Diabetic, alcoholic, toxic and small fiber sensory neuropathy (SFSN)

Understanding Types of Polyneuropathies (Polyneuritis)

Polyneuropathy, historically sometimes referred to as polyneuritis (though "neuritis" implies inflammation which is not always the primary pathology), is a condition characterized by damage or dysfunction of multiple peripheral nerves throughout the body. This typically results in symmetrical symptoms, often starting in the longest nerves (affecting feet and hands first, in a "stocking-glove" distribution). This section will discuss several common types of polyneuropathy.

 

Diabetic Polyneuropathy

Diabetic polyneuropathy is a common and serious complication of diabetes mellitus, representing a type of nerve damage that results from the systemic metabolic derangements and intoxication of the body due to impaired tissue metabolism. While multiple factors contribute, a leading pathogenic factor in the onset of diabetic neuropathy is **microangiopathy** (damage to small blood vessels) concomitant with diabetes. This angiopathy leads to impaired regional blood circulation (ischemia) supplying the nerves (vasa nervorum), contributing to nerve damage. Other contributing factors include direct glucose toxicity, oxidative stress, and inflammation.

Depending on the specific nerves affected and the level of nerve damage in diabetic polyneuropathy, patients experience a variety of symptoms, including sensory disturbances (numbness, tingling/paresthesias, burning sensations, pain), and in more advanced cases, muscle weakness and autonomic dysfunction. The severity and type of symptoms (sensory, motor, autonomic) will vary among patients.

 

Microvascular and Macrovascular Complications of Diabetes Mellitus

Diabetic neuropathy is one of the major microvascular complications of diabetes. Other complications include:

Microvascular Complications:

Retinopathy	Neuropathy	Nephropathy
Cotton wool spots (cotton-like exudate) Retinal hemorrhages Retinal vascular microaneurysms Macular edema (thickening of the macula) Proliferative retinopathy	Peripheral Neuropathy: Sensory loss or alterations (hyperesthesia - increased sensitivity, hypoesthesia - decreased sensitivity, paresthesias - tingling/numbness) Painless injuries (due to sensory loss) Decreased or absent reflexes (e.g., ankle jerk) Motor weakness (less common initially) Diabetic foot ulcers Autonomic Neuropathy: Resting tachycardia Orthostatic hypotension Gastroparesis (delayed stomach emptying) Urinary bladder dysfunction (frequent urination, incontinence) Erectile dysfunction Sudomotor dysfunction (abnormal sweating)	Glomerulosclerosis (scarring of glomeruli) Microalbuminuria progressing to macroalbuminuria Pyelonephritis (increased susceptibility) End-stage renal disease

 

Macrovascular Complications:

Coronary Artery Disease	Cerebrovascular Disease	Peripheral Vascular Disease (PVD)
Angina (chest pain) Myocardial infarction (heart attack) Congestive (chronic) heart failure Dyspnea (shortness of breath)	Transient ischemic attacks (TIAs) Cerebral infarction (ischemic stroke) Intracerebral hemorrhage (less common directly due to diabetes, but risk factors overlap) Cognitive impairment / Vascular dementia	Atherosclerosis of peripheral arteries Intermittent claudication (pain on walking) Critical limb ischemia Gangrene Trophic ulcers on the skin surface (often on feet) Increased risk of amputations

 

Alcoholic Polyneuropathy

Alcoholic polyneuropathy is a type of nerve damage that occurs in individuals with a history of chronic and excessive alcohol abuse. The exact mechanisms are multifactorial and include:

• Direct Toxic Effects of Alcohol and its Metabolites (e.g., acetaldehyde) on Nerves.
• Nutritional Deficiencies: Chronic alcoholism often leads to malnutrition and deficiencies in essential vitamins, particularly thiamine (Vitamin B1), but also pyridoxine (B6), cobalamin (B12), and folate, all of which are crucial for nerve health. Thiamine deficiency is a major contributor.
• Oxidative Stress and Impaired Axonal Transport.

Alcoholic polyneuropathy typically presents as a symmetrical, distal, sensorimotor neuropathy, predominantly affecting the lower extremities more severely than the upper extremities. Symptoms often include pain, paresthesias, muscle weakness, and gait disturbances. Autonomic dysfunction can also occur.

 

Toxic Polyneuropathy (Including Chemotherapy-Induced Polyneuropathy)

Toxic polyneuropathies are caused by exposure to various neurotoxic substances. Most manifest as a distal axonal degeneration that develops gradually over time in the patient. The causes are diverse and include:

• Medications:
  • Chemotherapeutic Agents: Many anticancer drugs are neurotoxic, including platinum compounds (cisplatin, oxaliplatin), taxanes (paclitaxel, docetaxel), vinca alkaloids (vincristine), bortezomib, and thalidomide. Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting side effect.
  • Antiretroviral Drugs: Some older nucleoside reverse transcriptase inhibitors (NRTIs) used for HIV treatment (e.g., stavudine, didanosine) can cause neuropathy.
  • Antimicrobials: Isoniazid, metronidazole, nitrofurantoin, fluoroquinolones (rarely).
  • Cardiovascular Drugs: Amiodarone, hydralazine, perhexiline.
  • Other Medications: Colchicine, phenytoin, dapsone, and overuse of pyridoxine (Vitamin B6).
• Heavy Metals: Lead, mercury, arsenic, thallium.
• Industrial Solvents and Chemicals: Organophosphates, acrylamide, carbon disulfide, ethylene oxide, n-hexane.
• Environmental Substances: Certain pesticides.

When assessing a patient's condition, a temporal relationship between exposure to a toxic substance (time of administration and dosage) and the onset of clinical manifestations of neuropathy is usually noted. In general, exposure to small doses of a drug or toxin over a long period tends to be less acutely toxic to nerves than large doses administered over a short period, even if the cumulative dose is similar (though cumulative toxicity is a major factor for many agents like platinum drugs).

The onset of neuropathy may occur during exposure or, in some cases, may continue to progress even after the administration of the toxic substance is discontinued (a phenomenon known as "coasting"). This coasting effect can occur with drugs like platinum-based chemotherapies, benzene-related compounds (though benzene itself is more known for bone marrow toxicity, its metabolites or related industrial chemicals might be implied), certain NRTIs, or excessive pyridoxine.

Clinical analysis of the patient's history includes identifying:

• The relationship between the moment the toxin entered the patient's body and the onset of motor and sensory symptoms of nerve damage.
• Any other concomitant diseases that could independently cause or predispose to toxic neuropathy.
• Symptoms of general systemic intoxication related to the specific toxin.

Nerve biopsy is rarely performed for toxic neuropathies unless the diagnosis is uncertain, but it sometimes reveals characteristic signs for specific types of nerve injury, such as:

• Osmophilic inclusions within Schwann cells during intoxication with amiodarone, perhexiline, and chloroquinoline (a synthetic antimalarial).
• Massive perinodal axonal edema with certain benzene-related neuropathies (or other solvent-induced neuropathies).

Detection of certain toxins in body tissues or fluids can aid diagnosis:

• Heavy metals can be detected in urine (e.g., arsenic, thallium), hair, and nails (e.g., arsenic).
• Laboratory analysis of drug levels in blood plasma can also be useful in establishing the diagnosis of drug-induced toxic neuropathy if therapeutic ranges are exceeded or if a known neurotoxic drug is implicated.

 

Small Fiber Sensory Neuropathy (SFSN)

Small fiber sensory neuropathy (SFSN), or simply small fiber neuropathy (SFN), is a disorder characterized by selective damage to the small-diameter myelinated (Aδ) and unmyelinated (C) sensory nerve fibers in the skin and autonomic nervous system. These fibers are responsible for transmitting pain and temperature sensations, and for autonomic functions.

 

Symptoms of SFSN

The symptoms of SFSN are primarily sensory and can be quite distressing:

• Pain: Often described as burning, aching, or sharp, electric shock-like brief painful sensations.
• Paresthesias: Unusual sensations such as pins-and-needles, pricking, tingling, crawling, or buzzing.
• Numbness or Altered Sensation: Reduced sensitivity to pain or temperature.
• Allodynia or Hyperalgesia: Pain provoked by normally non-painful stimuli (allodynia) or an exaggerated pain response (hyperalgesia).
• Autonomic Symptoms (if small autonomic fibers are involved): Abnormal sweating (hyperhidrosis or anhidrosis), dry eyes/mouth, orthostatic intolerance, gastrointestinal dysmotility, or bladder dysfunction.

Since SFSN typically does not involve the large sensory fibers (which convey proprioception/balance information) or motor nerve fibers, patients usually do not experience balance problems or muscle weakness unless there is coexisting large fiber neuropathy.

In most patients, these symptoms start distally in the feet and progress upwards in a length-dependent pattern (affecting the longest nerves first). In advanced cases, it may involve the hands. However, a smaller percentage of patients experience a non-length-dependent SFSN, with symptoms appearing more diffusely over the whole body, including the trunk and sometimes even the face, often with a subacute onset. Most non-length-dependent cases are idiopathic (of unknown cause).

The majority of SFSN cases are length-dependent. This type is often associated with:

• Diabetes mellitus or impaired glucose metabolism (prediabetes). Length-dependent SFSN in these cases may progress to typical diabetic polyneuropathy involving large fibers as well.
• Connective tissue diseases (e.g., Sjogren's syndrome, lupus).
• Certain infections (e.g., HIV).
• Amyloidosis.
• Paraneoplastic syndromes.
• Genetic mutations (e.g., in SCN9A or SCN10A genes).
• However, in a significant percentage of patients (up to 50%), no underlying etiology is found, and these are classified as idiopathic SFSN.

 

Diagnosis of SFSN

The diagnosis of SFSN is based on a combination of characteristic symptoms, clinical examination findings, and supporting laboratory investigations. Standard electromyography (EMG) and nerve conduction studies (NCS) are typically normal in pure SFSN because these tests primarily evaluate large myelinated nerve fibers.

Key diagnostic tools include:

• Detailed History and Neurological Examination: Focusing on sensory symptoms and signs (pinprick, temperature sensation).
• Quantitative Sensory Testing (QST): Can assess thresholds for temperature and pain perception.
• Skin Biopsy with Epidermal Nerve Fiber Density (ENFD) Measurement: This is considered a gold standard objective test. A small punch biopsy of the skin (usually from the distal leg and sometimes thigh) is taken, and the density of small nerve fibers in the epidermis is quantified. A reduced ENFD confirms the diagnosis.
• Autonomic Function Testing: If autonomic symptoms are present (e.g., QSART - quantitative sudomotor axon reflex test, thermoregulatory sweat test, cardiovascular reflex tests).
• Blood Tests: To screen for underlying causes like diabetes (fasting glucose, HbA1c, glucose tolerance test), vitamin deficiencies, autoimmune markers, etc.

Nerve and muscle biopsies are rarely needed for SFSN diagnosis unless a vasculitic neuropathy or other specific pathology is suspected.

 

Treatment of SFSN

Treatment of SFSN depends on identifying and managing the underlying etiology, if possible. If it is due to diabetes or a prediabetic state, then optimum glycemic control, exercise, and weight loss to reduce insulin resistance are crucial.

Symptomatic treatment for painful sensory paresthesias and neuropathic pain includes:

• Anti-seizure Medications (Anticonvulsants): Gabapentin, pregabalin, carbamazepine, topiramate.
• Antidepressants: Tricyclic antidepressants (TCAs) like amitriptyline or nortriptyline; serotonin-norepinephrine reuptake inhibitors (SNRIs) like duloxetine or venlafaxine.
• Topical Agents: Capsaicin cream, lidocaine patches.
• Analgesics: Simple analgesics like NSAIDs are often ineffective for neuropathic pain. In some cases, tramadol or, rarely, stronger opioid drugs may be considered for severe, refractory pain under strict medical supervision.
• Intravenous Immunoglobulin (IVIG): May be considered in some cases of autoimmune-mediated or idiopathic SFSN, though evidence is still evolving.

In severe painful conditions, patients may be referred to a specialized pain clinic or multidisciplinary pain management centers for a comprehensive approach involving medication management, physical therapy, psychological support, and interventional pain procedures.