Comprehensive Review in Clinical Neurology: A Multiple Choice Question Book for the Wards and Boards

Chapter 7. Neuroimmunology

Question

Questions 1–3

  1. A 24-year-old right-handed Caucasian woman comes to your clinic for the first time. One year ago she had one episode of a tingling sensation ascending to the mid-chest region lasting 2 weeks. One month ago she lost vision in her right eye and had pain behind the eye, worse with movement, that resolved incompletely after 2 weeks. Her MRI of the brain and cervical spine are shown in Figures 7.1 and 7.2. This presentation and MRI are consistent with:

FIGURE 7.1 Axial FLAIR MRI

FIGURE 7.2 Sagittal T2-weighted MRI

      a.  A clinically isolated syndrome of demyelination

      b.  Primary progressive multiple sclerosis

      c.  Acute disseminated encephalomyelitis

      d.  Fulminant multiple sclerosis because of two episodes in a year

      e.  Relapsing-remitting multiple sclerosis

  2. Other tests that may be useful diagnostically for this problem include:

      a.  Laboratory testing to exclude a vitamin B12 deficiency and lupus erythematosus

      b.  Skin biopsy for small-fiber neuropathy

      c.  Brainstem auditory-evoked potentials

      d.  CSF analysis for cells, protein, glucose, and oligoclonal bands

      e.  a and d

  3. What is correct regarding the prognosis?

      a.  Will progress to using a wheelchair within 5 years

      b.  Has benign multiple sclerosis and will not progress

      c.  Will likely be unable to walk after 15 years

      d.  Should avoid pregnancy due to worsening of her disease

      e.  Will likely have measurable disability on neurologic examination after 10 years

Questions 4–6

  4. A 32-year-old Caucasian woman developed left retro-orbital pain, worse with eye movement, 1 week ago. Over the past 2 days she has lost central vision, has reduced perception of light brightness, and colors seem “washed out.” You examine her and find a normal fundus, a left relative afferent pupillary defect (RAPD), and visual acuity of 20/200 in the left eye. The following are correct, except:

      a.  This condition usually improves over about 6 weeks

      b.  Oral steroids are appropriate treatment

      c.  This condition is sometimes associated with the emergence of multiple sclerosis

      d.  Intravenous steroids with an oral steroid taper are the treatment of choice

      e.  For visual acuity of 20/50 or better, steroid treatment has not been shown to be beneficial

  5. The presence of a relative afferent pupillary defect implies:

      a.  An imminent early third nerve palsy

      b.  Dampened efferent arm of the pupillary light reflex

      c.  A particularly good prognosis

      d.  A meningeal inflammatory component

      e.  Involvement proximal to the Edinger-Westphal nucleus

  6. Testing that is valuable in such a patient includes:

      a.  Syphilis serology

      b.  Angiotensin-converting enzyme

      c.  MRI of the brain and orbits with gadolinium

      d.  Brainstem auditory-evoked potentials

      e.  Retinal angiography

  7. A 45-year-old woman with relapsing-remitting multiple sclerosis of 5 years’ duration develops new right leg weakness, with trouble walking more than 10 feet unsupported. She has no recent fever or infection and has not recently started a new medication. You examine her in the office and note increased reflexes in the right leg compared with prior examination, a Babinski sign on the right, and a right crossed adductor. Which of the following answers is correct?

      a.  A Babinski sign is consistent with a spinothalamic tract demyelinating plaque

      b.  Her weakness is due to a lower motor neuron disorder

      c.  Intravenous methylprednisolone is the treatment of choice

      d.  She should immediately begin working out harder

      e.  A crossed adductor is a clear sign of cervical spinal cord disease

  8. Your patient with newly diagnosed multiple sclerosis comes to you and wants to know a few things about this disease. The only statement that is correct in multiple sclerosis is that:

      a.  Multiple sclerosis is more common further from the equator

      b.  Drinking milk definitely prevents multiple sclerosis

      c.  Her identical twin has a 100% chance of getting multiple sclerosis too

      d.  Multiple sclerosis is definitely due to mononucleosis

      e.  Multiple sclerosis is environmentally transmitted

  9. The pathology of active multiple sclerosis can consist of all of the following, except:

      a.  Involvement of cortical gray matter

      b.  Involvement of white matter

      c.  Loss of myelin from axons

      d.  Axonal transections

      e.  Profuse basophilic infiltration in the meninges

10. Typical symptoms of multiple sclerosis may include all of the following, except:

      a.  Tingling, burning, aching, or “numb” sensations

      b.  Weakness of the legs

      c.  Double vision

      d.  Distal limb atrophy

      e.  Ataxia

11. Your 34-year-old African-American female patient with relapsing neurologic symptoms has spinal fluid testing. Which of the following findings would prompt you to consider diagnoses other than multiple sclerosis?

      a.  Elevated kappa chains

      b.  WBC count of 22 (normal 0 to 5 cells/mm3)

      c.  Neutrophilic pleocytosis

      d.  Elevated immunoglobulin G synthesis rate

      e.  Normal CSF immunologic parameters

12. You see a 21-year-old male college student of Asian-American descent. He has had three episodes of neurologic symptoms, including an episode of hemiparesis lasting 3 weeks, one episode of optic neuritis in the left eye lasting 2 weeks, and one episode of paresthesias of both legs and lower abdomen with reduced bladder sensation with residual symptoms. His MRI of the brain is shown in Figures 7.3 and 7.4. The only statement that is true is:

FIGURE 7.3 Coronal T1-weighted postcontrast MRI

FIGURE 7.4 Axial T2-weighted MRI

      a.  This is multifocal glioma and he should have a brain biopsy

      b.  This may respond to intravenous steroids or may require other immunosuppression

      c.  The open-ring sign indicates abscess formation

      d.  Prognosis is dismal with this MRI finding

      e.  Chlamydia pneumoniae has been proven to cause this picture

13. Your patient with relapsing multiple sclerosis has an MRI with gadolinium. The following statements are incorrect, except:

      a.  Typical lesions of multiple sclerosis have decreased T2 signal and increased T1 signal

      b.  Spinal cord multiple sclerosis lesions usually extend over more than three segments

      c.  Spinal cord lesions in multiple sclerosis never show mass effect

      d.  Typical multiple sclerosis lesions are periventricular and oval shaped

      e.  Multiple sclerosis lesions are always well defined on FLAIR imaging

      f.  Higher-field-strength MRI magnets are less likely to show multiple sclerosis lesions

Questions 14–18

14. You see a 45-year-old Caucasian man in your office. Two months ago he developed a nearly complete loss of vision in the left eye, which has not resolved despite intravenous steroids and a tapering course of oral steroids. Two weeks ago he developed visual loss in the right eye, which has persisted. He has burning paresthesias of both feet and some urinary urgency, both of which have been present for 1 year. His MRI of the cervical cord is seen in Figure 7.5. His spinal fluid shows 50 WBCs/mm3, with 45% neutrophils and 55% lymphocytes, protein of 75 mg/dL, and negative oligoclonal banding. CSF VDRL is negative, HIV is negative, HTLV I and II are negative, and vitamin B12 level is normal. ANA is moderately elevated at a titer of 1:128. Which of the following is the most likely diagnosis?

FIGURE 7.5 Sagittal T2-weighted MRI

      a.  Lupus myelitis

      b.  Fulminant multiple sclerosis

      c.  Neuromyelitis optica

      d.  Subacute combined degeneration

      e.  Neurosarcoidosis

15. In terms of the most recent episode of neurologic symptoms:

      a.  Treatment is nonurgent as most of these events resolve

      b.  Intravenous steroids are ineffective and counterproductive

      c.  Interferon β-1b is the drug of choice

      d.  Recovery is often incomplete

      e.  Natalizumab is indicated due to its higher efficacy profile

16. Long-term treatment could consist of all of the following, except:

      a.  Oral steroids

      b.  Azathioprine

      c.  Cyclosporine pulse therapy

      d.  Rituximab therapy

      e.  Weekly intramuscular interferon β-1a

17. The disease course in this condition can be all of the following, except:

      a.  Gradual worsening over time

      b.  Relapsing

      c.  Monophasic

      d.  Severe

      e.  Isolated spinal cord involvement

18. In this condition, all of the following are true about the brain MRI findings, except:

      a.  The brain is always normal in this condition

      b.  The brain is often normal in this condition

      c.  Involvement of the spinal cord extending into the brainstem can occur

      d.  Posterior reversible encephalopathy syndrome can occur

      e.  Lesions atypical for multiple sclerosis can occur

Questions 19–21

19. A 12-year-old right-handed Caucasian girl comes to the hospital. She had a mild upper respiratory tract infection 2 weeks ago and then over the past 4 days developed headache, fever, visual blurring, trouble walking, and paresthesias of her limbs. Her MRI is shown in Figures 7.6 and 7.7. Her examination shows bilateral papillitis, brisk reflexes with some limb ataxia, and upgoing toes. She is moderately confused and febrile. CSF shows a mild lymphocytic pleocytosis and negative oligoclonal banding. This syndrome is most consistent with:

FIGURE 7.6 Axial FLAIR MRI

FIGURE 7.7 Axial FLAIR MRI

      a.  Relapsing-remitting multiple sclerosis

      b.  Acute disseminated encephalomyelitis

      c.  Hemorrhagic leukoencephalopathy of Weston Hurst

      d.  Balo’s concentric sclerosis

      e.  Viral meningitis

20. In terms of how this is related to multiple sclerosis:

      a.  It appears to be a separate neuroimmunologic disorder

      b.  It usually transitions into multiple sclerosis

      c.  It never transitions into multiple sclerosis

      d.  It is the pediatric equivalent of multiple sclerosis

      e.  It is the same as multiple sclerosis

21. You decide to treat the patient with the following:

      a.  Intravenous diphenhydramine

      b.  Intravenous ceftriaxone

      c.  Intravenous acyclovir

      d.  Intravenous gentamicin

      e.  Intravenous methylprednisolone

22. Regarding fatigue in multiple sclerosis, which of the following is true?

      a.  Is always due to depression

      b.  Is due to sleep disorders in most cases

      c.  Is a frequent symptom in patients with multiple sclerosis

      d.  Has a precisely defined pathophysiology

      e.  Is untreatable

23. You see a patient with multiple sclerosis who wants to become pregnant. You tell her that:

      a.  She should never get pregnant because it will worsen her multiple sclerosis

      b.  She will need to have a Cesarean section

      c.  She should start prenatal vitamins

      d.  She cannot receive steroids during pregnancy

      e.  She can continue her interferon β-1b during pregnancy

24. Your 37-year-old African-American female patient with early relapsing multiple sclerosis wants to consider a disease-modifying agent. You tell her that:

      a.  She should start nothing as these agents only work in 30% of patients

      b.  The agents reduce relapse rate and reduce MRI activity in relapsing-remitting multiple sclerosis

      c.  There is one best choice in terms of medicines

      d.  Antibodies that neutralize medicine form in all patients on these medications

      e.  She should expect to feel better after 6 months on medicine

Questions 25–27

25. Your 42-year-old right-handed Caucasian female patient has been on an interferon and then glatiramer acetate, but has continued to have exacerbations with weakness of the left leg and diplopia. Her MRI shows two enhancing lesions. You start her on monthly natalizumab 300 mg intravenously. Your initial counseling to her includes all the following, except:

      a.  This medicine reduces exacerbations by 60% to 70% in relapsing forms of MS

      b.  It requires participation in a monitoring program

      c.  It has a 1 in 1000 risk of causing progressive multifocal leukoencephalopathy

      d.  Natalizumab is more risky than using mitoxantrone for multiple sclerosis

      e.  There is a 1 in 50 risk of anaphylaxis during natalizumab use

26. During the third infusion of natalizumab, the patient develops shortness of breath, tachycardia, and a pruritic erythematous rash on her chest and abdomen. You recommend:

      a.  A trial of diphenhydramine prophylaxis

      b.  Referral to an allergist for desensitization

      c.  Retrial with 150 mg of natalizumab for the next dose

      d.  Evaluation for immunoglobulin A deficiency

      e.  Terminating the infusion, treating for anaphylaxis, and avoiding future doses

27. After 2 years on treatment, the patient develops headaches, mild right hemiparesis, and word-finding difficulty. There is a new subcortical lesion on MRI. You recommend all of the following, except:

      a.  Stopping natalizumab during evaluation

      b.  Double the natalizumab dose in future treatments

      c.  CSF for JC virus PCR

      d.  Considering plasmapheresis depending on evaluation

      e.  Careful clinical monitoring

28. Your 54-year-old male patient with multiple sclerosis has painful spasms of both legs, which are worse at bedtime, increased when he has to have a bowel movement, and worse with stress. His examination shows a spastic paraparesis. The following statement about spasticity is true:

      a.  Spasticity is the same as weakness

      b.  Treatment with baclofen or tizanidine is usually not beneficial

      c.  If he works out hard, it will go away

      d.  Stretching may be helpful

      e.  Botulinum toxin injections are not indicated in focal spasticity

29. You are called to the emergency department to see a 23-year-old female Caucasian patient. She has been previously well, but about a week ago without prodromal illness, she developed ascending paresthesias of the legs and trunk. She had progressive unsteadiness and leg weakness and now cannot walk. Her examination shows mildly reduced reflexes in the legs, upgoing toes, and a sensory level. Her MRI of the spine is shown in Figure 7.8. CSF shows a mild lymphocytic pleocytosis, negative studies for syphilis, herpes zoster, Mycoplasma, and HIV. Which of the following is the most likely diagnosis?

FIGURE 7.8 Sagittal T2-weighted MRI

      a.  Ascending myelitis

      b.  Transverse myelitis

      c.  Lupoid myelitis

      d.  Guillain-Barre syndrome

      e.  Early multiple sclerosis

30. Fingolimod is an oral agent used in relapsing multiple sclerosis. Its mechanism of action is best described by:

      a.  Interferon-based therapy that alters cytokine trafficking

      b.  Polymer that simulates the antigenicity of myelin basic protein

      c.  DNA polymerase inhibitor

      d.  Modulator of sphingosine-1 phosphate receptors

      e.  Selectively inhibits B-cell maturation

31. Dalfampridine is a medication that:

      a.  Reduces pseudobulbar affect in patients with neurologic injury

      b.  Reduces relapses in patients with relapsing-remitting multiple sclerosis

      c.  Is FDA approved to improve visual contrast sensitivity in multiple sclerosis

      d.  Is FDA approved to improve the speed of walking in multiple sclerosis

      e.  Is not indicated for patients with multiple sclerosis

32. A patient comes to you asking about new oral agents for multiple sclerosis in research studies. She is specifically interested in oral cladribine. All the following statements about this medicine are incorrect, except:

      a.  Oral cladribine is a chemotherapeutic agent and therefore cannot be used in multiple sclerosis

      b.  Oral cladribine is a purine nucleoside analogue

      c.  Oral cladribine is a nonspecific inhibitor of T-cell adhesion to endothelial cells

      d.  Oral cladribine has an unknown mechanism, but reduces immunoglobulin production

      e.  Oral cladribine has no hematologic side effects

33. Your patient with secondary progressive multiple sclerosis comes to her appointment asking about her low vitamin D. She wants to know what the relationship with multiple sclerosis is and exactly how much vitamin D she should be taking to prevent a worsening of her multiple sclerosis. You tell her all of the following, except:

      a.  The exact relationship between vitamin D and multiple sclerosis is not known

      b.  Low vitamin D is the reason why multiple sclerosis is more common further from the equator

      c.  In a large prospective cohort nursing study, nurses who used vitamin D supplementation were less likely to get multiple sclerosis

      d.  Vitamin D can be an immunomodulator in animal models of multiple sclerosis

      e.  Vitamin D is often lower in African-Americans who also tend to have more severe clinical multiple sclerosis

Answer Key

1. e

2. e

3. e

4. b

5. e

6. c

7. c

8. a

9. e

10. d

11. c

12. b

13. d

14. c

15. d

16. e

17. a

18. a

19. b

20. a

21. e

22. c

23. c

24. b

25. d

26. e

27. b

28. d

29. b

30. d

31. d

32. b

33. b

Answers

 1. e, 2. e,  3. e

This patient has relapsing-remitting multiple sclerosis (RRMS). Most patients with this disorder have onset between age 20 and 40, though age of onset ranges from early childhood to late adulthood. Females are affected more than males in a 3:2 ratio. It is more common further north and south of the equator, and more common in Caucasians. RRMS is defined by relapses consistent with demyelination, with or without clinical improvement, but with episodes of clinical stability in between relapses. The term “remitting” is confusing as these patients may not return to clinical normalcy after a relapse. In addition, on MRI, they may have new lesion formation while remaining clinically stable five to ten times as often as they have new clinical episodes. A “relapse” is defined as an episode of new or worsened neurologic symptoms, lasting more than 24 hours, not due to fever or infection. Other synonyms for this are an attack, bout, or exacerbation. The diagnosis is based on two relapses separated in time with clinical evidence of multiple lesions in the central nervous system. The diagnosis can also be made on the basis of multiple lesions on the MRI in combination with an appropriate history and examination, new lesion formation on MRI over time, and new clinical activity over time.

A clinically isolated syndrome of demyelination is a single clinical episode consistent with demyelination, but no “second episode” to make a clinical diagnosis of multiple sclerosis. Primary progressive multiple sclerosis usually occurs in older patients. These patients have a gradually progressive course from onset and do not have relapses. They may have a lower burden of MRI lesions than do patients with RRMS. Acute demyelinating encephalomyelitis is an acute disorder, more common in childhood, and often occurring soon after an infection or vaccination. Patients develop a subacute severe disorder with multifocal demyelination in the brain and spinal cord (see discussion to questions 19 to 21). Fulminant multiple sclerosis indicates a rapidly progressive course with repeated relapses that are refractory to standard treatment.

There are no laboratory tests that are presently useful in the diagnosis of multiple sclerosis. On occasion, other disorders can mimic multiple sclerosis. Diseases commonly tested for in early evaluation of multiple sclerosis include vitamin B12 deficiency, lupus, Lyme disease in endemic areas, and other inflammatory disorders depending on clinical suspicion. Skin biopsy for small-fiber neuropathy may be useful for patients with paresthesias that affect the limbs and face, that are persistent, and in whom there is no evidence to suggest central demyelination. Brainstem auditory-evoked potentials can be abnormal in the population with multiple sclerosis, but generally are not helpful diagnostically (insensitive in early multiple sclerosis for subclinical brainstem lesions). Somatosensory-evoked, or visual-evoked, potentials may be useful in selected patients to ascertain a second lesion or show slowing, suggestive of central demyelination. CSF may show mild elevation in WBCs, predominantly lymphocytes. Measures of immune activity are sometimes but not always abnormal, including immunoglobulin G synthesis rate and the presence of oligoclonal bands (indicating antibody formation in the spinal fluid compartment).

The prognosis for RRMS is better than most people expect. Various studies have shown a good prognosis over 10 years in a representative population without treatment. However, neurologic examination shows abnormalities after 10 years of disease in most patients. The diagnosis of benign multiple sclerosis is a retrospective one after 15 to 20 years of disease without measurable disability. This occurs in approximately 10% to 20% of patients with multiple sclerosis.

 Fox R, Bethoux F, Goldman MD, et al. Multiple sclerosis: Advances in understanding, diagnosing, and treating the underlying disease. Cleve Clin J Med. 2006; 73:91–102.

 4. b, 5. e,  6. c

This patient has optic neuritis. The results of a large randomized double-blind treatment trial for acute optic neuritis compared intravenous methylprednisolone with prednisone taper, oral prednisone taper, and placebo. This study showed that recovery was hastened by intravenous methylprednisolone with oral prednisone taper but that visual outcome at 1 year was not significantly affected. Oral steroids were at best no better than placebo, and possibly worse.

In about 80% of patients with acute optic neuritis, recovery occurs over weeks. This may be incomplete. Over a 15-year period after an episode of optic neuritis, multiple sclerosis occurs in about 50% of cases. Factors that increase the risk of multiple sclerosis developing include the presence of brain MRI lesions consistent with demyelination and abnormal CSF findings. In the Optic Neuropathy Treatment Trial, patients with visual acuity of 20/50 or better did not measurably benefit from intravenous steroids treatment.

Relative afferent pupillary defect is a sign seen in optic neuritis. In this condition, there is involvement of the optic nerve with impaired response to light stimulation. The afferent arm of the pupillary light reflex is affected, in the side of the optic neuritis as compared to the normal eye. This leads to a relative reduction in signal traveling to the Edinger Westphal nucleus in the midbrain from the affected eye. Thus light shone into the affected eye causes a normal consensual light reflex. (Both the pupils constrict.) When the stimulus is shifted to the “good” eye, pupils remain constricted, and then when shifted back to the affected eye, there is relatively less “light,” so the pupils dilate (see also Chapter 1). This is not an indication of an effect on the third nerve, which is the efferent arm of the pupillary light reflex. This does not suggest a particular prognosis. This does not imply a meningeal component.

MRI of the brain is ordered primarily to assess evidence and risk of progression to multiple sclerosis. On occasion, imaging of the optic nerve can confirm optic nerve involvement, but it is not critical for the diagnosis of optic neuritis. Rarely, retro-orbital or meningeal processes can cause sudden visual loss, simulating optic neuritis. On occasion, sinus cystic disease can cause impingement on or inflammation in the optic nerve. If there are one or more well-defined demyelinating lesions on MRI, the risk of multiple sclerosis goes from about 20% in 5 years to approximately 80% over 5 years. Multiple treatment trials in patients with a single episode of demyelination and MRI brain lesions have shown benefit from starting medicines that are FDA approved for multiple sclerosis treatment in such patients. In general, when the MRI does not show such lesions, treatment is not indicated beyond steroid therapy acutely.

Unless the patient has a history suggestive of syphilis, syphilis serology is not useful. Angiotensin-converting enzyme testing is not useful in this situation unless there are other indications to suggest sarcoidosis. Brainstem auditory-evoked potentials are of low yield in this situation. There is no indication for retinal angiography in typical optic neuritis. It may be useful if there are atypical features such as a horizontal scotoma or very sudden painless onset suggesting a vascular etiology.

 Balcer LJ. Optic neuritis. N Engl J Med. 2006; 354:1273–1280.

 Beck RW, Cleary PA, Anderson MM Jr, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 1992; 326:581–588.

 7. c

The patient is having an acute relapse. In this case there is a functional deficit interfering with walking, which is an indication for treatment rather than conservative management. Intravenous methylprednisolone usually given as a dose of 1000 mg daily for 3 to 5 days, with an oral steroid taper, is presently the treatment of choice for acute relapses. Other options include other forms of steroids, different dosing or duration of taper, not using a tapering dose, and high-dose steroids. The goal of treatment is to reduce the functional deficit and increase the speedy recovery of function.

The Babinski sign is elicited by stroking the lateral border of the sole of the foot with a moderately sharp object. A normal response is that the great toe goes down (plantar flexion). A positive Babinski sign is when the great toe goes up, often with fanning of the other toes. A full “triple flexion” response is when the ankle dorsiflexes, the knee flexes, and the hip flexes in addition to the Babinski sign. The presence of a Babinski sign implies dysfunction in the corticospinal (pyramidal) tract between the cortex and the lumbar spinal cord. A positive Babinski sign is an indication of an upper motor neuron disorder (corticospinal tract) and not a lower motor neuron disorder (problem affecting the lower motor neuron from the anterior horn of the spinal cord to the neuromuscular junction).

Increased exercise during an acute exacerbation has not been shown to be beneficial. However regular exercise in multiple sclerosis has been shown to improve quality-of-life measures and reduce fatigue and depression scales. A crossed adductor sign is seen when performing the patellar reflex. The opposite (crossed) leg adducts (moves medially from the hip). This implies a spread of reflex above the L4 level into L2 and L3 segments of the cord, indicating disinhibition of the reflex arc. This is another upper motor neuron sign.

 Frohman EM, Shah A, Eggenberger E, et al. Corticosteroids for multiple sclerosis: I. application for treating exacerbations. Neurotherapeutics. 2007; 4(4):618–626.

 8. a

Multiple sclerosis is more prevalent the further north or south of the equator one lives. The cause for this has not been established. Moving after the age of 12 does not seem to alter this risk. There is no evidence that drinking milk or other dietary measures affect the development of multiple sclerosis. However various epidemiologic studies suggest a link between vitamin D levels and multiple sclerosis, with lower vitamin D levels being correlated with higher risk of multiple sclerosis. Whether this is related to the cause of multiple sclerosis or common factors is unclear. Monozygotic (identical) female twins have a 33% chance of both being affected by multiple sclerosis if one develops multiple sclerosis. This indicates a mixture of genetic and nongenetic factors in the disease causation. Although mononucleosis has been linked to multiple sclerosis at times, the relationship is unclear and no definitive pathogenic relationship can be shown at present. The best evidence against environmental transmission of multiple sclerosis comes from adoption studies that do not show an increase in multiple sclerosis in children adopted into multiple sclerosis-affected families. Multiple sclerosis exacerbations are more likely to occur after infections, but are not related to any specific infection. Motor vehicle accidents and surgical procedures have not been linked to the onset or exacerbation of multiple sclerosis.

 Fox RJ, Bethoux F, Goldman MD, et al. Advances in understanding, diagnosing and treating the underlying disease. Cleve Clin J Med. 2006; 73:91–102.

 9. e

Multiple sclerosis is not associated with basophilic or eosinophilic infiltration of the meninges. Lymphocytes enter the CNS from the periphery. There are focal areas of demyelination (plaques) with glial cell infiltration and inflammatory cell accumulation. Macrophages are present in the core of the plaques. Areas of remyelination can be seen (“shadow plaques”). Oligodendroglial cells are reduced in the plaque core and increased at the periphery. Normal-appearing white matter may show loss of axons and some gliosis. Cortical gray matter is affected in multiple sclerosis, but this is poorly visualized with present imaging techniques and is thus under-recorded during life. White matter is typically affected in multiple sclerosis; myelin is removed from around axons, and early in lesion formation, axons are also injured and measurably transected.

 Lucchinetti CF, Parisi J, Bruck W. The pathology of multiple sclerosis. Neurol Clin. 2006; 23:77–105.

10. d

Multiple sclerosis is typically an upper motor neuron or CNS disorder and does not cause muscle atrophy. However there are reported cases of some peripheral involvement and muscle atrophy in late multiple sclerosis, but these would be atypical features and suggest other diagnoses. Paresthesias of various types including the above as well as focal areas of pruritus or a sensation of wetness are common in multiple sclerosis. These can occur anywhere on the body. Weakness and gait difficulties are key common symptoms in multiple sclerosis, but do not occur in every patient. Double vision can occur and is usually due to brainstem involvement. Gait or limb ataxia occurs commonly and can be due to cerebellar, cerebellar connection, or sensory tract involvement in multiple sclerosis.

 Noseworthy JH, Lucchinetti C, Rodriguez M, et al. Multiple sclerosis. N Engl J Med. 2000; 343:938–952.

11. c

White cells can be elevated in the CSF in multiple sclerosis. Usually there is a predominance of lymphocytes and no more than 50 cells/mm3. A neutrophilic pleocytosis would be unusual and might suggest another diagnosis. For example this can be seen in Devic’s disease at times (neuromyelitis optica; see discussion to questions 14 to 18). Elevated kappa chains are an indication of antibody formation in the CNS compartment and can be seen in multiple sclerosis. Immunoglobulin G synthesis rate elevation is one measure of increased intrathecal elaboration of antibody and can be seen in multiple sclerosis. Some patients with multiple sclerosis can have normal CSF. The frequency of this finding varies, but a normal CSF does not “rule out” multiple sclerosis.

 Noseworthy JH, Lucchinetti C, Rodriguez M, et al. Multiple sclerosis. N Engl J Med. 2000; 343:938–952.

12. b

This picture is consistent with tumefactive multiple sclerosis. Although the diagnosis of multifocal glioma is in the differential of multicentric lesions in the brain, the relapsing pattern and the presence of an open-ring sign with limited mass effect on the MRI in Figure 7.3 would all argue against this diagnosis. Tumefactive multiple sclerosis appears to be a subform of relapsing multiple sclerosis with large, mass-like lesions. These often have incomplete peripheral enhancement, showing the “open-ring sign,” which is suggestive of this pathology. Patients may improve with intravenous steroids but, on occasion, may require other immunologic treatment such as plasmapheresis or intravenous immunoglobulin. The open-ring sign is consistent with tumefactive multiple sclerosis and does not suggest abscess. The prognosis is similar to that seen in relapsing and remitting multiple sclerosis and is not “dismal.” There is no specific evidence that Chlamydia pneumoniae is causative for tumefactive multiple sclerosis. There is some evidence that may suggest that Chlamydia pneumoniae may be related to multiple sclerosis, but this has not been corroborated.

 Lucchinetti CF, Gavrilova RH, Metz I, et al. Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis. Brain. 2008; 131:1759–1775.

13. d

Typical multiple sclerosis lesions are periventricular and oval shaped. They have increased T2 signal. Characteristically, they are oval shaped and periventricular, but may be irregular, small or large, sharply defined or ill-defined, and may involve subcortical and juxtacortical brain. They may be seen in the infratentorial compartment typically around the fourth ventricle and in the brainstem white matter. They may show T1-reduced signal (so-called black holes). This appears to suggest more significant axonal loss or an older plaque. With gadolinium, some, but not all lesions can enhance. Enhancement of all lesions or persistent enhancement for weeks would be atypical for an multiple sclerosis plaque. Spinal cord lesions in multiple sclerosis usually extend only one to two vertebral segments and tend to involve a segment of the cord. A longitudinally extensive lesion over three or more segments suggests other disorders such as Devic’s disease (see discussion to questions 14 to 18), transverse myelitis, sarcoidosis, lupus, or an intraspinal mass. Spinal cord lesions may show mass effect acutely, with gradual reduction in mass effect over time and eventual focal atrophy. Some multiple sclerosis lesions can be ill-defined. Some patients have a poorly defined change in brain MRI signal on FLAIR and T2, known as “dirty white matter,” in which cloudy-appearing changes without sharply defined borders are seen. There is an increased detection of focal lesions with increased field strength. This can be very useful for infratentorial lesions that may not be evident with lower-field-strength magnets.

 Pretorius PM, Quaghebeur G. The role of MRI in the diagnosis of MS. Clin Radiol. 2003; 58:434–448.

14. c, 15. d, 16. e, 17. a, 18. a

Neuromyelitis optica (Devic’s disease) is a neuroinflammatory condition with a distinct pathology and clinical course. Histologically, focal areas of demyelination are seen with significant leukocyte infiltration and some areas of frank necrosis and cavitation. There may be nearly complete axon loss within lesions. There are antibodies, neuromyelitis optica immunoglobulin G (NMO-IgG), that bind selectively to the aquaporin-4 water channel. This is a component of the dystroglycan-protein complex located in astrocytic foot processes at the blood-brain barrier.

Lupus myelitis can be acute as well, but patients have other markers of lupus, such as skin rash, arthritis, and renal involvement. Relapsing optic neuritis and myelitis together would be unusual in lupus myelitis. Fulminant multiple sclerosis could cause this syndrome, but the presence of severe optic neuritis bilaterally should suggest the diagnosis of Devic’s disease first. Laboratory testing for NMO-IgG is positive in 70% of such cases. Subacute combined degeneration could cause paresthesias of the feet but does not cause a relapsing optic neuritis. Neurosarcoidosis can mimic most neurologic disorders but is usually a diagnosis of exclusion or diagnosed when systemic markers of this disease are present (e.g., skin, lung, and other organ involvement; see Chapter 16).

Devic’s disease progresses with relapses, but does not tend to progress in between relapses. It can have a monophasic or relapsing course. It can be severe. It can exhibit a spinal form. Relapses are frequently severe and may not recover completely. Treatment is urgent in relapses of Devic’s disease and many of the deficits do not resolve completely. Interferon β does not seem to be effective in Devic’s disease. There are no data on the use of natalizumab in Devic’s disease. Medicines that have been used anecdotally include steroids, azathioprine, Cytoxan, rituximab, and other immunosuppressants. For acute exacerbations, IV steroids or plasmapheresis can be used.

Early in Devic’s disease the brain tends to be spared. However, later in the course it may have some atypical features, with brainstem disease extending up from the spinal cord, lesions atypical for multiple sclerosis in the brain, and imaging findings consistent with posterior reversible encephalopathy syndrome.

 Lennon VA, Kryzer TJ, Pittock SJ. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. N Engl J Med. 2005; 202:473–477.

 Pittock SJ, Lennon VA, Krecke K, et al. Brain abnormalities in neuromyelitis optica. Arch Neurol. 2006; 63:390–396.

19. b, 20. a, 21. e

This syndrome is most consistent with acute disseminated encephalomyelitis (ADEM). ADEM is usually a monophasic syndrome often occurring after an infection or vaccination. It is a multifocal demyelinating syndrome with large lesions that can be peripheral and may involve the basal ganglia. CSF may show a pleocytosis, but usually does not show oligoclonal bands. Patients are often febrile and encephalopathic. It may leave residual deficits.

First-line treatment for ADEM is intravenous methylprednisolone. All treatment recommendations are anecdotal. Treatment consists of initial intravenous methylprednisolone and if this fails, trial of plasmapheresis. There is no indication for antibacterial or antiviral agents.

The hemorrhagic leukoencephalopathy of Weston Hurst is a severe immune-mediated encephalopathy with areas of hemorrhage often in the temporal lobes. It may be a subform of ADEM. Balo’s concentric sclerosis refers to a progressive demyelinating disorder in which concentric rings of demyelination are seen either pathologically or on MRI. This is not consistent with viral meningitis as the patient has CNS parenchymal findings on MRI.

ADEM appears to be a separate neuroimmunologic disorder from multiple sclerosis. However, some patients diagnosed with ADEM later develop a relapsing pattern consistent with multiple sclerosis. This may be due to a tendency in the pediatric population to diagnose ADEM rather than a first episode of multiple sclerosis.

 Tenembaum S, Chitnis T, Ness J, et al. ADEM. Neurology. 2007; 68:S23–S36.

22. c

Approximately 95% of patients with multiple sclerosis have fatigue as a symptom at some time during their course. This may be part of the biology of the disease, but its pathogenesis has not been fully defined. It is not usually due to depression or sleep disorders, but both of these are worth inquiring about. In addition, some medicines used for multiple sclerosis can cause fatigue. Fatigue in multiple sclerosis can be treated with good sleep hygiene, naps during the day, regular exercise, and sometimes medicines such as amantadine or modafinil.

 Fox RJ, Bethoux F, Goldman MD, et al. Advances in understanding, diagnosing and treating the underlying disease. Cleve Clin J Med. 2006; 73:91–102.

23. c

Pregnancy does not change the course of multiple sclerosis appreciably. Like other women contemplating pregnancy, patients should be on prenatal vitamins with folic acid. There are no specific issues in the conduct of pregnancy and patients can have an epidural anesthetic and can have a regular delivery or Cesarean section as needed obstetrically. Steroids can be used during pregnancy though should be limited as much as possible and preferably should not be given in the first trimester. Interferons (category C in pregnancy) should be stopped at least 1 month before conception. Glatiramer acetate is category B in pregnancy, but it is usually stopped before conception. Women with multiple sclerosis tend to have fewer exacerbations during pregnancy and more in the first 6 months after delivery (see Chapter 16). Breast-feeding may be protective against exacerbations. Children of women with multiple sclerosis have a 3% to 5% lifetime chance of developing multiple sclerosis.

 Ferrero S, Pretta S, Ragna N. Multiple sclerosis: Management issues during pregnancy. Eur J Obstet Gynecol Reprod Biol. 2004; 115:3–9.

24. b

All the standard disease-modifying agents for early relapsing-remitting multiple sclerosis (interferon β-1b, interferon β-1a intramuscularly or subcutaneously, and glatiramer acetate) reduce relapse rate, reduce new lesion formation on MRI, and tend to slow progression of measurable disability on neurologic examination. They are similar in effect profile. They vary in side effects, route of administration, and frequency of administration. The interferons as a class cause flu-like symptoms after injections and may cause injection site reactions. They require laboratory monitoring for liver function changes and hematologic change. Glatiramer acetate causes local injection site reactions and occasional idiosyncratic chest pain. Although all agents reduce attack frequency 30% on average, this varies widely in individuals. None of the agents promote neural repair or cause “improvement” as an outcome. There is no one best choice for treatment. Higher dose interferons tend to cause neutralizing antibodies in one-third of cases that may not interfere with the efficacy of these medicines.

 Fox RJ, Bethoux F, Goldman MD, et al. Advances in understanding, diagnosing and treating the underlying disease. Cleve Clin J Med. 2006; 73:91–102.

25. d, 26. e, 27. b

Natalizumab is a humanized monoclonal antibody against the cellular adhesion molecule α4-integrin. It binds to lymphocytes and prevents adherence at the endothelial surface of blood vessels in the brain and gut. It therefore reduces the entry of immunologically active cells into the CNS compartment. Trials have shown a 60% to 70% reduction in exacerbation rate, reduced activity on MRI, and slowed progression with the use of this medicine in relapsing forms of multiple sclerosis. In the United States, it is indicated for relapsing forms of multiple sclerosis usually when patients have failed other forms of disease-modifying therapy. Use of natalizumab requires an FDA-approved monitoring program.

There is an approximately 1 in 1000 risk of developing progressive multifocal leukoencephalopathy (PML) in patients on natalizumab. The risk appears to be higher with prior or additional immunosuppressing medicines and after 2 years of continuous use. There are no comparative studies of natalizumab and mitoxantrone in multiple sclerosis. Mitoxantrone has been associated with treatment-related acute leukemia and dose-dependent cardiomyopathy.

Anaphylaxis occurs in about 1 in 50 patients often by the second to fourth dose of natalizumab. Symptoms include shortness of breath, wheezing, hypotension, rash, and tachycardia. The infusion should be stopped immediately if this occurs and procedures for anaphylaxis instituted. This is an absolute contraindication to restarting natalizumab. There is no desensitization procedure, nor should the medicine be retried with premedication or at a lower dose. This is not related to immunoglobulin A deficiency. PML occurs in about 1 in 1000 patients treated with natalizumab. Symptoms include aphasia, visual field deficits, headache, hemiparesis, and cognitive dysfunction progressing over weeks. Patients develop focal subcortical lesions in multiple brain areas that can at times be difficult to discriminate from multiple sclerosis lesions. CSF may be positive for JC virus PCR. JC virus is the causative agent for PML. Treatment for PML in this population includes stopping natalizumab and beginning plasmapheresis to clear residual natalizumab more rapidly from the system.

 Carson KR, Focosi D, O’Major E, et al. Monoclonal antibody-associated progressive multifocal leukoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab. Lancet Oncol. 2009; 10:816–824.

 Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006; 354:899–910.

28. d

Spasticity is defined as a velocity-dependent increase in stretch reflexes. There are both tonic (stiffening in place) and phasic (movement of a limb with spasm) spasms. Spasticity can occur with or without concurrent weakness. It indicates disinhibition of the upper motor neuron pathway.

Both baclofen and tizanidine are indicated for multiple sclerosis-related spasticity. They have similar efficacy. Side effects of baclofen include fatigue, dizziness, and dose-related leg weakness at higher doses. Sudden cessation of baclofen may cause withdrawal seizures. Side effects of tizanidine include light-headedness and hypotension, fatigue, and rarely liver function changes. There is no evidence that exercise “takes away” spasticity. Judicious stretching and a regular exercise program both are part of spasticity management. For patients in whom medications are ineffective or cause too many side effects, selective botulinum injections may improve symptoms. For some patients, implantation of a subcutaneous pump that delivers baclofen at the spinal cord level through a catheter may be beneficial.

 Goldman MD, Cohen JA, Fox RJ, et al. Multiple sclerosis: Treating symptoms, and other general medical issues. Cleve Clin J Med. 2006; 73(2):177–186.

29. b

Figure 7.8 demonstrates an extensive lesion in the cervical spinal cord consistent with transverse myelitis. Transverse myelitis is a term used for patients with a subacute onset of myelopathy, which appears to be on an immunologic basis. It may occur after a viral illness, Mycoplasma infection, or vaccination, but is often not preceded by an illness. Symptoms include paresthesias and sensory deficit often ascending to a specific level, weakness, back pain, and bowel and bladder dysfunction.

Ascending myelitis does not exist. Myelitis can occur in systemic lupus erythematosus but is usually acute and in the setting of active lupus symptomatology. This would be in the differential diagnosis of this condition along with other inflammatory disorders of the spinal cord or a lesion impinging on or compressing the spinal cord. Vascular disorders of the spinal cord are usually acute in onset. Guillain-Barre syndrome is a lower motor neuron disorder and toes would not be upgoing. It rarely causes a sensory level and does not cause a longitudinally extensive lesion, such as shown in the figure.

 Kerr D, Ayetey H. Immunopathogenesis of acute transverse myelitis. Curr Opin Neurol. 2002; 15:339–347.

30. d

Fingolimod is an orally active modulator of four of the five sphingosine-1 phosphate (S1P1) receptors. It acts as a superagonist at the S1P1 receptor on thymocytes and lymphocytes. It induces an uncoupling and internalization of that receptor. This makes these cells unresponsive to such signaling. They therefore lack the signal necessary for egress from the lymph nodes and secondary lymphoid tissues. In clinical trials it reduces relapses of multiple sclerosis in patients with relapsing-remitting multiple sclerosis (RRMS), as well as reduces MRI measures of clinical activity. In addition, there appear to be direct effects on neurons and glial cells, which also express S1P1receptors. It is unclear if this effect is active in vivo, but may indicate some potential for neuroprotection.

 Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010; 362:387–401.

31. d

Dalfampridine was FDA approved as an oral medication to improve walking in patients with multiple sclerosis. Dalfampridine is a symptomatic therapy, and can be used in combination with disease-modifying agents. It is an extended-release form of 4-aminopyridine (previously known as fampridine). Dalfampridine is a broad-spectrum inhibitor of voltage-sensitive potassium channels. In laboratory studies, dalfampridine has been found to improve impulse conduction in demyelinated nerve fibers and to increase synaptic transmitter release at nerve endings. Dalfampridine is administered as a 10-mg timed-release pill every 12 hours. In two phase III trials in patients with multiple sclerosis randomized to dalfampridine versus placebo, a significantly greater percentage of patients were “responders” on dalfampridine than on placebo. A responder was defined as a patient who showed faster walking speed while on therapy than while not on therapy. About one-third patients responded to dalfampridine in these studies. The increased response rate in the dalfampridine group was observed across all four major types of multiple sclerosis (relapsing-remitting, secondary progressive, progressive relapsing, and primary progressive).

 Goodman AD, Brown TR, Krupp LB, et al. Sustained-release oral fampridine in multiple sclerosis: A randomized, double-blind, controlled trial. Lancet. 2009; 373:732–738.

32. b

Cladribine is a purine nucleoside analogue that interferes with the behavior and proliferation of certain WBCs, particularly lymphocytes, which are involved in the pathological process of multiple sclerosis. In phase III trials, oral cladribine reduced measures of multiple sclerosis disease activity, such as relapse rate and new lesion formation on MRI. Major adverse events in phase III trials included lymphocytopenia and herpes zoster.

 Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010; 362:416–426.

33. b

It is not a definite causation that low vitamin D is the reason why multiple sclerosis is more common further from the equator. Although vitamin D levels may be lower further from the equator, the exact relationship between vitamin D levels and multiple sclerosis is not yet known. There are a number of interesting epidemiologic observations that suggest there may be a link, but no definite causative association has been proven. Low vitamin D levels are more common further away from the equator, as is the prevalence and incidence of multiple sclerosis. In a large nursing health cohort study, multiple sclerosis was less common in nurses who took vitamin D supplements. African-Americans with multiple sclerosis have both lower vitamin D levels than Caucasians and a more severe clinical course. There is no well-defined dose of vitamin D for multiple sclerosis at present. Some trials are under way to further understand this link.

 Smoldersa J, Damoiseauxb J, Menheerec P, et al. Vitamin D as an immune modulator in multiple sclerosis, a review. J Neuroimmunol. 2008; 194:7–17.