Neuropathies

(I) Herpes zoster/shingles and postherpetic neuralgia: Herpes zoster or shingles, is a syndrome caused by reactivation of varicella zoster virus (agent of chickenpox). It is seen more commonly in old age. Postherpetic neuralgia is defined as pain persisting more than 3 months after the rash has healed. Herpes zoster is preceded by a prodrome that may include pruritus, dysesthesia, and pain along the distribution of the involved dermatome. This pre-eruptive pain may precede the rash by several days. The rash presents as grouped vesicles on a red base in a unilateral, dermatomal distribution and progresses through red macules, papules, vesicles and pustules which then form scabs (just like in chicken pox). The rash does not cross the midline. The most common sites are the thoracic nerves and the ophthalmic division of the trigeminal nerve. Ramsay Hunt syndrome which presents as facial paralysis and lesions of the ear that are often accompanied by tinnitus, vertigo, and deafness, results from involvement of the facial and auditory nerves.

Post herpetic neuralgia occurs from sensory nerve damage following herpes zoster. The pain is often intermittent and may be out of proportion to a stimulus, called “allodynia”, in which even light touch can precipitate severe pain. It may lead to clinical depression.

(II) Charcot-Marie-Tooth disease or hereditary motor and sensory neuropathy or peroneal muscular atrophy: Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders. It is a peripheral neuropathy that affects both motor and sensory nerves. It presents as weakness of the foot and lower leg muscles, foot drop and a high-stepped gait with frequent tripping or falls, high arches and hammertoes (a condition in which the middle joint of a toe bends upwards). In addition, the lower legs may take on an “inverted champagne bottle” appearance due to the loss of muscle bulk. Later in the disease, weakness and muscle atrophy may occur in the hands, resulting in difficulty with carrying out fine motor skills. It may be associated with pain and in rare cases, with respiratory muscle weakness.

CMT1A is an autosomal dominant disease that results from a duplication of the gene on chromosome 17 that codes for peripheral myelin protein-22 (PMP-22). Enlarged and hypertrophic nerves are caused by abnormally thickened myelin sheaths and they can be palpated easily. CMT2A, the most common axonal form of CMT, is caused by mutations in Mitofusin 2, a protein associated with mitochondrial fusion, or kinesins. CMTX is caused by a point mutation in the connexin-32 gene on the X chromosome.

(III) Complex regional pain syndrome (CRPS or reflex sympathetic dystrophy, causalgia): Complex regional pain syndrome is a chronic (lasting greater than six months) pain condition that most often affects one limb (arm, leg, hand, or foot) usually after an injury. CRPS is believed to be caused by damage to or malfunction of, the peripheral and central nervous systems. CRPS is characterized by prolonged or excessive pain and changes in skin color, temperature, and/or swelling in the affected area. CRPS is divided into two types: CRPS-I and CRPS-II. Individuals without a confirmed nerve injury are classified as having CRPS-I (previously known as reflex sympathetic dystrophy syndrome). CRPS-II (previously known as causalgia) is when there is an associated, confirmed nerve injury. Limb trauma, such as a fracture, followed by immobilization in a cast, is the most common cause of CRPS.

It is more common in middle aged females. The pain may be constant, described as “burning,” “pins and needles” sensation, or as if someone were squeezing the affected limb. Allodynia may be present. The affected arm or leg may feel warmer or cooler compared to the opposite limb. The skin on the affected limb may change color, becoming blotchy, blue, purple, pale, or red due to changes in microcirculation resulting from neuropathy. Peripheral nerve abnormalities found in individuals with CRPS usually involve the small unmyelinated and thinly myelinated sensory nerve fibres that carry pain sensations.

(IV) Fibromyalgia: It is a chronic pain syndrome presenting with more than 3 month history of pain and tenderness, stiffness, allodynia, fatigue, sleep problems etc, seen more commonly in young or middle-aged women. The pain of fibromyalgia is typically bilateral, and occurs in areas above and below the waist. Pain and tenderness occurs in at least 11 of 18 tender point sites. Anxiety, depression, rheumatoid arthritis, SLE or Hepatitis C infection may be associated. It has been postulated to be caused by abnormalities in pain processing such as excess of glutamate and substance P, low levels of serotonin and norepinephrine, decreased levels of GABA, suppression of dopamine and altered endogenous opioid metabolism. Low levels of growth hormone and high levels of nerve growth factor is seen. Inflammatory markers such as IL8 may be elevated.

(V) Phantom limb pain (PLP) : Phantom pain is a pain sensation to a limb, organ or other tissue after amputation and/or nerve injury. Patients with PLP complain of various sensations including burning, stinging, aching, and piercing pain with changing warmth and cold sensation to the amputated area which waxes and wanes. Onset of symptoms may be elicited by environmental, emotional, or physical changes. The phantom pain and sensation may have its onset immediately or years after the amputation. Various theories have been proposed for PLP.

Following amputation, neuromas and axonal sprouts form at the proximal nerve stump. They form connections with the neurons in the receptive field of the spinal cord. Some neurons in the areas of spinal cord that are not responsible for pain transmission also sprout into the Lamina II of the dorsal horn of the spinal cord, which is the area involved in the transmission of nociceptive afferent inputs. This is followed by increased neuronal activity, expansion of the neuronal receptive field, and hyperexcitability of other regions. This phenomenon is called central sensitization.

Another proposed theory is cortical reorganization. Cortical areas representing the amputated extremity are taken over by the neighboring representational zones in both the primary somatosensory and the motor cortex . The extent of cortical reorganization has been found to be directly related to the degree of pain and the size of the differentiated region.

At the molecular level, increasing glutamate and NMDA concentrations cause increased neuronal sensitivity leading to allodynia and hyperalgesia. Locally, upregulation of the sodium channels is correlated to more frequent bouts of pain.