse
myelitis, or other lesion conned to 1
anatomic localization at 1 point in time. This
sometimes represents the rst attack of MS.
Same symptoms. More than half
have an abnormal MRI, with
subclinical lesions elsewhere in
the brain.
Time. Another attack disseminated in
time and space will conrm MS.
Another lesion on MRI done 1 mo
later implies MS.
2. Balo concentric
sclerosis
A demyelinating disease with lesions
occurring in concentric bands of
alternating demyelination and preserved
normal white matter.
The symptoms may be identical to
those of MS.
The MRI scan will show typical
concentric white-matter lesions that
are diagnostic. These may be mixed
with MRI abnormalities very
characteristic of typical MS as well.
3. Schilder disease
(myelinoclastic diffuse
sclerosis)
Bilateral hemispheric demyelination with
onset usually in childhood. The
classication and terminology are
controversial. Onset of extensive
demyelination at an early age.
The symptoms are very similar,
with weakness, numbness, and
focal neurologic decits. The
MRI will show large conuent
areas of signal abnormality in
the white matter.
The onset is often in childhood and
usually includes symptoms seldom
seen in MS, including aphasia,
dementia, seizures, and increased
intracranial pressure.
4. Tumefactive MS A large focus of demyelination, often with
mass effect and edema, resembling a brain
tumor. In addition to focal signs, the
patient may also have headaches and
seizures.
The patient will have focal
neurologic ndings and
abnormal MRI scan, though the
lesion often appears distinctly
different on MRI with mass
effect and open-ring
enhancement.
This form of MS may need to be
conrmed with brain biopsy, but
often the diagnosis can be suspected
by nding oligoclonal bands and
IgG abnormalities in the spinal uid
or abnormal evoked potentials in
asymptomatic areas.
5. Marburg disease A fulminant, acute, severe, demyelinating
disease.
This is believed to be a variant of MS
that shows unusual virulence and
aggressiveness. The clinical
features and MRI scan may be
indistinguishable from MS.
This is felt to be a form of MS that is
particularly destructive, with
necrosis, axonal destruction, and
progression to death in less than
12 mo.
6. Devic disease, or
neuromyelitis optica
(NMO)
Acute inammatory demyelination
predominantly affecting the optic nerves
and spinal cord, associated with an
NMO-IgG antibody against the aquaporin-
4 channel.
Optic neuritis and transverse
myelitis characterize NMO and
are also common symptoms of
MS. As many as 15% of NMO
patients have lesions in areas
other than the optic nerves and
spinal cord, both clinically and
on MRI.
Diagnostic criteria for NMO include
lesions affecting the optic nerve and
spinal cord, but with myelitis
extending continuously over 3 or
more contiguous segments of the
cord. Patients should also be
seropositive for the NMO-IgG
antibody.
7. Acute disseminated
encephalomyelitis
(ADEM)
Monophasic demyelination occurring with or
just after an infection, vaccination, or other
immune-altering event.
The symptoms can be identical,
including involvement of optic
nerve, brain, and spinal cord,
and the MRI may show
identical scattered white-matter
signal abnormalities.
There is no infallible method of
distinguishing ADEM from MS. It
occurs in the setting of infections,
is more common in childhood, and
may include altered consciousness
and other unusual symptoms, and
the MRI may show hemorrhagic
lesions and/or gray matter lesions
(or may even be normal).
8. Chronic inammatory
demyelinating
polyneuropathy (CIDP)
A progressive, relapsing, demyelinating,
peripheral neuropathy, sometimes
associated with CNS demyelination.
May have MRI signal
abnormalities in the brain
associated with the neuropathy
symptoms of weakness and
numbness.
Brain MRI lesions are usually not as
widespread as in classic MS, and
IgG abnormalities are usually
absent in CSF. Of course, patients
have an associated peripheral
neuropathy clinically, on EMG, and
nerve biopsy.
9. Bickerstaff brainstem
encephalitis
An inammatory brainstem syndrome with
CSF pleocytosis in a young adult, often
accompanied by headache and malaise. It
may be subacute in onset, is monophasic,
and usually recovers fully. The etiology
(? infectious versus immune) is unknown.
Symptoms may be identical,
including brainstem symptoms
of ophthalmoplegia, facial
diplegia, dysarthria, and ataxia.
The MRI may show
white-matter signal
abnormalities.
Some symptoms are unusual for MS,
such as deafness, and CSF shows
signicant pleocytosis but no IgG
abnormalities or oligoclonal bands.
10. Subacute
myelo-optic neuritis
(SMON)
A toxic demyelination primarily affecting
optic nerves and spinal cord, caused by
toxins (such as in contaminated cooking
oil) and/or vitamin deciencies, seen
primarily in developing countries.
Similar symptoms of subacute
optic nerve and spinal cord
decits. MRI may show
white-matter abnormalities.
It affects all ages, usually in
developing countries and in a
clinical setting of poverty and
nutritional deciency. CSF does not
have IgG abnormalities.
TABLE 7. Continued
11. Eale syndrome A noninammatory small-vessel occlusive
disease predominantly affecting retinal
vasculature and also causing vitreous
hemorrhages, primarily affecting young
males from India and the Middle East.
Similar symptoms including visual
involvement, INO,
vestibulopathy, focal weakness,
and myelopathy. MRI may
show white-matter lesions.
Very rare in North America.
Ophthalmological examination,
including uorescein angiography,
is denitive.
12. Behet disease An autoimmune syndrome of oral and genital
ulcers, uveitis, and arthritis affecting
predominantly Mediterranean and Middle
East patients.
Rare reports of focal weakness
and myelopathy, along with
visual (uveitis/iritis) symptoms.
MRI may show white-matter
changes.
Rare in North America. CSF shows
pleocytosis without characteristic
IgG abnormalities. Biopsy of
mucocutaneous ulcers is denitive.
13. Sarcoidosis A granulomatous multisystem disease of
unknown etiology.
May involve optic nerve or spinal
cord. MRI may show white-
matter lesions. Rare patients
have oligoclonal bands in their
CSF.
Often systemic symptoms, especially
in the lungs. Serum and CSF ACE
levels may be elevated. MRI often
shows meningeal enhancement.
Biopsy (of skin, lymph node or
lung) is denitive.
14. Sjgren syndrome An autoimmune disease of dry eyes and
mouth with arthritis and vasculitis.
Occasional reports of neurologic
symptoms, especially progressive
myelopathy. MRI may show
white-matter lesions and spinal
uid may show oligoclonal bands
with increased IgG.
Positive serology for SS-A (Ro) and
SS-B (La) autoantibodies.
Prominent dry eyes and mouth.
Salivary gland biopsy can be
denitive.
15. Systemic lupus
erythematous (SLE)
An autoimmune multisystem disease,
including vasculitis that commonly affects
the central nervous system.
Common in young women and
may affect the nervous system,
especially optic nerve and
spinal cord. MRI white-matter
changes are common, and up to
60% have oligoclonal bands
and IgG abnormalities in CSF.
Positive serology with ANA and
double-stranded DNA
autoantibodies. Systemic
involvement especially includes
kidneys and skin and hematologic
changes. Can be very difcult to
distinguish from MS.
16. Eosinophilia-myalgia
syndrome (EMS)
Syndrome of uncertain etiology producing
eosinophilia and myalgia, often with other
systemic symptoms.
Associated with a hypercoagulable
state that can produce multiple
infarctions and thus focal
neurologic decits. MRI may
show white-matter lesions.
CBC shows marked eosinophilia. CSF
does not show bands or IgG
abnormalities. Patients usually have
other systemic symptoms.
17. Systemic sclerosis
(scleroderma)
Progressive deposition of connective tissue of
uncertain etiology, sometimes producing
neurologic decits.
Neurologic problems are primarily
peripheral but may produce
numbness of face or hands
(trigeminal or median
neuropathies). MRI may show
white-matter changes (possibly
ischemic from accompanying
vasculopathy).
CNS ndings on examination are rare.
CSF does not show IgG
abnormalities.
18. Inammatory ocular
disease (uveitis, iritis,
or retinitis)
Autoimmune inammation of the eye, often
as part of more systemic inammation.
Patients have a variety of ocular
signs and symptoms. Some
conditions are also accompanied
by typical MRI abnormalities.
Ophthalmologic examination, including
uorescein angiography, will conrm
the ocular inammation. (A uveitis
can rarely be seen with MS but is
seldom severe.)
19. Anterior ischemic optic
neuropathy (AION)
Infarction of the optic nerve due to vascular
disease, either atherosclerotic or vasculitic.
Sudden or subacute monocular
visual loss with ndings of
optic nerve damage mimic the
optic neuritis seen in MS.
Usually occurs in older patients (greater
than age 50) with atherosclerotic risk
factors. Patients would have no other
signs or symptoms, normal CSF, and
normal (or nonspecic aging
changes) MRI scans.
20. Cogan syndrome Syndrome of interstitial keratitis with
vestibular dysfunction (sudden attacks of
vertigo) and deafness.
Relapsing visual symptoms plus
dizziness in young patients.
Rare reports of abnormal MRI
scans. Occasional reports also
of ataxia.
Recognize the triad of inammatory
keratitis plus vertigo plus hearing
loss; deafness is rare in MS. CSF
will be normal.
21. Susac syndrome A microangiopathy of unknown etiology
affecting the brain, retina, and cochlea,
occurring in women.
Relapsing symptoms of vertigo,
vision loss, and encephalopathy,
with white-matter changes on
MRI scan in young women.
Ophthalmologic evaluation with
uorescein angiography and
audiograms will be abnormal. CSF
may have pleocytosis but no IgG
abnormalities. Brain biopsy
(showing multifocal microinfarcts)
may be necessary.
TABLE 7. Continued
22. Sneddon syndrome Antiendothelial cell antibodies causing livedo
reticularis and strokes in young people.
Young patients have multiple
strokes (recurrent focal CNS
decits), with accompanying
signal changes on MRI scan.
Presence of livedo reticularis
(clinically and on skin biopsy) is
diagnostic. Antiphospholipid
antibodies often present and gray
matter (vascular) symptoms may be
prominent.
23. Dego disease
(malignant atrophic
papulosis)
Multisystem occlusive vasculopathy
(including ischemic and hemorrhagic
strokes) with cutaneous and GI
manifestations.
Neurologic symptoms can include
paresthesias, visual symptoms,
weakness, and myelopathy. The
MRI has multifocal (ischemic)
signal abnormalities. Rare
reports of oligoclonal bands.
Skin lesions (porcelain white center
surrounded by pink ring) are
diagnostic and skin biopsy will
show vasculopathy.
24. Central nervous system
vasculitis (primary CNS
angiitis)
Autoimmune vasculitis primarily or entirely
restricted to the central nervous system,
often in young patients.
Relapsing, multifocal CNS decits
in a young patient with
multifocal MRI signal changes
and inammatory CSF.
May have abnormal serologies and
autoantibodies on screening blood
work. If not, angiography and brain
biopsy may be necessary.
25. Antiphospholipid
antibody syndrome
Recurrent venous and/or arterial occlusions
with clotting abnormalities associated with
IgG and IgM anticardiolipid antibodies.
May be idiopathic or associated with other
systemic inammatory diseases.
Recurrent focal (ischemic) CNS
decits with accompanying
MRI signal changes. Up to 20%
have bands in their CSF.
High titers of autoantibodies. May
have headaches, seizures, and
systemic involvement (thrombosis,
arthritis, skin changes) not seen in
MS.
26. Central serous
chorioretinopathy
(CSC)
Recurrent monocular visual loss in young
adults due to serous detachment of the
retina.
It mimics recurrent optic neuritis.
MS may be misdiagnosed if
other soft symptoms are also
present.
Ophthalmologic evaluation will detect
the retinal detachment. MRI of the
brain should be normal.
27. Stroke in the young Arterial (or rarely venous) occlusion with
ischemic strokes, often recurrent, in young
patients, many of whom have no obvious
stroke risk factors.
Recurrent focal strokes may
mimic MS symptoms. MRI
often shows multifocal
(ischemic) signal abnormalities.
Signs and symptoms are usually
typical of ischemic stroke rather
than demyelination, and MRI often
shows gray matter involvement.
Tests may show a specic stroke
etiology (hypercoagulable state,
congenital heart disease, etc).
28. Migraine Recurring complicated headache syndrome
that can produce neurologic symptoms in a
young person.
Young person with transient and
recurring focal neurologic
decits, often without signicant
headache, and often with signal
changes on MRI scan.
Typical symptoms of migraine are
often present (hemicranial headache
with nausea). CSF and evoked
potentials should be normal.
29. Binswanger disease or
leukoaraiosis
An ischemic leukoencephalopathy leading to
primarily periventricular white-matter
refraction; may be patchy and
asymptomatic (leukoaraiosis) or
accompanied by dementia and gait
disorder.
MRI scan may resemble MS
because of extensive white-
matter signal abnormalities.
Patients are usually older and may
have cerebrovascular risk factors.
Dementia may be prominent. CSF
should be normal.
30. Neuroretinitis (stellate
retinitis)
Usually unilateral visual loss (predominantly
idiopathic) caused by optic nerve capillary
leak, often with macular star formation.
Monocular (or rarely binocular)
sometimes recurrent visual loss
mimics optic neuritis and can
be confused with MS if other
soft signs are found.
MRI and CSF should be normal and
ophthalmologic evaluation with
uorescein angiography should be
diagnostic.
31. Familial cavernous
hemangiomata
Inherited multifocal CNS vascular
malformations.
Multifocal hemorrhages produce
recurrent CNS symptoms that
can mimic MS.
MRI scanning will show characteristic
appearance of hemangiomas.
32. Thrombotic
thrombocytopenic
purpura
Coagulopathy with low platelet counts and
recurring thrombosis, especially in young
women.
Recurrent focal thromboses may
produce symptoms resembling
MS, with accompanying MRI
abnormalities.
Symptoms (and MRI changes) often
involve gray matter. Clotting
studies will be abnormal and CBC
will show thrombocytopenia.
33. Progressive multifocal
leukoencephalopathy
(PML)
CNS infection by JC virus in an
immunosuppressed patient, causing
progressive (and sometimes relapsing)
decits leading to death within weeks or
months.
Can have multifocal CNS decits,
which sometimes relapse. The
MRI is abnormal, showing
white-matter lesions.
It occurs in immune-compromised
patients, the decits are usually
progressive rather than relapsing,
the time course is short, and MRI
lesions are generally larger and
more conuent. CSF PCR may be
positive for JC virus, but brain
biopsy may be necessary for the
diagnosis.
TABLE 7. Continued
34. Whipple disease Chronic CNS (and systemic) bacillary
infection causing primarily neurologic, GI,
and joint symptoms. Steatorrhea,
abdominal pain, and arthralgias may be
present.
May cause eye movement
abnormalities, myelopathy, and
sometimes dementia and
myoclonus. Usually progressive
but may have uctuations or
relapses.
Systemic manifestations (especially GI)
are present. The MRI shows more
gray-matter involvement and rarely
white matter, and the CSF PCR for the
bacillus is often specic. Occasionally,
small-bowel biopsy may be necessary
to conrm the infection.
35. HTLV-1 myelopathy Chronic retroviral infection of the nervous
system indigenous to the Caribbean,
causing progressive myelopathy.
Myelopathic symptoms, rarely
with brain lesions as well, with
white-matter abnormalities on
MRI scan and sometimes with
oligoclonal bands in CSF.
Clinical picture is usually conrmed
to a progressive myelopathy and
usually in people of Caribbean or
Asian background. Positive HTLV-
1 serology will make the diagnosis.
36. Lyme disease
(neuroborreliosis)
Infection by tick-borne spirochete
Borrelia burgdorferi.
It can cause persistent focal
neurologic ndings and signal
abnormalities on MRI scan of
the brain.
History of erythema migrans rash.
Western blot is the most denitive
serology, and CSF will show
positive PCR.
37. Syphilis Chronic CNS infection by the spirochete
Treponema pallidum.
Can cause optic neuritis,
myelopathy, and other focal
neurologic ndings.
MRI is usually normal. Negative
serology (FTA-ABS) rules out
syphilis. Infection now rare except
in HIV-positive or immune-
compromised patients.
38. HIV/AIDS Retroviral infection with HIV-1 that can
involve the nervous system, most
commonly in gay males or intravenous
drug users.
May cause optic neuritis,
myelopathy, mental status
changes, and focal decits with
white-matter changes on MRI
scan and abnormal CSF.
Occurs in high-risk populations who
may have diminished CD4 cell
counts and positive HIV serology.
39. Variant Creutzfeldt-
Jacob disease
Infection with the prion agent. The variant
disease form, linked to mad cow disease,
occurs in younger populations than classic
CJD.
May cause ataxia, diplopia, and
sensory symptoms, along with
dementia in a young person.
MRI and spinal uid are usually
normal. The course is rapidly
progressive over months. Brain
biopsy is seldom recommended.
May have abnormal EEG or 14-3-3
protein in CSF.
40. Brucellosis Systemic infection that can involve both
central and peripheral nervous system, rare
in developed countries and usually
associated with agricultural or animal
exposure.
Can cause optic neuritis,
myelopathy, and focal
neurologic ndings, along with
periventricular MRI signal
abnormalities.
Usually a systemic infection including
fever. Specic antibodies can be
found in serum and in CSF.
41. Subacute sclerosing
panencephalitis (SSPE)
Chronic CNS infection by measles virus,
most common in childhood but rarely in
young adults.
Progressing or relapsing
neurologic decits in a young
patient, occasionally with MRI
signal abnormalities and with
oligoclonal bands in the CSF
(which are directed against
measles antigens).
Dementia and behavioral changes are
usually prominent. The course is
rapidly progressive over weeks or
months. CSF PCR is available.
Brain biopsy is denitive but rarely
needed. EEG also shows
characteristic paroxysmal pattern.
42. Human herpes virus-6
(HHV-6)
Reactivation of ubiquitous herpes infection,
which is latent in the CNS.
May cause myelopathy or other
focal neurologic ndings in a
young person. MRI can show
Positive serologic testing is available for
HHV-6. The etiologic relationship of
HHV-6 to MS is currently the subject
of intensive research.
43. Hepatitis C The hepatitis C virus has occasionally been
reported to cause peripheral and rarely
central nervous system damage.
Optic neuropathy and other CNS
ndings may occur in a young
person. MRI may show signal
abnormalities.
Usually occurs in the setting of active
liver disease (often after IV drug
abuse or blood transfusions) and
serum antibodies and PCR are
available.
44. Mycoplasma An atypical pneumonia infection occasionally
complicated by CNS decits.
Can cause transverse myelitis,
cranial neuropathies, and other
neurologic abnormalities
accompanied by signal changes
on MRI.
Usually occurs in the setting of
systemic infections, including
pneumonia, fever, and malaise. CSF
may have pleocytosis but no IgG
abnormalities. Specic antibody
testing can be done in the serum.
45. Central pontine
myelinolysis (CPM)
Demyelination of the pons (and sometimes
other areas), usually occurring in the
setting of alcoholism or other severe
illness, and especially after rapid correction
of hyponatremia.
Can cause brainstem symptoms
and/or quadriceps, with
demyelination seen on MRI
scan.
Usually occurs in the setting of severe
illness, including hyponatremia. It
has a monophasic course. CSF will
be normal.
TABLE 7. Continued
46. Hashimoto
encephalopathy
Subacute sometimes-relapsing
encephalopathy associated with
autoimmune thyroid disease.
May cause strokelike episodes and
focal neurologic problems in a
young person. Rare white-
matter changes have been seen
on MRI and rare reports of
oligoclonal bands in the CSF.
Encephalopathy with confusion and
myoclonus is usually prominent.
EEG is diffusely abnormal.
Serology will show
antithyroglobulin and
antimicrosomal antibodies.
47. Vitamin B12 deciency CNS damage due to deciency of vitamin
B12, commonly caused by pernicious
anemia.
May cause CNS decits,
especially a progressive
myelopathy, rarely with MRI
CBC is often abnormal and serum
B12 levels are low. Methylmalonic
acid and homocysteine are often
abnormal.
48. Folate deciency Deciency of folate, which may cause CNS
abnormalities.
Can cause diplopia, myelopathy,
and other CNS decits,
occasionally with signal
changes on MRI.
Low blood folate levels, as well as
abnormal methylmalonic acid
homocysteine.
49. Celiac disease (gluten
sensitivity or sprue)
An immune disease with many
autoantibodies, including an immune
response to ingested gluten, as well as
antigliadin, antiendomysial, and
antitransglutaminase antibodies, often
causing small-bowel malabsorption, as well
as occasional relapsing neurologic decits.
Ataxia and brainstem signs are
common, as are periventricular
white-matter lesions on MRI.
Antibody testing is now available for
antigliadin antibodies. More than
90% or patients are HLA-DQ2.
Spinal uid is normal.
50. Amyotrophic lateral
sclerosis (ALS)
Acquired upper and lower motor neuron
disease causing progressive motor decits.
Can especially resemble primary
progressive MS, with a
progressive myelopathy.
MRI and CSF will be normal. EMG
will show peripheral nervous
system abnormalities of
denervation.
51. Primary lateral sclerosis Progressive upper motor neuron degenerative
disease causing upper motor neuron
(bulbar and spinal) decits.
Especially resembles primary
progressive MS, with a chronic
progressive myelopathy.
VER, MRI, and CSF should be
normal.
52. Adrenoleukodystrophy
and
adrenomyeloneuropathy
An X-linked genetic defect of a transporter
protein, causing peroxisome dysfunction
and an excess of very-long-chain fatty
acids.
Adult forms commonly cause
progressive paraparesis and
ataxia, usually with conuent
posterior white-matter changes
on MRI. Female carriers may
present with mild disease also.
Serum testing will show high levels of
very-long-chain fatty acids. The
ACTH stimulation test usually
shows impaired adrenal function.
53. Metachromatic
leukodystrophy
An autosomal recessive deciency of
arylsulfatase A.
May cause myelopathy and ataxia,
with symmetric diffuse signal
abnormalities on MRI.
Blood arylsulfatase A levels are low.
Abnormal metabolism can be
conrmed by study of cultured
broblasts obtained by biopsy.
DNA testing is now available.
54. Krabbe globoid cell
leukodystrophy
Autosomal recessive deciency of
galactocerebroside -galactosidase
generally seen in infancy but rarely in
young adults.
May cause paraparesis and visual
symptoms in young patients,
with conuent periventricular
MRI signal abnormalities.
Patients have accompanying
neuropathy, easily detected on
nerve conduction testing. DNA
testing is now available.
55. Fabry disease An X-linked deciency of the lysosomal
enzyme -galactosidase causing
accumulation of ceramide trihexosidase in
endothelium and smooth muscle cells. It is
often of adult onset and can cause renal
disease and angiokeratomas on the skin.
It causes recurrent strokes and
thus focal neurologic ndings in
a young person with MRI
Patients may have skin lesions,
corneal opacities, and renal disease.
CSF will be normal. DNA testing
and blood -galactosidase levels are
available.
56. Adult-onset autosomal
dominant
leukodystrophy
An autosomal-dominant leukodystrophy
presenting in adulthood, causing motor and
cerebellar decits, usually with prominent
autonomic dysfunction. The genetic defect
is unknown.
Especially resembles primary
progressive MS, with chronic
upper motor neuron and
cerebellar decits accompanied
by conuent white-matter lesions
on MRI and occasionally IgG
abnormalities in the CSF.
Family history with autosomal-
dominant inheritance. Automatic
involvement is also prominent
early.
57. Organic acidemias Autosomal-recessive diseases usually seen in
childhood but occasionally in adults.
May cause spasticity, ataxia, and
optic atrophy in young adults.
MRI is usually normal, as is CSF.
May have a positive family history.
Urinary organic acid screening will
be abnormal.
58. Spinocerebellar ataxias Nearly 2 dozen diseases have been described
with autosomal dominant progressive
ataxia and gait disturbances, some due to
triplet repeats.
Progressive myelopathy and
cerebellar decits in a young
person. Rarely, T2 lesions have
been described on MRI.
Strong family history. CSF will be
normal. DNA testing is
commercially available for many of
these syndromes.
TABLE 7. Continued
59. Friedreich ataxia Autosomal recessive GAA triplet expansion
of the gene coding for frataxin, with onset
usually in the early teens, causing
progressive ataxia and dorsal column
sensory loss.
Progressive ataxia and sensory
loss in a young person.
MRI and CSF usually normal.
Peripheral neuropathy also present
in Friedreich ataxia. DNA testing is
now available.
60. Olivopontocerebellar
atrophy (OPCA)
Autosomal-dominant mutation in the SCA-1
gene causing adult-onset progressive
cerebellar and brainstem decits.
Ophthalmoplegia, pyramidal
decits, optic atrophy, and
ataxia may all appear in a
young person. Rare reports of
abnormal MRI scans.
Positive family history. CSF will be
normal. Sometimes peripheral
neuropathy is also present. DNA
testing for SCA-1 is now available.
61. Mitochondrial
cytopathies (MELAS,
MERFF)
Maternally transmitted mitochondrial DNA
abnormalities seen in children and young
adults, which can cause optic atrophy,
paraplegia, ataxia, seizures, and dementia.
Multiple and recurrent focal
neurologic decits, with signal
abnormalities on MRI in a
young person.
Lactic acidosis usually present.
Muscle biopsy shows ragged red
bers. Specic genetic testing now
available.
62. Neuropathy, ataxia,
retinitis pigmentosa
(NARP)
Mutations in the mitochondrial gene for
ATPase-6 causing retinitis pigmentosa with
other neurologic features, including
sensory neuropathy, ataxia, and pyramidal
signs.
Prominent visual and motor
symptoms in a young person,
with MRI signal abnormalities.
Patients have retinitis pigmentosa as a
prominent feature. A sensory
peripheral neuropathy is also
present. Genetic testing for the
abnormal mitochondrial gene is
now commercially available.
63. Mitochondrial
neurogastrointestinal
encephalopathy
(MNGIE)
Mitochondrial genetic abnormality causing
GI malabsorption, as well as multiple
neurologic symptoms.
May cause ophthalmoplegia and
leukoencephalopathy, with
white-matter abnormalities on
MRI.
Prominent GI involvement. Patients
often have ptosis and peripheral
neuropathy, and muscle biopsy will
show abnormal mitochondria.
64. Leber hereditary optic
neuropathy
Mitochondrial mutation (many of which have
been described) causing subacute bilateral
optic neuropathy, often with other
neurologic features.
Bilateral optic neuropathy,
occasionally with myelopathy,
ataxia, and other neurologic
features, sometimes
accompanied by abnormal MRI
signal changes.
CSF will be normal. Mitochondrial
genetic testing now commercially
available.
65. Leigh syndrome Genetically heterogeneous but usually
autosomal recessive disease leading to
interference with the pyruvate
dehydrogenase system, causing elevated
lactate and pyruvate, usually in childhood.
Can occur later in life and cause
an acute necrotizing
encephalomyelopathy. MRI
scan usually shows brainstem
and basal ganglion necrosis.
Usually a childhood disease. Plasma
lactate and pyruvate will be
elevated. Genetic testing not yet
reliable.
66. Usher syndrome Congenital syndrome of retinitis pigmentosa,
with hearing loss, sometimes with
cognitive decits, and/or ataxia.
Neurologic symptoms with an MRI
scan that can have white-matter
abnormalities and CSF that can
show oligoclonal bands.
Retinitis pigmentosa and deafness are
prominent features.
67. Cerebral autosomal
dominant arteriopathy
with subcortical infarcts
and leukoencephalopathy
(CADASIL)
Autosomal-dominant mutation in the notch-3
gene, causing a microangiography
especially prominent in subcortical white
matter, often associated with migraines and
progressive dementia.
Multifocal neurologic symptoms
in a young person with
abnormal MRI scan.
Genetic testing is commercially
available. Family history of
neurologic problems usually
present. Often associated with
migraines. CSF usually normal.
68. Cerebroretinal
vasculopathy
Autosomal dominant microangiopathy of
brain and retina. A rare condition usually
presenting in the 20s.
Can have gait disturbance, dysarthria,
and visual abnormalities, with
periventricular lesions on MRI
scan.
Retinal changes are prominent,
including abnormal uorescein
angiography. Rare condition with a
strong family history.
69. Hereditary
endotheliopathy,
retinopathy,
nephropathy, and stroke
(HERNS)
An autosomal-dominant condition seen
primarily in Chinese patients, causing
leukoencephalopathy with renal
dysfunction.
Dysarthria, hemiparesis, and other
neurologic signs in young
patients, with periventricular and
white-matter lesions on MRI.
Very rare condition, described so far
only in the Chinese. Strong family
history. Dementia is usually
prominent.
70. Wilson disease Autosomal-recessive mutation in the ATP-7B
gene, causing copper deposition in tissues,
including brain and liver, usually
presenting in young people.
Neurologic decits, including
ataxia and tremor in a young
person. Rare reports of
abnormal MRI scans.
Movement disorder and dementia are
prominent. Liver functions may be
abnormal, slit lamp shows Kayser-
Fleischer rings, and serum copper is
elevated. Liver biopsy is rarely
required.
71. Adult polyglucosan
body disease
Autosomal recessive mutations in glycogen
branching enzyme genes, causing gait
disturbance, sensory symptoms, and
dementia.
Progressive neurologic symptoms
in a young person, with
extensive leukoencephalopathy
on MRI scan.
Peripheral nerves also involved and
are prominent. Biopsy will show
accumulation of polyglucosan
bodies.
TABLE 7. Continued
72. Hereditary spastic
paraparesis
Genetic (usually autosomal dominant)
syndrome of progressive spastic paraparesis,
occasionally with other neurologic ndings
as well. Over 10 different genetic variants
have been identied but most common in the
spastin gene.
Easily confused with primary
progressive MS because of its
steady progressive spastic
paraparesis, sometimes with
optic nerve or peripheral nerve
involvement.
MRI and CSF are usually normal.
Genetic testing not yet reliable.
73. Porphyria Usually autosomal-dominant disorder of
heme biosynthesis, which can cause
neurologic symptoms, including numbness
and cranial neuropathies.
Can cause focal neurologic
symptoms which relapse and
remit, and the MRI scan is
sometimes abnormal.
Psychiatric and behavioral symptoms
are usually prominent. Abdominal
symptoms also often present; 24-h
urine will show elevations in ALA
and PBG.
74. Vitamin E deciency Deciency of vitamin E often caused by an
autosomal-recessive defect in the TTPA
gene, leading to spinocerebellar
degeneration, often with retinitis
pigmentosa and other changes as well.
Progressive neurologic symptoms,
especially ataxia, in a young
person, rarely with abnormal
MRI scans reported as well.
Retinal pigmentation often present.
Serum vitamin E levels will be
decreased.
75. Abetalipoproteinemia Autosomal-recessive defect causing absence
of lipoproteins, leading to multiple
systemic symptoms, including neurologic
decits.
Progressive ataxia and
ophthalmoplegia are prominent.
Often has systemic symptoms,
including GI malabsorption and
retinitis pigmentosa. Cholesterol
and triglycerides are very low and
acanthocytes are present on blood
smear. MRI and CSF are normal.
76. CNS lymphoma Lymphoma of the central nervous system,
usually in immunocompromised patients.
Focal neurologic decits with
multifocal enhancing MRI
lesions.
CSF does not have IgG abnormalities
but will often show positive cytology.
Lesions are highly steroid responsive.
Brain biopsy may be necessary.
77. Intravascular lymphoma
(malignant
angioendotheliomatosis)
A rare intravascular lymphoma that can
prominently involve the nervous system.
The vasculopathy causes multiple
infarcts and focal lesions with
white-matter changes on MRI
scan.
Usually seen in elderly individuals,
with a progressive course. Dementia
is prominent. Sed rate is usually
high. CSF does not have IgG
abnormalities. Biopsy of skin or
brain may be necessary.
78. Paraneoplastic
syndromes
Indirect involvement of the central nervous
system by antibodies produced in systemic
cancers.
Symptoms of ophthalmoplegia and
ataxia may occur abruptly, and
oligoclonal bands are often
present.
MRI is usually normal. Symptoms may
be abrupt but are generally progressive.
Antibodies can be measured in the
serum (such as anti-Yo or anti-Hu).
79. Leukoencephalopathy
after chemotherapy or
radiation therapy
Leukoencephalopathy caused by toxic effects
of chemotherapy or radiation therapy for
systemic cancers.
Focal neurologic signs may be
present, and the MRI shows
extensive white-matter changes.
History of cancer and exposure to
radiation or chemotherapy.
80. Glioblastoma Primary malignancy of the central nervous
system, often multifocal and often
occurring in young people.
Focal neurologic decits in a
young person, with an abnormal
MRI scan.
MRI usually shows surrounding
edema and mass effect unusual for
MS. CSF would be normal. Brain
biopsy may be necessary.
81. Spinal tumor Usually astrocytoma or ependymoma in the
intramedullary spinal cord.
Progressive myelopathy in a
young person, with abnormal
signal in the spinal cord that
can resemble demyelination.
Absence of lesions outside the spinal
cord. VERs and CSF will be
normal.
82. Somatization disorder Psychiatric disorder characterized by a
chronic pattern of physical expression of
psychological distress.
Patients, who are often young,
have multiple recurring and
relapsing neurologic symptoms,
which can include weakness,
numbness, dizziness, and
similar complaints.
MRI, CSF, evoked potentials, and
neurologic examination will be
normal. Difculties arise when
testing shows nonspecic
changes. Many nonneurologic
symptoms usually present.
83. Conversion disorder Acute onset of motor or sensory loss
unexplained by physical ndings, not
intentionally produced.
Patients may present with
neurologic symptoms very
similar to those seen in MS.
normal. Difculties arise when testing
shows nonspecic changes. Many
nonneurologic symptoms usually
present.
84. Hypochondriasis Preoccupation with fears of having a serious
disease.
Patients may present with
neurologic symptoms very
similar to those seen in MS.
normal. Difculties arise when
testing shows nonspecic
changes. Many nonneurologic
symptoms usually present.
TABLE 7. Continued
85. Other: psychiatric
syndromes
Psychiatric disorders that often produce
somatic symptoms.
Fatigue and other neurologic
symptoms that can persist or
relapse in a young person.
Other evidence of depression, anxiety,
or psychiatric issues is often
evident. MRI, CSF and other tests
will be normal.
86. Spondylosis Spinal cord compression due to cervical
spondylosis and disc disease, resulting in
a progressive myelopathy.
Easily mistaken for primary
progressive MS, with a
progressive cervical myelopathy.
In an elderly patient, there are
often nonspecic brain MRI
signal changes.
MRI of the cervical spine will usually
show cord compression. CSF and
VERs should be normal.
87. Chiari malformation Descent of the cerebellar tonsils below the
foramen magnum, causing brainstem and
spinal cord compression.
May cause cranial neuropathies,
including ophthalmoplegia,
nystagmus, and ataxia.
MRI scanning, especially on sagittal
images, will detect the
malformation. MRI of the brain is
otherwise normal, as is CSF.
88. Syringomyelia Malformation of the spinal cord, with
enlarged central cavity producing
progressive myelopathic symptoms.
Causes a progressive myelopathy
in young patients, occasionally
involving lower cranial nerves
as well.
MRI scan will detect the syrinx. MRI
of the brain is usually otherwise
normal, as is CSF and VERs.
89. Spinal vascular
malformation
Dural arteriovenous stulas or intramedullary
AVMs that often cause a progressive (and
sometimes episodic) myelopathy.
Relapsing or progressive spinal
cord symptoms, often in a
young person. MRI of the
spinal cord can show intrinsic
signal abnormalities easily
mistaken for MS.
MRI of the brain will be normal, as
will CSF and VERs. No lesions
outside of the spinal cord.
90. Arachnoiditis Chronic inammation of the arachnoid
surrounding the spinal cord and roots,
often seen following spinal surgery or use
of intrathecal contrast or medications.
May cause a myelopathy or focal
(radicular) neurologic decits.
MRI scan usually shows enhancement
from the inammation. MRI of the
brain will be normal. CSF may
show inammation but no IgG
abnormalities, and VERs will be
normal.
91. Foramen magnum and
clivus lesions
Some tumors such as dermoid, teratoma, or
meningioma can occur at the base of the
skull in this central location and cause
primarily cranial nerve and upper
brainstem symptoms.
Progressive cranial nerve and
brainstem symptoms, often in a
young person.
MRI scanning will show the mass at
the base of the skull.
92. Cranial nerve palsies:
Bell palsy, abducens
palsy, etc.
Isolated cranial neuropathy, often idiopathic,
which can occur in young people.
Occasionally, MS can present as
an isolated facial weakness,
numbness, or diplopia.
No other neurologic signs or
symptoms are present, and MRI and
CSF should otherwise be normal.
93. Drugs Multiple drugs are capable of affecting the
nervous system, either as drugs of abuse
(toluene, alcohol, cocaine) or as
therapeutic agents (cyclosporine,
phenytoin, etc).
A variety of neurologic signs and
symptoms may appear as
manifestations of drug toxicity.
Many drugs also produce white-
matter changes on the MRI
scan.
Unfortunately, a history of drug
exposure is often difcult to obtain.
Symptoms are usually not relapsing
and remitting unless the drug
exposure continues. CSF should be
normal.
94. Environmental toxins Many toxins can cause neurologic damage,
including carbon monoxide, heavy metals,
and organic solvents.
Neurologic abnormalities often are
accompanied by white-matter
changes on the MRI scan.
Exposure to toxins is usually apparent.
Symptoms will not be progressive
or relapsing if exposure has ceased.
CSF should be normal.
95. Periventricular
leukomalacia
Periventricular white-matter necrosis
occurring in neonates, but often not
symptomatic until adulthood.
May be associated with a variety of
neurologic symptoms, and the
MRI will show periventricular
white matter lesions.
Symptoms are usually not relapsing or
remitting. CSF should be normal.
96. Migratory sensory
neuritis
Controversial entity of sensory neuritis
causing patchy relapsing areas of
numbness and paresthesias, presumably
due to peripheral nerve dysfunction.
Multifocal relapsing sensory
symptoms, often in a young
person.
Decits are purely subjective
(sensory) with no motor or other
ndings. MRI and CSF will be
normal.
97. Chronic fatigue
syndrome and
bromyalgia
Syndrome of chronic diffuse muscular pain
and chronic fatigue, often with other
somatic symptoms as well.
May report many neurologic
symptoms that can mimic MS
in a similar population (young
women).
Neurological examination is
objectively normal. Difculties arise
when the MRI shows nonspecic
abnormalities, but MRI, CSF and
VERs should be normal.
98. Myasthenia gravis Autoimmune disorder producing antibodies
against the acetylcholine receptor post
synaptically on the muscle.
Can cause uctuating weakness
and diplopia, especially in
young women.
Decits are conned to weakness and
fatigability in the motor system.
MRI, CSF and VER will be normal.
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99. Progressive necrotic
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Relapsing and progressive
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