Adv Pathophysiology Unit 2: Neuro Page 1 of 8

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1 Adv Pathophysiology Unit 2: Neuro Page 1 of 8 Learning Objectives for this file: 1. Amaurosis fugax presentation & DDX 2. Clinical diagnostics 3. Case study & followup

2 Adv Pathophysiology Unit 2: Neuro Page 2 of 8 CASE STUDY for MODULES 2 & 3: 29-year-old woman with sudden painless loss of vision HISTORY: This 29 y/o WF was admitted to the hospital with sudden amaurosis fugax (painless loss of vision in one eye) No associated symptoms of pain, fatigue, fever, or trauma. She is G2 P2, s/p tubal ligation. Takes no medications, prescribed or OTC. Pertinent history includes "trouble walking" one year ago, which improved spontaneously after 1 week. Other symptoms include a tingling dysesthesia down her back with neck flexion. She is cooperative, but seems to have difficulty verbalizing her history. Her menarche was age 12 yo. Social, Family history: unremarkable. Grew up in northern New York State near Vermont border.

3 Adv Pathophysiology Unit 2: Neuro Page 3 of 8 PE: abnormal neurologic exam suggestive of UMN lesion Alert and oriented white female in mild distress with normal speech pattern, although some hesitancy noted. No light perception in the right eye. EOMI, PERRLA (but sluggish reaction to light), sclera white, conjunctiva clear. No nystagumus. Neurologic exam reveals paraparesis with spasticity and mild sensory loss to light touch and pinprick in lower extremities. DTRs are brisk (3+/4+ bilat UE/LE) with positive Babinski sign. Physical findings = Upper Motor Neuron (UMN) lesions of the CNS & spinal cord. Paresis/paralysis, acute sensory loss, spasticity and abnormal reflexes are seen the CNS is unable to suppress the spinal reflexes, plus sensory pathways are interrupted. Abnormal (Pathologic) Reflexes indicate Upper Motor Neuron (UMN) lesion. Babinski reflex INITIAL BASIC ASSESSMENT: CBC: wnl. Chem-20: wnl Serum IgG: 1020 (normal mg/dl) Serology (serum): negative for Lyme, RA factor, STS, Crypto, and ANA.

4 Adv Pathophysiology Unit 2: Neuro Page 4 of 8 IMAGING DIAGNOSTIC OF CHOICE: Diagnosed on MRI Scan (patchy demyelination of CNS) McDonald Criteria for diagnosis require neuroimaging demonstration of dissemination of lesions in space (DIS) and time (DIT) (Polman, et al, 2011): MRI scan (brain): several areas of increased signal density present in the deep white matter representing demylenated plaques. LUMBAR PUNCTURE & CSF FINDINGS: Lumbar puncture (Cerebrospinal fluid, CSF): normal findings colorless, clear, 0 neut, neg RBC, 70 glucose, albumin 21, neg VDRL. positive findings total WBC 12/uL (0-5), Lymp 12% (0), TP 56 mg/dl (15-45), IgG 6 mg/dl ( ), IgG Index 1.1 ( ), myelin basic protein (MBP) 6 ng/ml (0-4). CSF Electrophoresis: Multiple sclerosis (MS) has elevated CSF IgG, increased IgG index, & oligoclonal bands from increased production of IgG by activated B-lymphocytes (plasma cells). The CSF does show an increase in TP, not due to albumin, therefore due to immunoglobulin. The presence of increased IgG index shows that the IgG is actually being produced inside the CNS (& not diffusing in from the bloodstream). Myelin basic protein (MBP) is elevated in 90% of MS cases during the acute exacerbation (acute plaque evolution) phase. Nonspecific so other causes must be ruled out (e.g. tertiary neurosyphilis, head trauma, leukodystrophies, hypoxia, leukemia, CVA, intrathecal chemotherapy, post-irradiation, Guillain-Barre syndrome).

5 Adv Pathophysiology Unit 2: Neuro Page 5 of 8 HISTOLOGY BRAIN BIOPSY: Brain biopsy: may be done in some severe or recurring patients, several stains are used to determine if plaques are old or evolving. The Luxol fast blue/periodic acid-schiff stain will stain positive for myelin; old plaques are seen to have no myelin left. Another stain, Oil red O, used under polarized light, will stain intact myelin red and will show myelin breakdown products as bi-refringent crystals (often seen within macrophages that are clearing myelin debris). Findings: Active "plaques" in the white matter (myelinated nerve tissue) of the CNS is due to demyelination, with presence of lipid-laden macrophages, inflammatory infiltrates, oligodendrocyte loss, and other reactive changes. The axons themselves are spared. Normal histology of brain with myelinated axons seen. These are white areas surrounding the axons. Glial cells are seen (these manufacture the myelin). Nonmyelinated axons are also seen (box). Histology of multiple sclerosis with mainly demyelinated neurons (these correspond to the plaques which also have inflammatory cells and other reactive changes.

6 Adv Pathophysiology Unit 2: Neuro Page 6 of 8 MULTIPLE SCLEROSIS PATHOPHYSIOLOGY: Progressive degenerative disease due to demyelination in the CNS Symptoms & Epidemiology: o Loss of FOCAL neurologic function o Often presents with amaurosis fugax (sudden painless loss of vision in one eye) o UMN lesion so may have abnormal spinal (primitive) reflexes (e.g. Babinski) and spasticity due to disinhibition of the spinal cord o More incidence at upper latitudes Pathology: o Probable autoimmune attack on myelin thus a demyelinating disease o plaques develop in CNS with presence of lipid-laden macrophages, inflammatory infiltrates, oligodendrocyte loss, and other reactive changes. o The axons themselves are spared o Human genome mapping shown some HLA gene clusters for genetic predisposition (chromosome 1 and the HLA class II region on chromosome 6) these gene regions are also associated with increased incidence of auto-immune disease o A unique immune cell type may be implicated persistence of fetal LTi cells: o Is there a TRIGGER that initiates the pathology? Most cases occur in the upper Northern Hemisphere (cluster of cases increases further north of the equator) but it turns out that persons with this particular genotype live in these northern regions this is currently what is thought to be what explains the geographical clustering rather than an environmental trigger Diagnosis: o Lumbar puncture with CSF showing elevated WBC, protein, IgG, and Myelin Basic Protein (MBP) (elevated in 90% of MS cases during acute plaque evolution) o MRI with increased signal density as evidence of demyelination o Brain biopsy with special staining techniques NIND NIH information page: Sclerosis-Information-Page Course of disease: o Clinical course is unpredictable, usually with exacerbations and remissions over the years. o However, fulminant cases may result in complete ambulatory loss and severe visual/motor/sensory problems that do not remit. o Relapsing-remitting (85-90% of patients): unpredictable attacks (relapses) followed by months/years of remission. Neurologic deficits may resolve or remain permanent after the attack. If deficits always resolve, this is a benign form of MS. o Secondary Progressive: 80% of those with initial relapsing-remitting MS who start to have decline between acute attacks without real remission. Can include cognitive dysfunction. Causes the greatest amount of disability. o Primary progressive (10%): never have remissions. Continue to decline. Often in those who are older when attack first happens o Progressive relapsing: Steady decline from the first, with superimposed attacks. Least common.

7 Adv Pathophysiology Unit 2: Neuro Page 7 of 8 Increased risk further north of the equator, world-wide:

8 Adv Pathophysiology Unit 2: Neuro Page 8 of 8 NATURAL HISTORY OF DISEASE: CASE SUMMARY: Acute amaurosis fugax, plus chronic multiple sensory/motor symptoms present for one year; abnormal neuro exam suggestive UMN lesion Immunological studies positive for increased CSF IgG and increased CSF IgG Index (local IgG production by CNS B-lymphocytes); increased monocytes; increased myelin basic protein. MRI positive for deep white matter lesions consistent with demyelinating disease. MS is the most common demyelinating disease TREATMENT: Acute sytemic corticosteroids palliate symptoms and restore sight (in this case) Chronic prophylactic drug therapy includes specific Interferons. Plasmapheresis removes "abnormal proteins" from the plasma; very erratic and only minimal success rates, and difficult and expensive. Stem cell therapy: