Peripheral neuropathies, neuromuscular junction

disorders, & CNS myelin diseases

Peripheral neuropathies…according to which part affected

Axonal Demyelinating …with axonal sparing

Many times: mixed features (axonal & demyelinating)

Electrophysiologic studies: Decreased signal strength/amplitude of nerve impulses

Electrophysiologic studies: Decreased nerve conduction velocities …preserved amplitude

…insults that directly injure the axon

…the entire portion distal to the transection of an affected

axon degenerates …secondary myelin loss of the distal

portion…this process (experimentally) is called:

Wallerian degeneration

…regeneration of the distal portion will occur but with

thinner myelin and shorter internodes

Peripheral neuropathies…according to anatomical distribution

Polyneuropathies Mononeuritis multiplex

Simple mononeuropathy

*Symmetric *Length-depenent …more pronounced axonal loss in distal segments of longest nerves *Loss of sensation and paresthesias that start in the toes and spread upward …by the time the sensory changes reach the level of the knees, the hands are also affected = “stocking-and-glove” distribution *Some toxic and metabolic conditions

*The damage randomly affects individual nerves *For example: right radial nerve palsy and wrist drop and, at a separate point in time, a left foot drop *Vasculitis

*Only a single nerve *-Traumatic injury -Entrapment (e.g., carpal tunnel syndrome) -Certain infections such as Lyme disease

Peripheral neuropathies …according to etiology

Guillain-Barré Syndrome • One of the most common life-

threatening diseases of the peripheral nervous system

• Rapidly progressive acute

• Demyelinating disorder

• Motor axons

• Ascending weakness

• Can lead to death from failure of respiratory muscles within days of onset of symptoms

*Triggered by an infection or vaccination that breaks down self-tolerance, thereby leading to an autoimmune response *Related infections: Campylobacter jejuni, Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus (HIV), and, most recently Zika virus *Most extensive in the nerve roots and proximal nerve segments *Mononuclear cell infiltrates rich in macrophages *Treatments: -Plasmapheresis (to remove offending antibodies) -Intravenous immunoglobulin infusions (which suppress immune responses through unclear mechanisms) -Supportive care, such as ventilatory support *Patients who survive usually recover with time

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

• The most common chronic acquired inflammatory peripheral neuropathy

• Mixed sensorimotor symmetrical polyneuropathy that persists for 2 months or more

• Immune-mediated

• Increased frequency in patients with other immune disorders and HIV infection

• A chronic, relapsing-remitting, or progressive course

• Treatment includes plasmapheresis and administration of immunosuppressive agents

• Usually: Recurrent bouts of symptomatic disease lead to permanent loss of nerve

function

Diabetic Peripheral Neuropathy • The most common cause of peripheral neuropathy

• Usually developing with long-standing disease

• Several forms of neuropathy that can occur singly or together:

-Autonomic neuropathy: bowel, bladder, cardiac, or sexual function

-Lumbosacral radiculopathy: asymmetric pain that can progress to lower

extremity weakness and muscle atrophy

-Distal symmetric sensorimotor polyneuropathy

…the most common form of diabetic neuropathy

…sensory axons are affected more with predominant symptoms of paresthesias &

numbness

…strict glycemic control is the best form of therapy

DISORDERS OF NEUROMUSCULAR JUNCTION

• Myasthenia Gravis

• Lambert-Eaton Syndrome

• Others…congenital and infections such as C. botulinum & C. tetani

Myasthenia Gravis • Autoimmune

• Autoantibodies that target the neuromuscular junction

• The most common antigenic target is the postsynaptic acetylcholine receptor (AChR)

…other pathogenic antibodies recognize muscle-specific kinase (MuSK) and low-density lipoprotein

receptor-related protein (LRP4)

…these Abs lead to loss of receptors and damage to the structure of the junctions

• Anti-AChR mediated cases have bimodal age distribution:

-Before age 50 years:

…more common in females

…frequently associated with enlargement of the thymus due to the presence of B cell

follicles and germinal centers (follicular thymic hyperplasia)

-Late onset cases:

…more equal gender distribution

…associated with thymoma

Myasthenia Gravis, clinical manifestations • Ptosis (drooping eyelids) or diplopia (double vision) because of weakness in the

extraocular muscles

• Different from most primary myopathic diseases (spared facial and extraocular muscles)

• Severity of the weakness often fluctuates rapidly, sometimes over periods of a few minutes

• Characteristically, repetitive firing of muscles makes the weakness more severe, whereas cholinesterase inhibitors improve strength markedly, features that are are diagnostically useful

• Treatment: cholinesterase inhibitors, immunosuppression, plasmapheresis, and (in patients with thymic lesions) thymectomy. These interventions have improved the 5-year survival rate to greater than 95%.

Lambert-Eaton Syndrome • Autoantibodies that inhibit the function of presynaptic calcium channels, thereby

reducing the release of acetylcholine into the synaptic cleft

• Improvement in weakness with repetitive stimulation, in contrast to those suffering from myasthenia gravis…Why?

• Often arises as a paraneoplastic disorder…particularly which cancer?

• Cholinesterase inhibitors are not effective

• The treatment mainly is: plasmapheresis or immunosuppression.

• The prognosis is worse than that of myasthenia gravis because of the frequent coexistence of an underlying malignancy

CNS myelin diseases

• Acquired demyelinating diseases:

1-Multiple sclerosis (MS)…immune-mediated

2-Infection…PML (JC papova virus infection)

• Mutations that disrupt the function of proteins required for the formation of normal myelin sheaths

…Leukodystrophy (dysmyelinating diseases)

Multiple sclerosis (MS) • Autoimmune demyelinating disease

• Episodes of disease activity, separated in time, that produce white matter lesions that are separated in space

• It is the most common demyelinating disorder

• 1 per 1000 individuals in the United States and Europe, and its incidence appears to be increasing

• May present at any age, but onset in childhood or after 50 years of age is rare

• Women are affected twice as often as men

• Immune reaction against myelin sheath components

• Multifactorial, genetic & environmental

• HLA-DRB1*1501 allele & IL-2 and IL-7 receptor gene mutations

Mainly Th1 & Th17 actions …also some CD8 & B cells & antibodies role

MS, morphology

MS, clinical features • Variable course

• Usually: multiple relapses followed by episodes of remission

• Many of the initial symptoms are partially reversible within a few months.

…but typically, recovery during remissions is

not complete

• There is usually a gradual, often stepwise, accumulation of neurologic deficits

• Serial MRI studies show ongoing disease activity despite apparent clinical quiescence

• Treatments aim at decreasing the rate and severity of relapses rather than recovering lost function

• Blurred vision or the loss of vision in one eye as a result of optic neuritis is often the presenting complaint

• When the initial lesion is in the brainstem, double vision and vertigo occur

• Internuclear ophthalmoplegia, caused by disruption of the medial longitudinal fasciculus, strongly suggests demyelinating disease when it occurs in a young person

• Acute demyelination within the spinal cord is called transverse myelitis and produces weakness of one or both legs and sensory symptoms in the form of numbness in the lower extremities.

• Changes in cognitive function can be present, but are often much milder than the other deficits

MS, CSF findings

• Mildly elevated protein level

• Increased proportion of immunoglobulin

• In one-third of cases, there is moderate pleocytosis

• When the immunoglobulin is examined further, oligoclonal bands usually are identified

• The antibodies here can be used as markers of disease activity