Exploring Treatment Options
and Indiviualizing Therapy in
MS
Rex Hobbs, MPAS, PA-C
Definition
A chronic degenerative disease of the central nervous system in which gradual destruction of myelin occurs in patches throughout the brain and/or spinal cord, interfering with the nerve pathways and causing muscular weakness, loss of coordination, and speech and visual disturbances. It occurs chiefly in young adults and is thought to be caused by a defect in the immune system that may be of genetic or viral origin.
-The American Heritage® Stedman’s Medical Dictionary, 2002.
Basic stats
~350,000 Americans, 2.5 million worldwide.
3:1 Female:male predominance.
Age of onset typically between 20-40 years of age. (range of early childhood to 8thdecade of life)
Higher socioeconomic status.
Highest incidence in Northern European lineage. Lowest in those of Asian, Middle Eastern and African descent.
Hauser S, Goodin D. Multiple sclerosis and other demyelinating diseases. In: Fauci A, Braunwald E, Kasper D, Hauser S, Longo D, Jameson J, Loscalzo J, ed. Harrison’s Principles of Internal Medicine, 17th ed. The
Geography & Vitamin D
The latitude gradient of MS incidence is, in part,believed to be due to lapses in adequate Vit. D production secondary to decreased UV exposure during the winter months.
Acute exacerbations of MS have also been found to occur during periods of low serum Vit. D.
Dietary intake/supplementation have been shown to lessen the risk of MS and reduce the frequency and severity of acute exacerbations.
Munger K, Zhang S, O’Reilly E, Hernan M, Olek M, Willett W, Ascherio A. Vitamin D and incidence of multiple sclerosis.
Neurology 2004; 62:60-65.
MS Latitude distribution
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Polygenic susceptibility with MHC on chromosome 6 having the strongest connection.
Others include IL-7 receptor alpha chain and IL-2 receptor alpha chain, both cytokines.
The genetics, like the presentation and progression, are very heterogeneous. This complicates the diagnosis and treatment for many patients.
The viral connection
Various viruses have been detected in the CSF and serum MS patients.
The increasing incidence of MS which defies the “equatorial” and pure genetic models.
Axonal damage/loss has been seen to precede myelin degradation.
Christensen T. Human herpesviruses in multiple sclerosis. The International MS Journal 2007; 14:41-47.
The viral connection
Human Herpes virus Family
Alpha Herpes viruses HSV-1 (70%) HSV-2 (0%) VZV (>99%) Beta Herpes viruses CMV (50%) HHV-6 (>90%) HHV-7 (0%) Gamma Herpes viruses EBV (>99%) HHV-8 (0%)Christensen T. Human herpesviruses in multiple sclerosis. The International MS Journal 2007; 14:41-47.
Etiology
Genetic predilection Environmental (infectious, etc.)Autoimmune
response to
multiple
CNS
components
Immune response: very briefly
Ag (antigen) is generally a virus,
bacteria, etc. In MS, myelin basic protein (MBP) and other CNS components become the Ag.
After an Ag is “processed” by the
APC, T-helper cells (Th) initiate
B-cells to produce antibodies against the Ag as well as causing the release of cytokines and interleukins.
As with any immune response, T-suppressor cells and other factors reduce the immune response when the Ag is no longer present. In MS, the response waxes and wanes since the Ag, MBP, is still present
Autoimmune Cascade DNA/Mitochondrial damage Decreased ATP production Decreased clearance of intra-cellular potassium causing axon/neuron destruction Proliferation of microglia and astrocytes resulting in gliosis Decreased active transport Decreased neurotransmitter production Demyelination Sodium channel diffusion along axon
Disrupted blood-brain barrier
Increased extrinsic
immune migration immune proliferationIncreased intrinsic
Decreased, effective interneuron communication and progressive CNS
volume loss
Stadelmann C, Albert M, Wegner C, Bruck W. Cortical pathology in multiple sclerosis. Current Opinion in Neurology 2008; 21:229-234. Rieckmann P. Neurodegeneration and clinical relevance for early treatment in multiple sclerosis. The International MS Journal 2005; 12:42-51.
Duddy M, Bar-Or A. B-cells in multiple sclerosis. The International MS Journal 2006; 13:84-90.
Pathophysiology
Key points
Early onset axonal damage/loss
Grey matter involvement is prevalent and difficult to detect by current MRI (<3T).
Autoimmune cascade is comprehensive (macrophages, T & B cells, antibodies, complement, various cytokines) but not always homogeneous.
Inflammation results in gliosis and neuronal dysfunction & destruction.
Progressive loss of CNS volume even during symptom free
phases
Acute Presentation
Onset may be abrupt and severe or so insidious and mild that patients feel they are of no concern.
MRI findings may be seen incidentally even when symptoms are not currently present.
Symptoms will vary pending lesion location, number and volume. History may include recurrent bouts of completely or partially resolved
neurologic symptoms (visual deficits, vertigo, fatigue, etc.).
Presentation: initial
Symptom Percent of cases
Sensory loss 37 Optic neuritis 36 Weakness 35 Paresthesias 24 Diplopia 15 Ataxia 11 Vertigo 6 Bladder incontinence 4 Lhermitte 3 Pain syndrome 3 Dementia 2
Hauser S, Goodin D. Multiple sclerosis and other demyelinating diseases. In: Fauci A, Braunwald E, Kasper D, Hauser S, Longo D, Jameson J, Loscalzo J, ed. Harrison’s Principles of Internal Medicine, 17thed. The McGraw-Hill Co. Inc.; 2008:2611-2621.
What is an attack (clinical event)?
Neurological disturbance typical of MSSubjective or objective observation
Must be of a 24 hour minimum duration
Dissemination of attacks: at least 30 days separating event 1 from event 2 (or 3 from 4, etc.).
Progressive Presentation
Increased incidence of spasticity,diplopia, sensory symptoms and pain syndromes, bladder dysfunction, constipation, fatigue and ataxia.
Symptoms typically worsened transiently with heat exposure (Uhthoff’s symptom).
Lhermitte’s symptom: cervical pain radiating into the legs with neck flexion, indicates cord involvement.
Depression is extremely common
Cognitive dysfunction
Relapsing/remitting MS
Makes up ~90% of cases initially. Defined by attacks evolving over days to weeks and resolving completely/near completely over weeks to months.
Patients are neurologically stable (not worsening) between attacks.
Diagnosis
Multiple sclerosis
No other diagnosis more likely Dissemination of events over space and time Two clinical events involving the CNS MRI Criteria?Primary progressive MS
Makes up ~10% of cases. Not typified by “attacks” but experience a steady decline in function and symptom progression.
Most common to occur in those with onset over 40 years; has equal M:F distribution.
Most treatments have been studied in patients with an RRMS course.
Acute Attack Treatment
Goal:Limit the severity of neurologic deficits/symptoms
Maximize the speed and level of recovery to normal function
Steroids:
Methylprednisolone 1000mg daily for 5 days without oral taper Bioavailability of oral prednisone 1250mg is equivalent to
methylprednisolone 1000mg but lacks the initial peak concentration Plasma Exchange:
Reserved for those with incomplete response to steroid therapy Not as effective as steroid therapy due to the lack of homogeneity of
MS lesions and the causative immune cascade
Chronic MS management
Goals:
Reduce the frequency and intensity of acute attacks
Reduce the overall immune-mediated inflammatory process thereby reducing long term brain atrophy and sclerosis
Disease Modifying Drugs (DMD)
Interferon beta-1a (Avonex, Rebif, Plegridy)
A cytokine that modulates antigen processing, reduces BBB permeability and down-regulates the inflammatory response.
Only available in injectable forms.
Should be initiated as early in the course of the disease as possible.
Only studied in those patients with RRMS
All versions prone to the formation of neutralizing antibodies
DeAngelis T, Lubin F. Multiple sclerosis: new treatment trials and emerging therapeutic targets. Current Opinion in Neurology 2008; 21:261-271.
Disease Modifying Drugs (DMD)
Glatiramer:
Amino acid polymer mixture that is antigenically similar to MBP
Results in immunomodulation and induces T-helper suppressor cells
Subcutaneous injection only
Neutralizing antibodies do form but may not be impactful on overall function
Similar impact on treatment goals as the interferons but with a greater incidence of site reactions
Disease Modifying Drugs (DMD)
Fingolimod:
Alters lymphocyte migration resulting in lymph node sequestration.
Available in an oral form
Lessens MS disability progression and relapse rates; TRANSFORMS trial showed slight but significant superiority to the interferons
Serious adverse events are higher with this drug than with interferons: disseminated zoster infections, skin and breast cancer and bradycardia/AV Block
Disease Modifying Drugs (DMD)
Dimethyl fumarate:
An immunomodulatory drug with neuroprotective properties
Similar efficacy as Glatiramer
Available in an oral form
Flushing and GI symptoms are common
Monitor for lymphocytopenia with regular CBCs
Disease Modifying Drugs (DMD)
Teriflunomide:
Inhibits pyrimidine biosynthesis; disrupts T-cell interaction with antigen presenting cells (APC)
Nausea, diarrhea, hair loss can occur as well as elevated LFTs (monitor closely)
Cat. X, pregnancy screening done regularly; also found in semen
Those interested in pregnancy should have rapid
drug elimination with cholestyramine otherwise the drug can stay in the serum for up to 2 years
Disease Modifying Drugs (DMD)
Novantrone
Can be used for RRMS and PPMS
Has limited disease goal benefits, especially for those over age 50 and with substantial disability
Significant risk for cardiotoxicity ( CHF) and low, but significant, risk for acute leukemia relegate this therapy to refractory cases only
Disease Modifying Drugs (DMD)
Natalizumab
Associated (rarely) with progressive multifocal leukoencephalopathy (PML)
Only used for those who are resistant or refractory to other DMDs
Disease Modifying Drugs (DMD)
Others:
Azathioprine Cladribine Cyclophosphamide Daclizumab IVIGDisease Modifying Drugs (DMD)
Brand name Other name
Adverse effects Route Frequency Annual cost
Avonex® IFNB-1a Flu-like sxs, depression, incLFT, leukopenia IM qWk $60,000
Rebif®
Plegridy® IFNB-1a
Flu-like sxs, depression, inc LFT, leukopenia SC
tiw
Q 2 wks
$67,600
~$50,000
Copaxone® Glatirmer Flushing, chest tightness, site reaction SC daily $70,000
Gilenya® Fingolimod
Bradycardia, inc LFT, melanoma, macular
degeneration oral daily $67,000
Aubagio® Teriflunomide Alopecia, diarrhea, inc LFT,
periph neuropathy oral daily $63,000
Tecfidera® FumarateDimethyl Flushing, abd. Pain,
lymphocytopenia, inc LFT oral daily $68,000
Mitoxantrone® Novantrone CHF, leukemia, inc LFT IV q3months $900
Tysabri® Natalizumab
Progressive Multifocal
Spasticity
Baclofen (Lioresal) 10-40mg, tid
Tizanidine (Zanaflex) 2-8mg, bid-tid
Gabapentin (Neurontin) 300-900mg tid-qid
-Higher doses cause fatigue and weakness -Follow LFT’s and monitor for rare cases of leukopenia
Calabresi P. Diagnosis and management of multiple sclerosis. American Family Physician 2004; 70(10):1935-1944.
Fatigue
Drug Dose Max Dose Adverse effects
Amantadine 100mg bid 600mg Restlessness, visual hallucinations, constipation, heart failure, vertigo
Modafinil 100-300mg qd 400mg
Nervousness, insomnia, lowered seizure threshold, nausea, palpitations
Pemoline 20mg bid 60mg Weight loss, tremor, tachycardia, elevated LFT’s, seizures
Acetyl-L-carnitine with Alpha Lipoic acid
400mg bid 2000mg Insomnia, tremor, nausea, palpitations
Depression
SSRI’s at appropriate doses are preferred because of their activating properties.
Venlafaxine (Effexor XR®) is a helpful alternative if sexual side effects make the SSRI’s less favorable.
Group therapy and counseling are also helpful.
Encourage a supervised exercise program.
Plan of action:
Keep MS in the differential for all patients with acute neurologic deficits/alterations.
Refer to MS specialty clinic when possible.
Individualize follow-up plan/schedule with each patient for those with CIS.
If Neurologist consult difficult or months away for a patient with CDMS be aggressive with DMD’s, symptomatic management and rehabilitation and Social Worker consults.