Multiple Sclerosis and Other Myelopathies Flashcards
Natalizumab
Anti-α4 integrin subunit. Prevents T cell recruitment to regional lymph nodes.
Progressive multifocal leukoencephalopathy is a common consequence of use. PML is an opportunistic CNS viral infection caused by the John Cunningham Virus. The risk of developing PML with natalizumab treatment is related to three factors:
- Whether the patient has antibodies to the JC virus
- Whether the patient has received prior immunosuppressive therapy
- Length of treatment with natalizumab beyond 2 years
anti-JC antibody screening required. In patients who are not found to have JC virus antibodies, the risk of developing PML is exceedingly low. Given these risks, JC virus antibody–negative patients on natalizumab therapy must be screened for JC virus antibody every 6 months to evaluate for seroconversion
Fingolimod
S1P receptor agonist. Oral therapy for MS.
Downregulates S1P receptor within the lymphatic system, preventing T cells from following the chemotactic gradient and egressing. In effect, fingolimod decreases the cycle frequency of T cells and increases the lymphatic T cell storage at any given moment.
Bradycardia and macular edema are sometimes seen. Baseline electrocardiogram (ECG) and cardiac monitoring are required with the first dose. Baseline ophthalmologic examination and subsequent periodic ophthalmologic monitoring are also necessary.
John Cunningham virus
One of the two major polyomaviruses.
Causes progressive multifocal leukoencephalopathy. In this disease, patients develop CNS white matter damage. May cause memory loss, poor speech, and impaired coordination.
Uthoff’s phenomenon
Recurrence or emergence of neurologic symptoms with heat (due to environmental temperature in the summer, hot bath, or exercise).
This occurs with any demyelinating disease/myelitis. This is why MS tends to flare in the early summer.
L’hermitte’s sign
Electrical sensation down the spine with forward flexion of the neck.
This can occur in any type of cervical myelopathy and is not specific to MS
Internuclear ophthalmoplegia
Due to disruption of the medial longitudinal fasciculus (MLF)
Afferent pupillary defect
Due to prior optic neuritis.
An afferent pupillary defect may be present even in patients who have not had a clear clinical episode of optic neuritis
When you swing the light, if both pathways are intact, pupillary size should not change. If one pathway is relatively defective, both pupils will dilate when the ipsilatreal eye is illuminated.
Neuroimaging of MS
- Key diagnostic test for MS is MRI
- Classic radiologic features of MS are small, ovoid T2/FLAIR hyperintensities that are perpendicularly oriented to the lateral ventricles and corpus callosum.
- Acute lesions may demonstrate enhancement with gadolinium, often in an open ring (as compared to the complete ring of contrast enhancement seen with tumor and abscess)
- The damage caused by lesions over time can lead to T1 hypointensities at sites of prior demyelination (T1 black holes).
Visual Evoked Potentials
- Examine a particular EEG of visual stimulation (P100) to evaluate conduction along the visual pathway.
- If the latency of P100 between the two eyes is significantly different, this suggests slowed conduction in one optic nerve, a sign of optic nerve dysfunction
- In cases of possible MS, abnormal VEPs can suggest prior optic neuritis.
- The optic nerve can also be examined by optical CT to look for prior damage to the nerve.
Pupillary reflex pathway
In order to diagnose MS, you need . . .
. . . multiple lesions that are separated by BOTH time AND space
In other words, many different lesions all at once is NOT MS, and repeated episodes of unifocal myelitis at one spot is NOT MS.
Optic neuritis
- Painful loss of visual acuity in one eye
- Common presenting symptom of MS, but may be due to a number of different myelopathies
- Features:
- Loss of visual acuity
- Red desaturation
- RAPD
- Optic disc pallor or atrophy on exam
- Pulling or tugging pain with EOMI
Transverse myelitis
- Inflammatory demyelination of the spinal cord
- Reflexes may be exaggerated below the level of the lesion
- Babinski signs may be present
- Patients may report a “band of tingling or pain” around the torso at the level of the lesion
Internuclear ophthalmoplegia
Five major features that suggest MS
- Optic neuritis
- Transverse myelitis
- Internuclear ophthalmoplegia
- Lhermitte’s sign
- Uhthoff’s phenomenon
Four different phenotypes of multiple sclerosis natural history
- Relapsing-remitting (no baseline symptoms between episodes)
- Progressive relapsing MS (starts as progressive symptoms, then with superimposed relapsing MS. Never remitting)
- Secondary progressive phase (starts as relapsing remitting, then progresses with or without further superimposed relapses)
- Primary progressive multiple sclerosis (no episodic exacerbations, just baseline change)
LP for MS diangosis
Oligoclonal bands are the classic finding
Reflect the intrahectal production of IgG by plasma cell clones within the CNS
Nonspecific and can be seen in CNS infections and other CNS inflammatory conditions
Fingolimod
Mixed agonist-antagonist of the S1P Receptor
Downregulates S1P receptor within the lymphatic system, preventing T cells from following the chemotactic gradient and egressing. In effect, fingolimod decreases the cycle frequency of T cells and increases the lymphatic T cell storage at any given moment.
Bradycardia and macular edema are sometimes seen. Baseline electrocardiogram (ECG) and cardiac monitoring are required with the first dose. Baseline ophthalmologic examination and subsequent periodic ophthalmologic monitoring are also necessary.
Alemtuzumab
- Anti-CD52 monoclonal antibody
- Indicated for patients with relapsing forms of MS who have failed at least two other MS medications
- Both T cells and B cells express CD52, however CD34+ HSCs do not
Ocrelizumab
A different anti-CD20 monoclonal antibody
Indicated for relapsing-remitting and primary progressive MS
Contraindicated in patients with active hepatitis B
Acute disseminated encephalomyelitis
- Monophasic myelopathy leading to large areas of demyelination within the CNS
- Commonly follows an immune response (viral infection, vaccination)
- Presentation is similar to MS, but lesions are NOT distributed in time
- Features that may be seen in ADEM:
- MS phenomena, behavioral and cognitive abnormalities, seizures
- Dx: Suspected based on clinical presentation and radiologic findings. LP shows lymphocytic pleocytosis and elevated protein
Facial myokymia
- Rare form of involuntary movement affecting the facial muscles
- Clinically defined as continuous twitching of small bands or strips of muscles that give an undulating or rippling appearance to overlying skin
- Descriptively called as `bag of worms’ appearance.
- May be a presenting symptom of MS
- https://www.youtube.com/watch?v=KaM3-qy8uqU
Trigeminal neuralgia in MS
Very brief, but severe, lancinating maxillary or mandibular pain
Occurs in 1% of MS patients
May have multiple etiologies, but when this occurs in a young patient MS should be high on the differential
Charcot’s triad
- Well-recognized syndrome of MS, but occurs rarely
- Triad of:
- Intention tremor
- Dysarthria
- Nystagmus
Bladder symptoms in MS
- Very common in MS patients
- Most often involves overactive bladder
- However, underactive bladder may also occur, and spinal cord lesions may also cause acute urinary retention
Patients with MS have a high incidence of ___
Patients with MS have a high incidence of migraine headache
Oligoclonal bands may be seen in. . .
- MS
- SLE
- Neurosarcoidosis
- Subacute sclerosing panencephalitis (SSPE)
- Subarachnoid hemorrhage
- Syphilis
- CNS lymphoma
CSF WBC count suggestive of MS
4-50 WBC
4-10 is the typical range
Anything more than 50 and you have something more inflammatory than MS
Studies to rule out MS mimics
- Laboratory studies
- B12 level
- Serologies
- Lyme
- Syphilis
- Antiphospholipid antibodies
- Inflammatory markes
- ESR
- CRP
- ANA
“Clinically isolated syndrome”
First demyelinating event that is suggestive of MS, but diagnosis of MS cannot be made due to lack of evidence of events separated by time and space
Most often in the setting of INO, 6th nerve palsy, cerebellar symptoms, partial transverse myelitis, or optic neuritis
“Radiologically isolated syndrome”
Also called “preclinical MS”
Radiologic evidence of demyelinating disease is seen on imaging, but the patient reports no associated clinical symptoms
One in three of these patients will experience an attack leading to a diagnosis of MS within 5 years.
Treatment of MS
- Acute management:
- IV seteroids for 5 days
- Not disease modifying, but hastens time to recovery from a flare
- Maintenance therapy:
- Should be started as soon as the diagnosis of MS is made, since future events in MS can lead to permanent neurologic damage
- Fingolimod (oral)
- Teriflunomide (oral)
- Dimethyl fumarate (oral)
- Glatiramer acetate
- Natalizumab (JCV titer)
- Ocrelizumab (PPMS drug of choice)
- Mixoxantrone (second-line due to cardiotoxicity)
- Alemtuzumab (must have failed two other agents)
- Interferon (not used anymore)
Teriflunomide
- Oral therapy for MS
- Pyrimidine synthesis inhibitor, decreases T and B cell proliferation
- Pregnancy class X AND men must use birth control as well as levels may be detected in the semen
Dimethyl fumarate
- Oral therapy for MS, but twice-daily
- Promotes anti-inflammatory and cytoprotective activity by activating the Nrf2 antioxidant response pathway
- Frequently associated with flushing and GI upset
Only medication shown to be disease-modifying in patients with primary progressive MS
Ocrelizumab
an anti-CD20 monoclonal antibody
Treating spasticity in MS
Baclofen, tizanidine
Both muscle relaxants
Therapy for fatigue in MS
Amantadine (pro-dopaminergic, also Influenza A antiviral)
Modafinil (amphetamine stimulant, also used for narcolepsy)
Dalfampridine (K channel blocker, enhances conduction in damanged nerves)
Dalfampridine
K channel blocker
Enhances conduction in damaged nerves
May be useful for some patients with MS and significant atrophy. Can improve walking and fatigue in patients experiencing these symptoms.
Neurodegeneration in MS
Seen in the progressive forms of MS. When progressive patients have new symptoms, MRI usually will not show any abnormality other than atrophy.
This is because there is not a strong active inflammatory response. Rather, neurodegeneration is driving these symptoms.
Glatiramer acetate
Polypeptide formulation injected subcutaneously in progressive and relapsing-remitting MS
It is a structural mimic of myelin basic protein that is given in a ‘desensitization’ fashion in order to skew the Th response away from a Th1 phenotype and towards a Th2 and Treg phenotype.
In ADEM as opposed to MS, lesions are typically. . .
. . . multiple, more patchy, bilateral, and confluent
Neuromyelitis optica
- Characterized by the development of transverse myelitis and optic neuritis
- These may develop simultaneously or separately
- Demyelination in the brain should be absent or minor
- In comparison to MS:
- Pain is a more prominent feature
- Focal deficits tend to be more severe
- CSF pleocytosis (sometimes neutrophilic) is seen with greater frequency
- Diagnosis: Presence of anti-AQP4 antibodies (aka NMO Ab) OR of anti-myelin oligodendrocyte glycoprotein (anti-MOG) Abs.
- Treatment:
- Acute: IV steroids, sometimes plasmapheresis
- Maintenance: Azathioprine, mycophenolate mofetil, rituximab
Progressive Multifocal Leukoencephalopathy
- Characterized by dementia, focal cortical dysfunction, severe cerebellar abnormalities
- Seen in a very select group of patients: AIDS+, leukemic, lymphomic, the otherwise severely immunocompromised, and those on natalizumab therapy
- John Cunningham virus is the causative agent
- Pathology: Demyelination due to infection of oligodrndrocytes
- Diagnosis:
- MRI shows multiple foci of white matter abnormalities, especially in the posterior regions of the brain.
- CSF analysis is usually normal
- Treatment:
- There is no treatment other than supportive care
Posterior reversible encephalopathy syndrome (PRES)
- Leukoencephalopathy that develops in the context of rapidly developing hypertension, eclampsia, or due to calcineurin inhibitors
- Tacrolimus, cyclosporine A
- Characterized by acute confusional state and cortical visual loss (blindness with preserved pupillary reflexes)
- Diagnosis: MRI showing posterior white matter hyperintensities
- Treatment: May be reversible by treating the underlying condition, but not always. Calcium channel blockers may be effective.
Adrenoleukodystrophy
- Presentation: Addison’s disease plus diffuse myelopathy in a young child
- X-linked mutation in ABCD1, which codes for a peroxisomal ATP-binding cassette transporter protein
