Hyperesthesia

Etiology

Neuropathic pain symptoms, including hyperesthesia, develop secondarily to a disease or a lesion of the nervous system that results in abnormal functioning of the somatosensory system. The etiology of hyperesthesia can be categorized anatomically or etiologically. Anatomically speaking, the source can be either central or peripheral.

Peripheral

• Systemic disease: diabetes mellitus (DM), nutritional deficiency, hypothyroidism, vasculitis, sarcoidosis, carcinoma/paraneoplastic, Guillain-Barre syndrome/acute inflammatory demyelinating polyneuropathy, chronic demyelinating inflammatory neuropathies, monoclonal gammopathy (amyloidosis, multiple myeloma, plasmacytoma, monoclonal gammopathy of undetermined significance), porphyria, Sjogren’s syndrome, and critical illness. 
• Infectious: human immunodeficiency viruses (HIV), human T-cell lymphotropic virus, herpes simplex virus, varicella-zoster virus, Ebstein-Barr virus, West Nile virus, hepatitis C virus, rabies virus, cytomegalovirus, diphtheria, Campylobacter jejuni, Mycobacterium tuberculosis, Mycobacterium leprae, Brucella spp., Clostridium botulinum, and Borrelia burgdorferi.[5]
• Toxic: 
• Drugs: isoniazid, chemotherapeutics (vinca-alkaloids, taxanes, platinum compounds), statins, amiodarone, antimicrobials (isoniazid, linezolid, and metronidazole), and immunosuppressants (tumor necrosis factor inhibitors, leflunomide, and nucleoside analog reverse-transcriptase inhibitors).[6]
• Other toxins: ethanol and heavy metals
• Mechanical: trauma, compressive mononeuropathies, complex regional pain syndrome type, post-amputation pain/phantom limb pain, trigeminal neuralgia, post-mastectomy pain syndrome, failed back surgery syndrome, and radiculopathies (nerve root compression)
• Hereditary: Charcot-Marie-Tooth disease and metachromatic leukodystrophy

Central

• Systemic disease: B12 myelopathy, multiple sclerosis, spinal cord stroke, brain stroke/central post-stroke pain syndrome(CPSP), opioid-induced hyperalgesia, and infectious (Herpes simplex virus, myelitis, encephalitis)
• Mechanical: spinal cord injury, tumor compression (brain and spinal cord), syringomyelia, and myelopathy[1][7][8][9]

Epidemiology

Epidemiological studies of hyperesthesia are technically challenging to perform. Barriers to performing accurate epidemiological studies include the vast amount of conditions that can cause hyperesthesia and the subjective nature of hyperesthesia. Two epidemiological studies that focused on the prevalence of chronic pain with neuropathic pain features estimated the prevalence of neuropathic pain among the general population to be 7 to 8%.[2][3]

One study that used a questionnaire to assess sensory symptoms in patients with painful diabetic neuropathy (PDN) and postherpetic neuralgia (PHN) found that allodynia was present in about 50% of the PHN patients. That study contained 1600 patients with PDN, of which 18% reported pain to light touch, and 14% reported occasional pain with heat or cold.[10] Another study performed quantitative sensory testing of 1236 patients with diagnosed neuropathic pain. The study used both mechanical and thermal stimuli. Their results showed that 20% of patients had brush-provoked allodynia. The study also found that mechanical hyperalgesias (pinprick 29% and blunt pressure 36%) occurred more often than thermal hyperalgesias (hot 24% and cold 19%).[11]

Pathophysiology

The pathophysiology of neuropathic pain has been extensively studied, and several important mechanisms have been identified. Some of the identified mechanisms provide clear explanations for the development of hyperesthesias.[7] The mechanisms that lead to the development of hyperesthesia are central sensitization of the somatosensory system, peripheral sensitization of the somatosensory system, and dysfunction of endogenous pain inhibition. It is believed that mechanical hyperesthesia(e.g., light pinprick and light manual pressure) and mechanical allodynia (i.e., stroking the skin with a brush) are due to the sensitization of the somatosensory system (i.e., peripheral sensitization and central sensitization) and dysfunction of endogenous pain inhibition.[12] Cold hyperesthesias are believed to be due to either peripheral sensitization or central disinhibition. Heat hyperesthesias are believed to be due to peripheral sensitization of nerve fibers.[13]

1. Central sensitization is defined as an increase in the synaptic efficacy and excitability of nociceptive pathways in the central nervous system (CNS). Through this mechanism, pain signals entering the CNS are amplified. The process by which the central sensitization of the somatosensory system occurs is not well understood. One proposed mechanism suggests that A-beta touch cells undergo phenotypic changes, which then express increased levels of neuropeptides and increased activity of amino acid transmission.[12][13] 
2. Peripheral sensitization most often occurs after peripheral nerve inflammation and leads to a reduced threshold for activation and hyperexcitability of primary afferent neurons. This is believed to occur due to post-translational changes, trafficking, and expression of the transient receptor potential cation channel subfamily V member 1 (TRPV1) that arise after nerve damage. After these changes, peripheral nerves are more sensitive to mechanical and thermal stimuli.[13] 
3. Dysfunction of endogenous pain inhibition most likely occurs due to reduced GABA and glycine inhibition of second-order neurons leading to a net excitation of these neurons.[14]

History and Physical

History

A thorough history should be performed, as this should be sufficient to make a diagnosis of hyperesthesia. 

• Past medical history (diabetes mellitus, stroke, fractures, irritable bowel syndrome)
• Psychiatric history (mood disorders) 
• Medications (use of neurotoxic drugs) 
• Surgery 
• Family history 
• Sexual history
• Substance use (alcohol or opioid)
• Functional history: A functional history that examines the effect of the patient’s symptoms on their ability to function should be performed. It should focus on any impairments to the patient’s activities of daily living, instrumental activities of daily living, ambulatory status (use of assistive devices), work, or sleep.[4]
• History of presenting illness: The examiner should gather a thorough description of the patient’s pain symptoms. The description of the patient’s symptoms should include all of the following components.
  • Location 
  • Intensity (0-10 rating scale) 
  • Quality (burning, cold, hot, or allodynia) Pain descriptors such as burning, tingling, or shooting are the most characteristic of neuropathic pain syndrome and have a high likelihood of being present along with hyperesthesia.[7]
  • Onset (did the symptoms occur after an inciting event)
  • Temporal variation: At what time of the day is the pain worse? (neuropathic pain tends to be worse towards the end of the day) Has the pain progressively worsened over some time? 
  • Radiation (does the pain have axial origin)
  • Positional variation (i.e., is the pain worse in the lower back or the thigh)
  • Aggravating/alleviating factors
  • Attempted treatments (neuropathic pain symptoms are typically non-responsive to acetaminophen or nonsteroidal anti-inflammatory drugs) 
  • Frequency 
  • Associated symptoms (loss of range of motion, skin or hair changes, muscle spasms, muscle weakness, changes in sensation, redness, or swelling) 

Physical Exam

A complete neurological exam should be performed in addition to a general focused physical exam. 

• Cranial nerve testing (CNS lesions may have cranial nerve involvement) 
• Manual motor testing (weakness may be present in both peripheral and central etiologies, and any weakness should be differentiated as either real weakness or antalgic weakness) 
• Deep tendon reflexes (may be brisk in central etiologies and diminished in peripheral etiologies)
• Sensory testing
• Light touch (allodynia)
• Pinprick (hyperalgesia) 
• Vibration and  proprioception 
• Temperature (ice and hot packs for possible thermal allodynia)
• Straight leg test or slump test (radiculopathy)
• Tinel’s sign (peripheral nerve entrapment) 
• Myofascial trigger points 
• For complex regional pain syndrome (CRPS), a skin examination should be performed focusing on cutaneous temperature discrepancies, color changes, hidrosis, scars in a dermatomal distribution, and hair changes.

Evaluation

The first step should be to determine whether the etiology is peripheral or central. It is essential to accurately diagnose the cause of hyperesthesia to provide treatment for any treatable underlying cause.

Laboratory Tests

• Routine: Should be considered as part of a standard workup of peripheral hyperesthesia
• Complete blood count
• Comprehensive metabolic panel
• Fasting blood glucose
• Erythrocyte sedimentation rate
• Thyroids stimulating hormone
• Vitamine B12
• If indicated, based on clinical suspicion:
• Hemoglobin A1c (HbA1c)
• HIV antibodies
• Liver panel
• Lyme antibodies
• Rapid plasma reagin (RPR), venereal disease research laboratory (VDRL)
• Urinalysis
• Urine protein electrophoresis
• Serum protein electrophoresis
• Angiotensin-converting enzyme levels
• Antinuclear antibody (ANA) test
• Perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) test
• Antineutrophil cytoplasmic antibodies (C-ANCA) test
• Tests for rare conditions
• Paraneoplastic panel
• Antimyelin associated glycoprotein
• Antiganglioside antibodies
• Salivary flow rate
• Cerebrospinal fluid analysis
• Genetic testing

Imaging: imaging is typically not needed to diagnose hyperesthesia, but it helps diagnose specific conditions.

• Computed tomographic scan and magnetic resonance imaging (nerve root compression, herniated disc, myelopathy, tumor in the brain or spinal cord)
• Triple-phase bone scan (can be used to support a diagnosis of CRPS)[7]

Special Tests:

• Electrodiagnostics: electromyography and nerve conduction studies (only tests large fibers)
• Punch skin biopsy (identifies small-fiber neuropathy)[7]

Treatment / Management

Treatment of hyperesthesia and other neuropathic pain symptoms is challenging but is best achieved by using a multidisciplinary team approach that can focus on treating underlying causes, administering pharmacotherapy, applying interventional therapy, addressing functional impairments, and providing mental health services if needed.[7][9] Realistic goals for hyperesthesia should be established early on. Any comorbidities, such as mood disorders or sleep disturbances, should be addressed promptly. Patients typically require close follow-up to monitor response to therapy and continued evaluation of the underlying cause.

For peripheral neuropathy, the most common treatable causes are diabetes mellitus, hypothyroidism, and nutritional deficiencies.[8] Other causes of hyperesthesia, such as nerve root compression or peripheral nerve entrapment, may be initially treated conservatively with symptomatic pharmacotherapeutic support, physical therapy, lifestyle modifications, and minimally invasive procedures (i.e., epidural steroid injection or peripheral nerve injection). However, if there is worsening or stagnation of function, surgery may be required.

Pharmacological treatments can be used to treat both central and peripheral causes of hyperesthesia. Of the pharmacological options available, antidepressants and antiepileptic drugs are the most widely used.[15] General guidelines for treatment are provided below; however, recommendations for the treatment of choice for specific etiologies are provided.(A1)

First-line drugs: These drugs have the most substantial evidence to support their treatment of neuropathic pain symptoms. This group contains two classes of antidepressants and one class of antiepileptic drugs.

• Antidepressants: all medications in this class have the added benefit of treating comorbid mood disorders.
• TCAs: amitriptyline, imipramine, and nortriptyline
• Indications: painful diabetic neuropathy (PDN), postherpetic neuralgia (PHN), central poststroke pain (CPSP)
• SNRIs: duloxetine and venlafaxine
• Indications: PDN, post-traumatic neuropathic pain, CRPS, radiculopathy, and central pain
• Antiepileptic drugs:
• Gabapentinoids: Gabapentin and pregabalin
• Indications: PDN, PHN, central pain, posttraumatic neuropathic pain, CRPS, radiculopathy. Pregabalin has proven to be effective in the treatment of spinal cord injury central pain.[16][17]
(A1)

Second-line treatments:

• Topicals
• Lidocaine 5% patch
• Capsaicin 8% patch: should ideally be applied by specially trained healthcare providers, as it requires pretreatment with topical lidocaine. May require postprocedural analgesics for 7-10 days. Relief may last up to 3 months. 
• Indications: PHN and HIV-associated neuropathy

• Analgesic
• Tramadol: Nonspecific analgesic, Mu-opioid receptor agonist but also blocks serotonin and norepinephrine reuptake.

Third-line treatments: 

• Strong Opioids
• Indications: Phantom pain, CRPS, central pain, PHN, and PDN
• Botulinum toxin-A
• Indications: PHN

Not all patients will respond to monotherapy; in fact, 45% of individuals with neuropathic pain are on two or more medications for their pain. If a patient fails first-line monotherapy, they can be used in combination (i.e., gabapentinoid + TCA or SNRI).[18]

Interventional Therapies:

• Epidural steroid injections: considered third-line therapy.
• Indications: Radiculopathies[19][20]
• Sympathetic nerve block
• Indications: CRPS patients who have failed other treatments.[21]
• Neurostimulation: Fourth-line treatment[18]
• Spinal cord stimulation:
• Indications: CRPS and failed back surgery syndrome (FBSS)[22]
• Motor cortex stimulation:
• Indication: CPSP and facial pain
• Transcutaneous electrical nerve stimulation (TENS)
(A1)

Some interventional treatments currently being practiced lack robust trials to be recommended by the guidelines. Some of the interventions that require continued research are radiofrequency denervation of the dorsal root ganglion, adhesiolysis for FBSS, TENS, spinal cord stimulation, and motor cortex stimulation.

Differential Diagnosis

• Nociceptive source of pain
• Myofascial pain syndrome
• Fibromyalgia
• Chronic fatigue syndrome

Prognosis

It is difficult to completely eliminate hyperesthesias and other neuropathic pain symptoms. This should be explained to the patient early during the treatment course. Monotherapy should be initially started; however, 45% of the patients with neuropathic pain are on two or more medications for their pain.

Complications

Complications of hyperesthesia include increased morbidity if symptoms are not controlled. The patient may also experience increased morbidity from extensive interventional procedures. Also, if the patient is started on potent opioids for treatment, the patient may become addicted.