Peripheral Neuropathy1

The first source is clearly delineated as neural plate which gives rise to central nervous system, the motor nerves and autonomic nerves.

The second source is the neural crest cells. These are migratory cells from the neural crest and contain mainly ependymal and mesenchymal elements and they form the entire peripheral nervous system including the somatic sensory nerves, the somatic and autonomic ganglia and adrenal and chromaffin cells.

The third source is the ectodermal placodes. This is a group of cells which originates at the edge of neural plate. They contribute to hypophysis, inner ear and the cranial sensory ganglia.

The intrinsic system runs longitudinally along the nerves and forms microvessels in the endoneurium. In the extrinsic system, there are neuritive and epineural vessels.

There is considerable degree of anastomosis between the two systems and this renders high degree of resistance to ischemia in the peripheral nerves.

Just as in the brain there is blood-brain barrier; there is a unique blood nerve barrier which is deficient in dorsal root and autonomic ganglia, and parts of the peripheral nerves. This barrier operates at the level of endoneurial capillary walls.

The classification of peripheral nerve fibers is based on various parameters such as conduction velocity, function and fiber diameter.3

The first classification system divides the fibers into three major classes designated A, B and C, corresponding to the peaks in the distribution of their conduction velocities. In the group A, fibers are divided into α (alpha), δ (delta) and γ (gamma) subgroups.

Different types of changes that can occur in the nerve fibers including degeneration and regeneration are shown in Figures 1.2A to D.

Aα fibers (efferent axons) innervate cutaneous joints, muscle receptors and some large elementary enteroreceptors.4

Aδ fibers innervate thermoreceptors and nociceptors including those in dental pulp. C fibers have thermoreceptive, nociceptive and interoceptive functions.

Aα fibers are up to 20 mm in diameter. They innervate extrafusal muscle fibers and conduct at the speed of 120 m/s.

Aγ fibers are exclusively fusiomotor to plate and trail endings on intrafusal muscle fibers.

C fibers are postganglionic sympathetic and parasympathetic axons.

Second classification system used for efferent fibers of somatic muscles divides myelinated fibers into Groups I, II and III.

Group I fibers are large (12–22 μm) and include primary sensory fibers of muscle spindles (Group I a) and smaller fibers of Golgi tendon organs (Group I b).

Group II fibers include terminals of muscle spindles with diameter of 6–12 μm.5

Group III fibers are 1–6 μm in diameter have free sensory endings in the connective tissue sheaths around and within muscles and are believed to be nociceptive, relaying pressure, and pain in externally stimulated muscles.

Group IV fibers are unmyelinated with diameter below 1.5 mm. These include free endings in the muscles and are primarily nociceptive.

Nerve fibers (axons) are coated with short segment of myelin of variable length (250 to 1000 mm) each of which is enveloped by a Schwann cell and its membrane. The Schwann cell membrane surrounding the axon is myelin sheath. This axonal membrane has gaps called nodes of Ranvier which have specialized function containing high concentration of sodium channels (figs 1.3A and B).

In most sensory neuropathies, all sensory modalities like touch, pressure, pain, temperature, vibratory and joint position sense are impaired or lost. Vibratory sense is more affected than position and tactile sensation. It is even possible to delineate large fiber neuropathy based only on selective impairment of sensory modalities such as pain, temperature with sparing or lesser impairment of touch pressure, vibratory and position sense. This pattern resembles dissociated sensory loss of syringomyelia.

The differential diagnosis of peripheral neuropathies is better defined now as new epitopes on dorsal root ganglion cell, Schwann cell and peripheral myelin are identified and the corresponding genes are cloned. However, the diagnosis is still based on time honored criteria such as the pattern of motor and sensory loss, the time course, associated medical conditions, and exposure to toxins and drugs. Newer criteria increase diagnostic accuracy and effective therapeutic results. These are principally based on the fiber size involved in the peripheral nerve which is affected and on the genetics. 9In small c fiber neuropathies, the predominant symptom may be burning pain and autonomic dysfunction. Group A delta myelinated fibers are also small sized. Symptoms, however, may be of different kind, expressed as lancinating pain, cold sensation, deep ache, there may be increased perception to pain and altered response to cold and heat. These small fiber neuropathies are associated with decreased sensation to pain and temperature threshold, minimal weakness and retained reflexes. Large fiber neuropathies, 12–22 m predominantly show motor deficit and impaired vibratory and propioceptive function. Thus, clinical presentation may be associated with impaired balance, positive Romberg's sign, loss of reflexes, ataxia of sensory type and proximal motor weakness. In general terms, both large and small fiber neuropathies have mixed features, which are motor, sensory and autonomic features.

There may be acute thigh pain which may later progress to quadriceps and adductor weakness. There is usually history of acute weight loss and general ill health, weeks prior to the onset of pain, which may be so excruciating that it may require the use of narcotics. Due to the insidious onset and weight loss, malignancy may be suspected. The condition usually improves over 2 years; nevertheless, it may leave sequela of wasting of quadriceps. The distribution of pain and muscle weakness suggests it is L2, L3, L4 roots that are damaged and not the femoral nerve.

Generally, it is of acute or subacute type and painful onset with preceding weight loss in the setting of long standing diabetes mellitus. Cranial nerves III, IV, and VI, are most commonly involved. There may be partial involvement of III nerve with sparing of pupils. VII nerve palsy (Bell's palsy) is common in diabetics. Cranial nerves IX, X and XI are rarely involved.

There are many heavy metals which can cause peripheral neuropathy. Of these, few are discussed in detail due to their common exposure in the environment.

In severe cases, there may be a requirement for ventilatory support, especially when reflexes are depressed and absent.

In acute massive exposure, the clinical picture may simulate acute infective demyelinating neuropathy (AIDN), especially, when present with rapid ascending motor weakness and respiratory paralysis. In chronic exposure, there may be keratotic lesions of feet and hands with sensory neuropathy. Hyperkeratosis is seen in palms and soles and may simulate keratosis of neurosyphilis (Tabes Dorsalis).

Elementary mercury in thermometers and metallic mercury is volatile at room temperature. Organic mercury is used in disinfectants and latex paints. Inorganic mercury salts and elementary mercury are used in dental amalgams.

There have been reports of major mercury intoxications in Minamata Bay in Japan. Organic mercury enters the body 16through GI tract. Elemental mercury may be inhaled. Effects of mercury intoxication on the peripheral nervous system are on the ganglions of the nerves and thus the patients may become ataxic. The polyneuropathy is of subacute onset, less than few weeks and presents principally as diffuse motor peripheral neuropathy.

Pathologic changes may occur in the dorsal root ganglion, cell body (neuropathy), myelin (myelinopathy). There is differential affectation of various degrees. Hence c fibers, A-alpha, and autonomic fibers may be affected.18

Misonidazole is a cell sensitizer used for cancer radiotherapy. Its sensitizes hypoxic cells to deep X-ray therapy and gives rise to similar type of peripheral neuropathy as 20seen with metronidazole. The dose at which normally neuropathy occurs is 50 gm/cumulative.

This is a small fiber type neuropathy with pain temperature and autonomic dysfunction as constant features.

There are two other varieties: One of which was first detected amongst the British families in Iowa (USA) and other in the Finnish patients in Finland. The patients from Iowa show generalized polyneuropathy, while Finnish patients show multiple cranial nerve lesions and corneal dystrophy.

Diabetic neuropathies again show optic disk involvement and nephropathy.

A point to note is that Charcot joints are also seen in amyloid neuropathy like in leprosy, syringomyelia, diabetes, syphilis, etc.

Abdominal pain is the classical feature of porphyria; gene of hereditary coproporphyria is on chromosome 3.

Attacks of porphyia should be treated with intravenous glucose—at the rate of 10–20 gm per hour and hematin 4 mg/kg body weight per 12 hours, which reverses the metabolic defect. Chlorpromazine is a good sedative.

In general when one suspects inherited neuropathies; the large and small fibers are affected with dissociated sensory loss; sometimes mimicking syringomyelia or cord syndrome. This should be borne in mind and appropriate investigations planned to arrive at the correct diagnosis of peripheral nerve diseases.

There are deficient repairs of the transcribed genes.

GBS may be associated with transverse myelitis where there may be urinary and bowel involvement and asymmetrical reflex changes. Reflexes may be brisk in the upper limbs and sluggish to absent in the lower limbs.46

Sural nerve action potentials are normal but median and ulnar nerve sensory potentials are reduced or absent. Fibrillations may occur in about 20 to 60% cases in the first-four weeks. Abnormal spontaneous activity may be noted within 2 to 4 months in affected muscles.47

In axonal form of Guillain-Barré syndrome, poor recovery is an important feature. Paralysis is rapid, CSF proteins are raised; sensory loss occurs distally, there is axonal degeneration and demyelination of motor nerves is absent.

This form of neuropathy has to be considered under various settings including the following:

It may present as polyneuropathy, radiculopathy or mononeuritis multiplex. Central nervous involvement as encephalitis and transverse myelitis form concomitant clinical picture in large majority of patients.

Common peroneal nerve and tibial nerve separate from the Sciatic nerve most often in the mid thigh or upper popliteal fossa.