Clinical Approach to Peripheral Neuropathies

Introduction to Peripheral Neuropathies

• James Triplett, a neurologist and neurophysiologist at Concord Hospital, provides an exhaustive overview of the clinical approach to peripheral neuropathies.

• This lecture series is divided into two parts:

  • Part 1 (Current): Defining common presentations, describing types, developing a diagnostic approach, and identifying common causes.

  • Part 2 (Upcoming): Inflammatory neuropathies, specifically focusing on Guillain-Barré Syndrome ($GBS$) and Chronic Inflammatory Demyelinating Polyradiculoneuropathy ($CIDP$).

Prevalence and Etiological Classification

• Peripheral neuropathies represent a common clinical syndrome in the general population.

• Estimated prevalence ranges between $2\%$ and $3\%$.

• The prevalence increases significantly with age, reaching as high as $8\%$ in individuals over the age of $55$.

• Clinical causes of neuropathies are generally categorized into three equal groups:

  • $1/3$ of cases have a identified genetic cause.

  • $1/3$ of cases have an acquired cause identifiable through laboratory evaluation.

  • $1/3$ of cases are idiopathic (no identifiable cause despite evaluation).

• There are over $100$ known distinct causes for peripheral neuropathy, necessitating a structured diagnostic approach.

Four-Step Clinical Approach to Neuropathy

• To manage the complexity of over $100$ potential causes, a four-step framework is utilized to summarize each patient's presentation and refine the differential diagnosis:

  1. Fiber Type Involvement: Identifying whether the neuropathy is sensory, motor, or autonomic, and the size of the fibers affected (small vs. large).

  2. Distribution: Determining the pattern of nerve involvement (e.g., length-dependent, mononeuropathy, plexopathy).

  3. Temporal Evolution: Assessing the speed of development (acute, subacute, or chronic).

  4. Clinical Setting: Evaluating the medical context in which the neuropathy developed.

Classification by Fiber Type and Distribution

• Fiber Types:

  • Small Sensory Fibers: These are unmyelinated fibers responsible for transmitting pain, temperature, and sharp touch sensations.

  • Large Sensory Fibers (Myelinated): These are responsible for vibration sense and joint position sense (proprioception).

  • Motor Fibers: These are myelinated fibers responsible for muscle movement.

  • Autonomic Fibers: These are small unmyelinated fibers that manage involuntary bodily functions.

  • Sensorimotor Neuropathy: A common combination involving both sensory and motor fiber dysfunction.

• Patterns of Distribution:

  • Length-Dependent Neuropathy: The most common form, characterized by symptoms starting distally and moving proximally. Typically, by the time symptoms reach the level of the knees, the hands begin to demonstrate symptoms (the "glove and stocking" distribution).

  • Mononeuropathy: Involvement of a single specific nerve.

  • Mononeuritis Multiplex: Involvement of multiple individual, non-contiguous nerves.

  • Plexopathy: Involvement of a nerve plexus, such as the brachial plexus (upper limb) or lumbosacral plexus (lower limb).

Temporal Evolution and Diagnostic Testing

• Temporal Categories:

  • Acute: Development within $2$ weeks (e.g., Guillain-Barré Syndrome).

  • Subacute: Development over $4$ to $8$ weeks (e.g., early stages of $CIDP$).

  • Chronic: Very slowly progressive and indolent (e.g., diabetic neuropathy or hereditary neuropathies).

• Diagnostic Tools:

  • Nerve Conduction Studies ($NCS$): Primarily used to determine if the process is demyelinating or axonal in nature.

  • Electromyography ($EMG$): Used to determine if a neuropathy is active or chronic.

  • Autonomic Studies: May be beneficial in specific circumstances to assess small fiber autonomic function.

The Most Common Presentation: Length-Dependent Sensorimotor Neuropathy

• The most frequent clinical presentation of peripheral neuropathy is the symmetric, length-dependent sensorimotor pattern.

• Clinical Features:

  • Symmetric glove and stocking distribution.

  • Can involve small fibers, large fibers, or both.

  • Sensory fibers are typically involved more than motor fibers.

  • Weakness, if present, is characteristically distal greater than proximal (distal > proximal).

  • Reduction of reflexes follows the same pattern (distal > proximal).

• Patient History: Patients usually report tingling, numbness, or burning pain in the feet. This gradually progresses up the legs. Once it reaches the knees, similar sensory disturbances begin in the fingers.

Diabetes Mellitus: The Leading Cause of Acquired Neuropathy

• Diabetes is the most common cause of acquired neuropathy in the Western world (excluding regions where leprosy is prevalent, such as the Indian subcontinent).

• Statistics:

  • Approximately $20\%$ of Type 2 diabetics have evidence of neuropathy at the time of diagnosis.

  • Up to $50\%$ of all diabetic patients will develop neuropathy during the course of their disease.

• Correlation: Neuropathy risk and severity correlate with glycemic control; longer periods of poor control increase the likelihood of suffering from neuropathy.

• Presentations:

  • Length-dependent sensorimotor neuropathy.

  • Lumbosacral plexopathy.

  • Brachial plexopathy.

• Clinical Note: A $2019$ Mayo Clinic study from Rochester, Minnesota suggested that patients in that region were more likely to present with diabetic lumbosacral plexopathy than with $CIDP$.

Vitamin B12 Deficiency and Nutritional Neuropathies

• Vitamin $B_{12}$ Deficiency: Found in approximately $2\%$ of peripheral neuropathy patients.

  • Testing may reveal total low $B_{12}$ or a "low normal" level with low levels of functional $B_{12}$.

  • Follow-up testing for active $B_{12}$ or methylmalonic acid ($MMA$) is often required.

  • Presentation: Preferential involvement of large sensory fibers leads to sensory loss and ataxia. Potential dorsal column involvement in the cervical spine can cause simultaneous onset of symptoms in both hands and feet.

  • Treatment: Supplementation of Vitamin $B_{12}$.

• Other Nutritional/Toxic Causes:

  • Copper Deficiency: Presents similarly to Vitamin $B_{12}$ deficiency.

  • Vitamin $B_6$ Excess: Can lead to toxic neuropathy.

  • Vitamin E Deficiency: Often associated with fat malabsorption.

  • Medications: Chemotherapeutic drugs are significant contributors.

Paraprotein Associated Neuropathies and POEMS Syndrome

• Paraproteinemias are seen in up to $10\%$ of all peripheral neuropathy patients.

• Required Testing: Serum Protein Electrophoresis ($SPEP$/$EPG$) and Immunofixation ($IFE$).

• Variants:

  • $IgM$ Monoclonal Gammopathy of Uncertain Significance ($MGUS$): Typically manifests as a distal symmetrical sensory and ataxic variant, often referred to as the Distal Acquired Demyelinating Symmetric ($DADS$) variant. Characterized by significant sensory impairment but minimal weakness.

  • Waldenström's Macroglobulinemia: Can present with various neuropathy types.

  • POEMS Syndrome: A debilitating, rapidly progressing pansystemic syndrome requiring hematological management. The acronym stands for:

    • P: Peripheral neuropathy (mixed axonal and demyelinating).

    • O: Organomegaly.

    • E: Endocrinopathy.

    • M: Monoclonal gammopathy.

    • S: Skin symptoms.

  • AL Amyloidosis: May present in an asymmetrical pattern, falling between a mononeuritis multiplex and a length-dependent pattern.

Hereditary Neuropathies (Charcot-Marie-Tooth Disease)

• Hereditary neuropathies, primarily Charcot-Marie-Tooth ($CMT$) disease, account for approximately $1/3$ of all neuropathy cases.

• General Characteristics:

  • Often involve motor dysfunction more than sensory dysfunction (motor > sensory).

  • Typically painless (except for Hereditary Sensory and Autonomic Neuropathies or $HSAN$).

  • Approximately $30\%$ of patients have no known family history at presentation.

  • Displays genetic and phenotypic heterogeneity: different mutations can cause the same phenotype, and the same mutation can cause different clinical phenotypes.

• Classification:

  • Type 1: Demyelinating hereditary neuropathy.

  • Type 2: Axonal hereditary neuropathy.

• Clinical Signs:

  • Pes Cavus: A characteristic high arched foot deformity resulting from the chronic nature of the condition.

  • Muscle Wasting: Significant wasting of the intrinsic muscles of the foot.

  • Clawing of the Toes: Also known as "hammertoes," resulting from intrinsic muscle weakness.

Summary of Peripheral Neuropathy Presentations

• Peripheral neuropathies affect $2-3\%$ of the general population.

• Clinical characterization is based on the pattern of involvement, temporal characteristics, and fiber types affected.

• The fundamental distribution of causes remains approximately $1/3$ genetic, $1/3$ acquired, and $1/3$ idiopathic.