PBL 5: MS

• The goal is to utilize knowledge of normal body structure and function to investigate a case of a young woman presenting with vision deficits.

Case Resolution and Review

• The diagnosis is multiple sclerosis (MS), a disease attacking and destroying CNS myelin around axons, producing sensory and motor signs and symptoms.
• MS is relatively rare, affecting 300 cases per 100,000 in the US, but it is the most common progressive neurological disease in young adults worldwide.
• Ms. Thompson initially presents with vision loss in her left eye.
• Ophthalmologist consultation is likely needed for further testing.
• Pupillary constriction testing can be performed during the initial office visit with a penlight, eye chart exam, and eye movement tests.
• A thorough examination of the retina and optic disk is best done with a dilated pupil using a short-acting antimuscarinic agent like tropicamide.
• A normal funduscopic appearance suggests the problem lies within the optic nerve pathway leading to the brain, not the eye itself.
• An important finding is the afferent pupillary defect (APD), consistent with unilateral optic nerve damage.
• Light shone in the left eye should cause pupillary constriction in both eyes.
• Patients with APD may have sluggish pupillary constriction or no response in the affected eye when light is shone but normal constriction in both pupils when light is shone in the right eye.
• Optic neuritis alone can cause a unilateral central scotoma (visual deficit), APD, and loss of color vision, though loss of color vision in MS can occur without optic nerve damage.
• The patient's visual deficits are significant but not enough to narrow down the diagnosis to MS.
• Mild sensorimotor symptoms and detailed history taking also point to MS.
• Sudden weakness during a hot shower that led to a fall a few months ago indicates Uthoff's phenomenon, characterized by weakness upon exposure to warm temperatures.
• The underlying cause of heat sensitivity in MS is hypothesized to be temperature-induced conduction blockage at demyelinated sites (plaques) along axons.
• Being a smoker increases the risk for MS.
• Epstein Barr virus (EBV) is transmitted by saliva and sexual fluids, and most MS patients are sero-positive for EBV, increasing their risk.
• Regular exercise ameliorates MS symptoms, but not progression.
• Stress is a risk factor for MS development, which is a concern due to the patient's stressful graduate work and career worries.
• People of Northern European descent and those living at higher latitudes have a greater risk for MS, possibly due to lower vitamin D levels and less UV light exposure.
• Family history showing second-degree relatives with autoimmune diseases also indicate susceptibility alleles in MS.
• MS-prone families may have psoriasis, autoimmune thyroiditis, rheumatoid arthritis, and inflammatory bowel disease history.
• MS was previously diagnosed based on occurrences that lasted more than 24 hours and aren't associated with fever or infection.
• There is no definitive blood test for MS, but tests can rule out other diseases that produce similar symptoms.

Diagnostic Tests for MS:

• Includes magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, and visual evoked potentials (VEP).
• MRI can detect damaged myelinated pathways.
• CSF analysis shows a CNS inflammatory response by the presence of oligoclonal bands in cerebrospinal fluid.
• MRI and CSF results together can prove definitive.
• VEP tests can objectively measure damage to brain pathways if MRI findings are unclear.
• MRI is sensitive for detecting white matter lesions, aiding in earlier MS detection.
• Active lesions show gadolinium (GD) enhancement because GD can cross the blood-brain barrier at sites of leakage, while inactive lesions do not show GD enhancement.
• Three imaging signatures of MS include:
  • Inflammatory response affecting the left optic nerve in the orbit scan.
  • Dawson's fingers in the subcortical white matter, observed horizontally.
  • Focal area of enhancement in the cervical spinal cord (inflammatory response), in peripheral regions of the cord, where white matter tracts are located.
• A lumbar puncture (spinal tap) obtains a CSF sample to examine for CNS inflammation compared to the blood.
• Oligoclonal bands in the IgG sector of the protein isoelectric focusing pattern are detected in over 90% of MS patients but in fewer than 5% of controls.
• It is not detected in blood sample.
• The majority (85%) present with a clinically isolated syndrome with loss of neurologic function gradually worsening over a week that then stabilizes.
• Relapses can last weeks, followed by recovery of varying extent and duration, with periods of disease quiescence lasting months or years.
• This is termed relapsing-remitting multiple sclerosis (RRMS).
• A trigger for MS relapse is an upper respiratory viral illness.
• Symptoms vary as myelin loss accumulates in the CNS white matter (plaques).
• Secondary progressive MS (SPMS): relapses diminish and steadily worsen nervous system impairment.
• Secondary progressive MS (SPMS) represents 15% of cases.
• Primary progressive MS (PPMS) occurs from symptom inception (less common).

Additional Symptoms and Deficits in MS:

• Internuclear ophthalmoplegia (paralysis of adduction on lateral gaze with nystagmus in the abducting eye).
• Dysfunction of the central vestibular and cerebellar pathways (vertigo, poor balance, intention tremor, dysarthria, ataxia).
• Facial pain mimicking trigeminal neuralgia and facial weakness resembling Bell's palsy.
• Demyelination of ascending somatosensory tracts (diminished/ abnormal sensations).
• Lhermitte sign (electric shock-like sensations down the back/arms after neck flexion).
• Demyelination of the descending corticospinal pathway (muscle fatigue, stiffness, spasticity, weakness).
• Hyperreflexia, clonus, and the Babinski sign.
• Urinary frequency/urgency indicate a hyper-reflexive neurogenic bladder.
• Constipation and sexual dysfunction.
• Intense fatigability.
• Depression: found in half of MS patients.
• Short-term memory deficits can progress to cognitive decline.
• MS is thought to be an autoimmune disease.
• There is a possible genetic association with the class II major histocompatibility complex (MHC) allele.
• HLA-DRs present antigenic peptides to CD4+ T cells (a major disease-promoting role for CD4+ T cells).
• Antigens made by B cells that resemble a protein made in the CNS have been identified.
• Interferon gamma activates macrophages, which target myelinated segments of axons to produce plaque areas of damage.
• EBV infection stimulates a pathway for autoimmune targeting of cells.
• MS attacks can be acutely treated with intravenous (IV) glucocorticoids (methylprednisolone) for 3-5 days.
• Steroid treatment accelerates recovery from an MS attack (relapse) by reducing inflammation but does not improve accumulating disability.
• Long-term steroid treatment has been proposed to worsen MS.
• Long-term medications modify the disease course, suppress relapses, and manage symptoms.
• Examples of medications used include interferon-β formulations and monoclonal antibody therapies.
• Patients can maintain a high quality of life with appropriate treatment and therapy.
• Life expectancy is close-to-normal and patients can maintain their occupation.
• MS patients can have children, but certain medications may need to be adjusted.