Neuropathies

(I) Herpes zoster/shingles and postherpetic neuralgia: Herpes zoster or shingles is a syndrome caused by reactivation of varicella zoster virus (the agent of chickenpox). It’s seen more commonly in older adults. Postherpetic neuralgia is defined as pain that persists for more than 3 months after the rash has healed.

Herpes zoster is often preceded by a prodrome that may include pruritus, dysesthesia, and pain along the distribution of the involved dermatome. This pre-eruptive pain may begin several days before the rash appears. The rash presents as grouped vesicles on a red base in a unilateral, dermatomal distribution. It typically progresses through red macules, papules, vesicles, and pustules, and then forms scabs (similar to chickenpox). 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 (often accompanied by tinnitus, vertigo, and deafness), results from involvement of the facial and auditory nerves.

Postherpetic neuralgia occurs due to sensory nerve damage following herpes zoster. The pain is often intermittent and may be out of proportion to the stimulus. This is called allodynia, where 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 with weakness of the foot and lower leg muscles, foot drop, and a high-stepped gait with frequent tripping or falls. Other common findings include high arches and hammertoes (a condition in which the middle joint of a toe bends upwards). The lower legs may take on an “inverted champagne bottle” appearance due to loss of muscle bulk. Later in the disease, weakness and muscle atrophy may occur in the hands, leading to difficulty with fine motor skills. It may be associated with pain and, in rare cases, respiratory muscle weakness.

CMT1A is an autosomal dominant disease caused by a duplication of the gene on chromosome 17 that codes for peripheral myelin protein-22 (PMP-22). Enlarged and hypertrophic nerves result from abnormally thickened myelin sheaths, and these nerves can be palpated easily. CMT2A, the most common axonal form of CMT, is caused by mutations in Mitofusin 2 (a protein involved in 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 pain condition (lasting greater than six months) 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. It 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 diagnosed 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 and described as “burning,” a “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. These changes reflect altered microcirculation resulting from neuropathy. Peripheral nerve abnormalities in CRPS usually involve the small unmyelinated and thinly myelinated sensory nerve fibres that carry pain sensations.

(IV) Fibromyalgia: Fibromyalgia is a chronic pain syndrome that presents with a history of more than 3 months of pain and tenderness, along with symptoms such as stiffness, allodynia, fatigue, and sleep problems. It is seen more commonly in young or middle-aged women. The pain is typically bilateral and occurs in areas above and below the waist. Pain and tenderness occur 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 that fibromyalgia is caused by abnormalities in pain processing, including excess 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 are seen. Inflammatory markers such as IL8 may be elevated.

(V) Phantom limb pain (PLP) : Phantom pain is a pain sensation perceived in a limb, organ, or other tissue after amputation and/or nerve injury. Patients with PLP report sensations such as burning, stinging, aching, and piercing pain, sometimes with changing warmth and cold sensations in the amputated area, which may wax and wane. Symptom onset may be elicited by environmental, emotional, or physical changes. Phantom pain and sensation may begin immediately after amputation or years later. Various theories have been proposed for PLP.

Following amputation, neuromas and axonal sprouts form at the proximal nerve stump. They form connections with neurons in the receptive field of the spinal cord. Some neurons in spinal cord areas not responsible for pain transmission also sprout into Lamina II of the dorsal horn of the spinal cord, which is 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 neighboring representational zones in both the primary somatosensory and 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 increase neuronal sensitivity, leading to allodynia and hyperalgesia. Locally, upregulation of sodium channels is correlated with more frequent bouts of pain.