Disorders of nerves

Disorders of nerves Acute inflammatory demyelinating polyneuropathy • Acute inflammatory demyelinating polyneuropathy (AIDP) is an autoimmune process that is characterized by progressive areflexic weakness and mild sensory changes. • Sensory symptoms often precede motor weakness. • About 20% of patients end up with respiratory failure • AIDP often is referred to as Guillain-Barré syndrome [GBS] • Myelin breakdown and axonal degeneration were observed in nerve biopsies from patients with AIDP by Haymaker and Kernohan in 1949. • An autoimmune process was supported by Waksman and Adams. Pathophysiology • AIDP is believed to be caused by an immunologic attack that is directed against myelin components. • This results in a demyelinating polyneuropathy. • Both cellular and humoral immune mechanisms appear to play a role • Humoral molecules such as antimyelin antibodies and complement likely contribute to the process by directing macrophages to Schwann cells by opsonization, • Complement and antibodies have been found to coat the myelin sheath. • The changes are observed in nerve roots, peripheral nerves, and cranial nerves. • In acute motor axonal neuropathy (AMAN, an AIDP variant), deposited complement is found at the nodes of Ranvier, while myelin often is left undamaged. • Damage to the myelin sheath leads to segmental demyelination. • This results in decreased nerve conduction velocity and, at times, conduction block • Early inflammatory lesions consist of a lymphocytic infiltrate that is adjacent to segmental demyelination. • Macrophages are more prominent several days later. • The peripheral nerve changes consist of varying degrees of perivascular edema, accumulations of mononuclear cells, and paranodal and less commonly, segmental demyelination. • They are often multifocal with some predilection for the nerve roots, sites of entrapment, and distal ends • In the axonal variant of GBS, axonal degeneration often predominates. • Severe GBS is often associated with axonal degeneration as well, which results in wallerian degeneration. • Axonal degeneration occurs either as a primarily axonal process or as a bystander-type axonal degeneration, associated with demyelination. • Rarely, the pathologic process extends into the central nervous system. • As the regeneration occurs, nerve sprouting and increased scarring often results Outcome • Mortality rate ranged from 2-6%. • Death is due to complications of ventilation like cardiac arrest, pulmonary embolus, sepsis, bronchospasm, pneumothorax, adult respiratory distress syndrome (ARDS), and dysautonomia. • More than 75% of patients have complete or near-complete recovery with no deficit or only mild residual fatigue and distal weakness. • About 15% of patients end up with significant neurological residuals Age distribution • Age from 2 months to 95 years. • Age distribution is apparently bimodal, with most patients presenting from 15-35 years or 50-75 years. Clinical features • AIDP typically manifests as an ascending paralysis. • The hallmark of classic AIDP is progressive weakness that usually begins in the feet before involving all 4 limbs. • At presentation, 60% of patients have weakness in all 4 limbs. Progressive weakness • Weakness plateaus at 2 weeks after onset in 50% of patients and by 4 weeks in over 90%. • It is usually symmetric, although mild asymmetry is not uncommon early in the disease course. • In the arms, weakness may be worse proximally than distally. • At presentation, half of patients have some facial weakness, although only 5% have varying degrees of ophthalmoplegia. • Oropharyngeal or respiratory weakness is a presenting symptom in 40% of patients. Improvement in strength usually begins 14 weeks after the plateau. About one third of patients require mechanical ventilation because of respiratory failure. Sensory symptoms – Mild to moderately severe paresthesias in the distal limbs are common and often precede the onset of weakness by 1 or more days. – Proximal sensory changes are uncommon but may occur in more severe cases of AIDP. Autonomic disorders – About two thirds of patients have one or more autonomic abnormalities. Sustained sinus tachycardia is the most common dysfunction. Postural hypotension leading to presyncope or syncope can occur. – Sweating dysfunction is common but rarely noted by patients. Urinary retention and constipation are more likely to occur later in the course of AIDP. Autonomic dysfunction is more common in intubated patients Pain – Mild lower back and/or hip pain is very common and occasionally precedes the onset of weakness. – The pain is severe in about 15% of patients Variants • The Miller-Fisher variant, appearing with ophthalmoplegia, areflexia, and ataxia, is the most common variant and is seen in as many as 5% of patients with AIDP. • Most patients with the Miller-Fisher variant have antibodies against ganglioside GQ1b • Regional variants of GBS, such as pharyngealcervical-brachial weakness or only leg weakness, are rare and resemble AIDP in time course. • The AMAN variant is seen in China and in developing countries. It presents with weakness only. • Pure pandysautonomia with little, if any, weakness parallels classic AIDP in time course and antecedent infections. The difference is that this variant is manifested primarily by autonomic failure. Many of these patients also have areflexia. Examination • Weakness – Although patients often report only weakness in the legs, careful examination usually demonstrates arm weakness (proximally and distally). – Some patients with Miller-Fisher or other regional variants may have weakness of cranial muscles only. • Deep tendon reflexes – Hyporeflexia or areflexia is seen in 70% of patients at presentation and eventually in all patients. – A progressive decrease in reflexes is a useful finding that may precede electromyographic (EMG) changes • Autonomic dysfunction – Fluctuations in heart rate, specifically a sustained sinus tachycardia, are seen often. – Some intubated patients also may have bradycardia, especially after vagal stimulation with Valsalva and/or tracheal suctioning maneuvers. – Orthostatic hypotension can occur and is likely due to dysfunction of the baroreceptor reflex. – At times, the labile blood pressure is observed with severe hypertension that may be due to dysfunction of the afferent limb of the baroreceptor reflex. – Urinary retention is common, especially in intubated patients. The rare patient may even develop an ileus. • Findings that are inconsistent with a diagnosis of AIDP – Weakness that remains markedly asymmetric – Sharp sensory level – Severe bladder or bowel dysfunction at onset • Diagnostic criteria for GBS include – progressive weakness, – areflexia, – relative symmetry, – mild sensory involvement, – cranial nerve involvement, – at least partial recovery, – autonomic dysfunction, and – absence of fever Causes • Viral – Infection with influenza, coxsackie, EpsteinBarr virus, or cytomegalovirus can cause upper respiratory infection. – Herpes simplex virus or human immunodeficiency virus (HIV) • Bacterial – Strains of Campylobacter jejuni that cause enteritis are associated closely with the subsequent development of AMAN. – Molecular mimicry between gangliosidelike epitopes of the C jejuni lipopolysaccharide and peripheral nerve gangliosides in nerve is a proposed mechanism. – In children, an association exists between AIDP and Mycoplasma pneumoniae infection. • Rare cases of AIDP in individuals infected with toxoplasma, malaria, or filaria have been reported • Vaccination – Several cases have been reported after immunization against rabies, influenza, measles, mumps, or rubella. • Malignancies and systemic illnesses – Hodgkin lymphoma, acute myelogenous lymphoma,systemic lupus erythematosus, and hypothyroidism. • Pregnancy: Most cases occur during the last trimester or during the first 2 weeks of the postpartum period. • Bone marrow transplantation • Surgery: Most patients also had an infection or blood transfusion • Diphtheria: Weakness may follow the pharyngeal infection by 2-3 weeks, beginning with palatal paralysis and, often, paralysis of accommodation. Limb weakness is not common. • Hypophosphatemia: An acute areflexic paralysis may follow hypophosphatemia in the setting of total parenteral nutrition, alcohol abuse, or rapid refeeding after starvation. The weakness rapidly responds to phosphate replacement. Investigations • Cerebrospinal fluid – Increased CSF protein without an increased WBC count (albuminocytologic dissociation) is observed classically in AIDP. However, this finding is not specific to AIDP. • About two thirds of patients have this CSF finding during the first week of symptoms and 82% have it by 2 weeks after symptom onset. • Although protein values can be elevated by 10-fold or more, no association exists between protein level and clinical severity • Measurement of antiviral or antibacterial antibodies may confirm an association. • Stool cultures may confirm C jejuni enteritis. – Some patients have oligoclonal banding of the CSF. – Myelin basic protein also is increased in some patients . • Nerve conduction studies (NCS) can document demyelination, the hallmark of AIDP. – Early on, findings of NCS studies are often normal. However, 90% are abnormal within 3 weeks of symptom onset. • Patients who meet 3 of the 4 NCS criteria listed below have a clear primary demyelinating neuropathy – Reduced conduction velocity – Conduction block or abnormal dispersion – Prolonged distal latencies – Prolonged F-waves • Needle EMG can document the extent of denervation • Autonomic tests such as sympathetic skin responses and cardiovagal testing may be indicated in patients with autonomic failure. • Pulmonary function tests, useful in determining the timing of intensive care unit (ICU) transfers and elective intubation, should be performed in all patients: – Transfer to an ICU generally is indicated when forced vital capacity (FVC) is less than 20 mL/kg. – Intubation is usually warranted when FVC drops to 15 mL/kg or negative inspiratory pressure drops to less than -25 cm H2O. • Mechanical ventilatory assistance is required in about one third of patients with AIDP and lasts for an average of 49 days. • Intubation should be performed when FVC drops to less than 15 mL/kg or negative inspiratory pressure is worse than -25 cm H2O. • Tracheostomy is usually recommended if mechanical ventilation will be required for more than 2-3 weeks. Treatment • Immunomodulation with IVIg and plasmapheresis has led to faster recovery, relatively mild disability, and shorter hospital stays. • Treatment is less likely to be effective if initiated more than 2 weeks after the onset of symptoms Prognosis – younger patients have a better prognosis than older patients. Those patients with more severe weakness and those who are intubated have a worse prognosis than those with milder weakness. – Diarrhea as an antecedent association often is associated with C jejuni infection. These patients may have a more prolonged recovery. – Early improvement in strength during treatment is associated with a more rapid recovery. Low compound muscle action potential (CMAP) amplitudes (<20% of normal) are considered a bad prognostic indicator. Metabolic Neuropathy Introduction • The term metabolic neuropathy includes a wide spectrum of peripheral nerve disorders associated with systemic diseases of metabolic origin. • The common hallmark of these diseases is involvement of peripheral nerves by alteration of the structure or function of myelin and axons due to metabolic pathway dysregulation. • Diabetic mellitus is the most common cause of metabolic neuropathy, followed by uremia. Diabetic Neuropathy • Hyperglycemia and insulin deficiency contribute to the development of diabetic neuropathy and that glycemia reduction lowers the risk of developing diabetic neuropathy by 60% over 5 years. • Involvement of the polyol pathway. • Myoinositol and taurine depletion have been associated with reduced Na+/K+-ATPase activity and decreased nerve conduction velocities (NCVs) • Aldose reductase inhibitors may also improve NCVs and protect small sensory fibers from degeneration. • Sural nerve biopsy has suggested changes suggestive of microvascular insufficiency, including membrane basement thickening, endothelial cell proliferation, and vessel occlusions. • Impaired neurotrophic support. – Nerve growth factor (NGF) and other growth factors, such as NT3, IGF-I, and IGF-II, may be decreased in tissues affected by diabetic neuropathy. Other factors such as abnormalities in vasoactive substances and nonenzymatic glycation have demonstrated possible involvement in diabetic neuropathy development. • A glycoprotein called laminin promotes neurite extension in cultured neurons. Lack of expression of the laminin beta2 gene may contribute to the pathogenesis of diabetic neuropathy. Uremic polyneuropathy • In uremic polyneuropathy, conduction velocity slowing is believed to result from inhibition of axolemma-bound Na+/K+ATPase by uremic toxins, leading to intracellular sodium accumulation and altered resting membrane potentials. • Eventually, this results in axonal degeneration with secondary segmental demyelination. Thyroid neuropathy • Microvascular and endoneurial ischemic involvement. • Deposit of mucopolysaccharide-protein complexes within the endoneurium and perineurium. Age • Diabetic neuropathy may be more common in elderly patients. Milder diabetic neuropathy has been reported in type 2 diabetes, which most commonly affects the elderly population. • Rarely, metabolic neuropathies are associated with congenital and hereditary causes and are more common in childhood (ie, inherited metabolic disorders, mitochondrial diseases). Clinical features • Symptoms in metabolic neuropathy can reflect sensory, motor, or autonomic involvement. • C/O tingling and numbness (ie, paresthesias) and painful dysesthesias, worse at night. • Motor and autonomic complaints are less common. – Symmetric polyneuropathies • Sensory or sensorimotor polyneuropathy • Autonomic neuropathy – Focal and multifocal neuropathies • • • • Entrapment neuropathies Cranial neuropathy Radiculopathy/plexopathy Asymmetric lower limb motor neuropathy – Mixed forms • Symptoms of metabolic neuropathy according to this classification are as follows: • In symmetric polyneuropathy, initial symptoms begin insidiously and are most prominent distally in the lower extremities. Sensory disturbances exhibit a typical ―length related pattern,‖ with involvement of the toes that advances to the feet and legs • The upper limbs are affected more rarely; however, when upper limbs are involved, symptoms develop in the same pattern, with involvement of the fingers spreading to the hands and forearms in a glovelike pattern • In advanced stages, sensory symptoms may involve the anterior part of abdomen and trunk (hence the term ―trunk neuropathy‖), leading sometimes to the erroneous diagnosis of myelopathy. • In extreme cases, the vertex of the head may be affected. • Sensory symptoms – Symptoms in most patients are mild in severity. However, when pain becomes severe, it presents with lancinating paresthesias and burning sensations that are typically worse at night. – Involvement of nerves by entrapment is common in metabolic neuropathies. – Sensory symptoms such as pain and paresthesias along the distribution of the nerve and worsening at night are typical manifestations. – The nerves most commonly involved are the median nerve (carpal tunnel syndrome [CTS]), ulnar nerve, and median and lateral plantar nerves (tarsal tunnel syndrome [TTS]). • Cause injury to both large and small nerve fibers. • Involvement of large fibers can cause alteration in vibration and proprioception and a sensory ataxia. • Involvement of small fibers produces alteration in temperature perception or autonomic function. • Small-fiber involvement can cause alteration in pain and temperature, leading to the so-called ―pseudosyringomyelia.‖ • Motor symptoms – Mild distal weakness is a common complaint, but patients also may experience proximal leg weakness, which is often asymmetric. – Asymmetric motor involvement in lower limbs is more common in patients with diabetes and is termed ―amyotrophy.‖ – Motor weakness can be asymmetric and focal, suggesting the diagnosis of plexopathy; when painful, it suggests the presence of radiculoplexopathy. – Involvement of cranial nerves can cause signs and symptoms such as diplopia, facial drooping, lacrimation, dysgeusia, and facial pain. Autonomic involvement – Pupillary and lacrimal gland dysfunction • Miosis • Disturbance of dilatation • Argyll Robertson pupil – Cardiovascular disturbances • • • • Tachyarrhythmias and bradyarrhythmias Postural hypotension Asymptomatic myocardial infarction Sudden death • Thermoregulatory disorders – Distal anhydrosis – Gustatory sweating – Abnormal vasomotor responses to temperature changes • Alimentary tract disorders – Esophageal atony – Gastric and duodenal atony – Gallbladder atony – Diarrhea, constipation – Colonic atony – Anal sphincter weakness • Genitourinary disturbances – Bladder atony – Retrograde ejaculation – Impotence – Female sexual dysfunction – Disturbances of respiratory control Examination • Sensory findings – Symmetric distal sensory loss suggests polyneuropathy. – Asymmetric hypoesthesia in distal territories of multiple nerves suggests mononeuritis multiplex. • Signs of entrapment. • Tinel sign: percussion around the site of the median nerve in the wrist produces paresthesias in the first 4 digits • Phalen sign: sustained flexion of the wrist causes paresthesias in the digits. • These signs also may be triggered with percussion of the ulnar nerve at the wrist or elbow, at the fibular head (peroneal nerve entrapment), or at the posterior part of the internal malleolus (tibial nerve entrapment). • Altered perception of pain and temperature with a pseudosyringomyelia state suggests involvement of small fibers. • Some patients experience loss of visceral pain sensation, which may manifest as painless myocardial infarction or loss of testicular sensation. • Foot ulceration is one of the most severe complications of diabetic neuropathy; it can lead to gangrene and result in the need for amputation. • Damage to large sensory fibers leads to loss of touch-pressure sensitivity, vibration and joint position sense, and tendon reflexes, with a resulting sensory ataxia. • Motor findings – Mild distal weakness may be noted in patients with sensory polyneuropathy. – Asymmetric motor neuropathy, which is subacute painful asymmetric lower limb (rarely upper limb) weakness – Double-crush phenomenon: Simultaneous compromise of nerve roots and peripheral nerves by entrapment can be found in metabolic diseases. • Cranial neuropathies: – The most common finding in patients with diabetes is an isolated third nerve palsy without pupillary involvement. – Sixth or seventh cranial nerve. – These neuropathies are usually not painful and occur most commonly in elderly patients. – Diabetes may involve the optic nerve and retina, causing diabetic retinopathy, which leads to blindness Symptoms and Signs of Neuropathy* Small-Fiber Sensory Large-Fiber Sensory Autonomic Burning pain Cutaneous allodynia Paresthesias Lancinating pain Loss pain/temperature Foot ulcers Visceral pain loss Loss of vibration Proprioception loss Loss of reflexes Slowed NCVs Sensory ataxia Weakness Heart rate changes Postural blood pressure change Abnormal sweating Gastroparesis Impotence Abnormal ejaculation • Uremia – Uremic polyneuropathy is usually subacute, sensorimotor, distal, and more prominent in the lower extremities. It commonly is associated with muscle cramps and the restless leg syndrome – The earliest finding in uremic neuropathy is loss of ankle jerks or elevation of the vibratory sensation threshold. • The most common mononeuropathy in chronic renal failure is CTS, but mononeuropathies of ulnar or femoral nerves may be caused by compression by fistulas or dialysis catheters. Multiple cranial nerve neuropathies also have been reported in uremia. • Thyroid neuropathy – Entrapment neuropathy of the median nerve is the most common neuropathy associated with hypothyroidism. – Compromise of the eighth nerve causing deafness is not uncommon. Multiple cranial nerve involvement is rare. – Polyneuropathy is usually subacute, sensory, and occurs in 31-65% of patients – Sensory complaints include painful dysesthesias in the hands and feet and radiating lancinating pains, occasionally suggesting nerve root compression. Examination findings may reveal distal gloveand-stocking sensory loss and ataxia. – Weakness is a common complaint, but it usually is related to myopathic involvement – Hyporeflexia and delayed relaxation phase of the ankle jerk are common. Transient swelling on percussion of the skin (mounding phenomenon) may be observed. – Occasionally, hyperthyroidism may be associated with polyneuropathy • Neuropathy in chronic liver disease – Nonalcoholic chronic liver disease may be associated with an asymptomatic or mild sensory-motor demyelinating polyneuropathy in approximately 4550% of patients. – Peripheral neuropathy also has been reported in primary biliary cirrhosis and following acute viral hepatitis. – Acute motor peripheral neuropathy similar to that of Guillain-Barré syndrome and associated with liver disease • Polyneuropathy in chronic obstructive pulmonary disease (COPD): – mild polyneuropathy associated with COPD. – Treatment of patients who have COPD with drugs that may affect peripheral nerves secondarily • Acromegaly and amyloidosis are associated more often with entrapment neuropathies and less commonly with peripheral neuropathy. • Monoclonal gammopathies, such as cryoglobulinemia, monoclonal gammopathy of undetermined significance (MGUS), and myelinassociated glycoprotein (MAG)–associated gammopathy, can present with peripheral neuropathy. • Amyloid neuropathy (nonfamilial) – Progressive involvement of small-diameter fibers with loss of pain and temperature sensation is typical of amyloid neuropathy, but occasionally patients can develop large-fiber neuropathy as well. – Presents commonly as CTS or as a painful peripheral neuropathy. – Initial symptoms of neuropathy are sensory, with more extensive involvement of the lower extremities. With time, motor symptoms develop and are more prominent in the lower limbs. – Occasionally, amyloid neuropathy may manifest as autonomic dysfunction with severe orthostatic hypotension, syncopal episodes, or sexual impotence. – In patients whose amyloidosis begins with neuropathy, the clue to the diagnosis may be involvement of the heart, bowel, or kidneys. • Porphyric neuropathy – Disorders of porphyrin metabolism are a rare cause of peripheral neuropathy. Only hepatic porphyrias are associated with neurologic disease. – Acute intermittent porphyria may be associated with attacks of acute motor neuropathy with mild sensory symptoms very similar to Guillain-Barré syndrome. – Attacks are precipitated by drugs like phenytoin and phenobarbital and may be accompanied by abdominal pain, confusion, and seizures Causes • Common causes of metabolic neuropathy include the following: – – – – – – – – – Diabetes Uremia Chronic liver disease Polycythemia COPD Amyloidosis Acromegaly Monoclonal gammopathies Hypothyroidism • Rare causes : – – – – Hyperthyroidism Porphyria Mitochondrial disorders Adrenal insufficiency (rare reports of autonomic involvement) – Disorders of lipid or glycolipid metabolism (eg, Refsum disease, Fabry disease, abetalipoproteinemia, hypobetalipoproteinemia) – Leukodystrophies with peripheral nerve involvement (adrenomyeloneuropathy, adrenoleukodystrophy) • Risk factors for metabolic neuropathy: – Uncontrolled metabolic status – Hypertension, obesity, and smoking (for diabetic neuropathy Investigations • • • • Routine Metabolic parameters NCV,EMG Nerve biopsy Management • The best medical care for patients with metabolic neuropathy is control of the underlying metabolic condition, which results in better control of the neuropathy. • Treatment of painful neuropathy: duloxetine hydrochloride, a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), for the treatment of diabetic peripheral neuropathic pain Surgical Care: • Surgical release of entrapment neuropathy (CTS, ulnar neuropathy at the elbow, TTS) • Specialized surgical care of diabetic foot and foot ulcers, including vascular and plastic surgery evaluation • Jejunostomy for severe gastroparesis • Pancreatic islet transplants have been reported to improve diabetic neuropathy and pancreas-kidney transplantation in patients with diabetes and renal failure • Liver transplantation (may improve familial amyloid neuropathy) • Renal transplantation (may improve uremic neuropathy Nutritional neuropathy Introduction • Peripheral neuropathies due to nutritional deficiencies have few individual characteristic signs, but they can be differentiated by observing other symptoms of the patient's underlying systemic disease. Pathophyisiology • Neuropathies occur in 2 forms: – an isolated deficiency (of usually 1 of the B vitamins) – complex deficiency resulting from several concurrent metabolic disorders (usually including malabsorption). • Alcohol exposure – Ethanol intercalates into cell membranes, increasing membrane fluidity. – Alcohol also affects many signal-transduction proteins, including ion channels, secondary messengers, neurotransmitters, neurotransmitter receptors, G proteins, chaperonins, and regulators of genetic expression. • Peripheral neuropathy is often the earliest symptom of chronic alcohol dependence. • Peripheral nerve damage results from 3 processes – Nutritional deficiency- especially thiamine deficiency, as ethanol interferes with thiamine absorption in the intestine. Other deficiencies may involve niacin, folate, or protein. – direct toxicity from abnormal products (eg, phosphatidyl ethanol, fatty acid ethyl esters) and from metabolites (eg, acetaldehyde that reacts with proteins to form adducts). – indirect toxicity (ie, neuropathy from hepatic dysfunction). • Neuropathy generally occurs after consumption of at least 100 g/d for several years Thiamine deficiency • Thiamine (vitamin B-1) is found in wheat germ, or the outer layer of seeds, nuts, and most vegetables. • Thiamine pyrophosphate is essential for the proper transfer of the aldehyde groups, and it is an essential coenzyme for glycolytic and pentose pathways of glucose metabolism. • Four enzymes need thiamine: pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, transketolase, and branchedchain alpha-ketoacid dehydrogenase. • Body tissues store about 30 mg but use about 12 mg daily. • Recommended daily allowance [RDA] is 1.5 mg. • Daily intake of less than 0.2 mg causes discontinuous degeneration of the axonal sheath with subsequent impairment of the axon, producing a polyneuropathy in about 3 months. • The vagal nerve is affected particularly, causing symptoms in the distributions of the cardiac, laryngeal, and recurrent nerves. • Thiamine deficiency can cause – wet beriberi, for which congestive heart failure is the primary symptom, or – dry beriberi, in which a peripheral neuropathy is the primary symptom, depending on the percentage of carbohydrates in the diet. – Deficiencies preferentially affect the nervous and cardiac tissue because thiamine pyrophosphate is bound less strongly there than elsewhere. Niacin deficiency • Niacin (vitamin B-3) is found in yeast, beef, pork, and chicken. • The active form of this coenzyme, nicotinamide adenine dinucleotide (NAD), is essential for electron and acyl-group transfer in glycolysis. • A deficiency of niacin causes pellagra. • RDA for men is 20 mg. Pyridoxine deficiency and excess • Pyridoxine (vitamin B-6) widely occurs in plant and animal tissues, such as muscle meats, liver, vegetables, and whole-grain cereals. • Vitamin B-6 consists of pyridoxine, pyridoxal, and pyridoxamine. • It is involved in primary carboxylation and transamination, playing a role in metabolizing tryptophan, glycine, serotonin, and glutamate, as well as sulfur-containing amino acids. • Pyridoxine is used in the synthesis of both heme and gamma-aminobutyric acid (GABA). • Deficiencies are usually associated with increased excretion due to isoniazid ingestion and cause a sensorimotor neuropathy and seizures. • A high-protein diet increases pyridoxine requirements, • RDA for men is 2 mg. • The toxic effect of long-term, excessive pyridoxine consumed on the dorsal root ganglions causes a pure sensory neuropathy. • Pyridoxine inhibits methionine metabolism, causing an increase in S-adenosylmethionine, which in turn inhibits myelin synthesis. • In general, exposure of 2 g/d is needed to cause the neuropathy, but cases due to longstanding use of as little as 200 mg/d have been reported. Cyanocobalamin deficiency • Cyanocobalamin (vitamin B-12) is found in meats, especially liver and kidney and in cheese, milk, eggs, and fish. • This inactive precursor is converted into 2 active metabolites: methylcobalamin and adenosylcobalamin. • Methylcobalamin is essential for folate metabolism and for the formation of choline-containing phospholipids, which are the building blocks of myelin. • Adenosylcobalamin is required for the formation of succinyl coenzyme A, the lack of which causes impairment in the formation of neural lipids. • The liver stores 4 mg of cyanocobalamin, representing a 3- to 6-year supply. • primary deficiencies are rare, except in strict vegetarians and nursing infants, • malabsorptive disorders. • The manifestations, which appear throughout the white matter, are a result of a focal disintegration of medullary sheath known as subacute combined degeneration. • RDA for men is 2 mg. Pantothenic acid deficiency • Almost all foods contain this constituent of coenzyme A, the concentration of which in tissues is 10 times that of thiamine and 50% that of nicotinic acid. • Deficiencies are rare because of this large amount of storage, though pantothenic acid has been implicated in the pathogenesis of burningfoot syndrome. • The daily requirements are 6-10 mg. Alpha-tocopherol deficiency • Alpha-tocopherol (vitamin E) is a lipidsoluble antioxidant. • Its lack causes a syndrome resembling spinocerebellar degeneration, reversible in early stages but with devastating consequences if allowed to progress. • RDA is 10 IU Gluten-sensitivity neuropathy (celiac disease) • Antibodies to gluten in wheat, barley, and oats in susceptible individuals also attack Purkinje cells and other neurons, leading to cerebellar ataxia, myoclonus, and neuropathy. Clinical features • Neuropathies mostly affect the long fibers first, starting in the feet and progressing upward. • Once they have progressed to the calf, symptoms may appear in the hands. • Cyanocobalamin (vitamin B-12) deficiency occasionally manifests in the upper extremities Alcohol neuropathy – paresthesias (decreased pain and temperature sensation in a stocking-glove distribution), pain, and weakness, especially in the feet but extending proximally to the arms, causing difficulty in climbing stairs and walking. – Autonomic symptoms are less common. – The neuropathy may be seen in conjunction with Wernicke encephalopathy (ie, ophthalmoplegia, ataxia, encephalopathy) or Korsakoff syndrome (ie, amnestic dementia). Thiamine (vitamin B-1) deficiency – Dry beriberi is characterized by severe burning dysesthesias (feet more than hands), weakness and wasting (distal more than proximal), trophic changes (shiny skin, hair loss), – The neuropathy begins with fatigue and loss of sensation, pain, and heaviness in the legs. Then, pretibial edema develops, along with glove-andstocking paresthesias – muscles on the dorsum of the feet atrophy and paralysis can ensue. – Difficulty with talking or swallowing may also be noted Niacin (vitamin B-3) deficiency – Pellagra is characterized by the 3 Ds, – (1) dermatitis, ie, hyperkeratotic skin lesions, particularly on hands, feet, face, and neck (ie, sun-exposed regions); – (2) diarrhea; and – (3) dementia, ie, peripheral neuropathy and other CNS signs, such as depression, excitation, seizures, insomnia, dizziness, cog-wheeling of the extremities, tremor, loss of hearing, tingling fingers, muscle tenderness, and bilateral symmetric glove-and-stocking numbness. • Polyneuropathy is not always associated with pellagra and may be related to accompanying thiamine or pyridoxine deficiency • It is characterized by acrodistal sensory excitation, the itching and burning in the hands, feet, and trunk, and it sometimes manifests as hydromania, or the compulsion to immerse oneself in cold water. • Paresis is rare, but bulbopontine symptoms can ensue, with abnormalities of the cranial nerves, especially the vestibular, acoustic, and ocular nerves (where symptoms manifest as optic atrophy or amblyopia), as well as seizures. Pyridoxine (vitamin B-6) deficiency or excess – Deficiency must be suspected any time a sensory polyneuropathy occurs after hyperesthesia-causalgia syndrome. – First, bilateral numbness and tingling begin in the distal feet. This proceeds proximally up the feet and legs, occasionally appearing in the fingers and hands. Then pain becomes prevalent in these areas, and symptoms can include a burning sensation in the feet. Cyanocobalamin (vitamin B-12) deficiency – About 80% of all cases are due to pernicious anemia, and another 10% are due to achlorhydria. – The disease predominantly affects the spinal cord; therefore, separating the painful sensory and sensorimotor paresthesias of the peripheral neuropathy from the symptoms of spinal cord involvement is difficult • The symmetric glove-and-stocking paresthesias, or tingling in the distal aspect of the toes, numbness, coldness, a pins-and-needles feeling, and occasional feelings of swelling or constriction, are slowly progressive and insidious. • The subacute combined degeneration that develops results in a severe myelopathy, involving posterior columns and lateral corticospinal tracts, with other manifestations including optic (retrobulbar) neuropathy, sensorimotor polyneuropathy, and dementia. Pantothenic acid deficiency • This manifests as painful burning paresthesias in the feet, ataxia, and hyperreflexia, followed by weakness, fatigue, apathy, and psychiatric disturbances 5-8 weeks later. Alpha-tocopherol (vitamin E) deficiency – Symptoms include hyporeflexia progressing to areflexia, decreased proprioception and vibration sense with preserved pain and temperature senses, distal muscular weakness progressing to ataxia, dysphagia, and cardiac problems, and nyctalopia (night blindness). – Nystagmus, ophthalmoplegia, and blindness, and dementia follow. Examination • Mouth: – Glossitis suggests cyanocobalamin (vitamin B-12) deficiency – glossitis and cheilosis suggest pyridoxine (vitamin B-6) deficiency; – gingivitis, stomatitis, and glossitis: niacin (vitamin B-3) deficiency. • Skin: – Nasolabial seborrhea suggests pyridoxine (vitamin B-6) deficiency; – pellagrous skin rash, niacin (vitamin B-3) deficiency; and – hyperpigmentation, cobalamin (vitamin B-12) deficiency. • Cardiovascular: CHF suggests thiamine (vitamin B-1) deficiency. • Hematologic: Megaloblastic anemia suggests a cobalamin (vitamin B-12) or folate deficiency. • Hypochromic anemia is usually iron deficiency but also can represent a pyridoxine vitamin (B-6) deficiency Management • Supplement with deficient nutrient Hereditary sensory and motor neuropathy Introduction • 1968, Dyck and Lambert classification  HMSN types 1A and B (dominantly inherited hypertrophic neuropathies)  HMSN type 2 (neuronal type of peroneal muscular atrophy)  HMSN type 3 (hypertrophic neuropathy of infancy [Dejerine-Sottas])  HMSN type 4 (hypertrophic neuropathy [Refsum] associated with phytanic acid excess)  HMSN type 5 (associated with spatic paraplegia)  HMSN type 6 (with optic atrophy)  HMSN type 7 Pathophysiology • HMSN 1 is the most common form of hereditary neuropathy. • Severely and uniformly slowed nerve conduction velocities (NCVs) and primary hypertrophic myelin pathology with prominent onion bulbs and secondary axonal changes are the hallmarks of the disease • HMSN 2, on the other hand, represents the nondemyelinating neuronal type with relatively normal NCVs and primary axonal pathology. • Although nerves are not enlarged in the neuronal form, weakness often is less marked and onset of this neuropathy is delayed Incidence • Worldwide meta-analysis estimated a prevalence of 1 per 10,000 individuals (Emery, 1991). • Charcot-Marie-Tooth disease type 1 accounts for about two thirds of cases and Charcot-Marie-Tooth disease type 2 accounts for about one third of cases. • Other forms of Charcot-Marie-Tooth disease are very rare. Mortality/Morbidity:  Usually, life expectancy is normal.  Disability is highly variable and difficult to predict in young individuals. This is related to the variable genetic penetrance of the disorders.  In general, Charcot-Marie-Tooth disease is a slowly progressive condition. If progression accelerates, other causes, such as acquired neuropathies or other inherited neuromuscular conditions, should be sought Age  The onset of HMSN 1 in the first decade of life is typical, but disease develops in some patients in young or mid adulthood.  Patients with HMSN 2 are usually asymptomatic until later in life, and the symptoms most commonly begin in the second decade of life.  The onset of HMSN 3 is in early childhood. • Clinical features • HMSN type I – Insidious onset, some patients are unaware of their disease or seek medical attention only late in life. – In contrast to acquired neuropathies in which pain in a prominent feature, patients with HMSN1 experience a relative lack of pain. Motor symptoms predominate over sensory symptoms. Often, patients report loss of balance, muscle weakness, and foot deformities. Onset in the first decade of life is typical, but disease develops in some patients in young or mid adulthood. Patients report tripping over objects because of foot drop. Ankle sprains and fractures are frequent.  Because of hammertoes and high arches, patients have difficulty finding well-fitting shoes or experience painful calluses.  Cold feet, often associated with hair loss or leg edema, is common.  Not infrequently, asymptomatic individuals are discovered during screening of families after one relative has been diagnosed • Hereditary motor and sensory neuropathy type 2: – Not infrequently, asymptomatic individuals are discovered during screening of families after one relative has been diagnosed. Hereditary motor and sensory neuropathy type 3 (Dejerine-Sottas syndrome)  This is a rare hypertrophic neuropathy of infancy inherited as an autosomal recessive trait.  The clinical features are those of a severe neuropathy with onset in early childhood.  Motor development is delayed.  Jumping and running are impaired.  Muscular weakness is progressive, affecting legs and arms. Examination  HMNS I  Classic phenotype: distal weakness, decreased tendon reflexes, foot deformities, with or without sensory loss. Weakness and muscle atrophy, which is dominant distally, affect the legs more severely and earlier than the arms.  Sensation may be normal until adulthood, but mild diffuse sensory loss is common.  Hyporeflexia or areflexia is the rule Foot deformities include high arches or flat feet, hammertoes, and tight Achilles tendons. Enlargement and excessive firmness are found in the nerves of more than 25% of patients and are often visible in the superficial cervical nerves and palpable in the arms. Tremor occurs in up to 25% of patients.  Hereditary motor and sensory neuropathy type 2  Peripheral nerves are not enlarged clinically, and weakness of feet and leg muscles predominates; hands are less severely affected than the legs.  Patients experience sensory loss in the distal extremities, and foot deformities (ie, pes cavus) tend to be less marked than those of HMSN 1.  Hereditary motor and sensory neuropathy type 3  General areflexia with prominent enlarged peripheral or cranial nerves is typical.  Patients experience a definite sensory loss, and some patients have marked sensory ataxia Causes  Genetic defects in inherited demyelinating neuropathies. Current estimates indicate that up to 60% of patients with CMT1 have the chromosome 17 duplication.  HMSN type 1A - Duplication on chromosome 17 (region containing human peripheral myelin protein 22 [PMP22] gene), point mutation in PMP22 gene, autosomal dominant inheritance, with the HMSN 1 locus mapped on the short arm of chromosome 17 (p11.2-p12 band)  HMSN type 1B - Point mutation in the P0 gene (an important structural protein of peripheral nerve myelin) on the long arm of chromosome 1, linked to the Duffy blood group  HMSN type 2 - Gene localized to chromosome 1  HMSN type 3 (Dejerine-Sottas disease) Missense and point mutation in PMP22 (recent genetic studies) and the P0 gene, other undetermined causes Investigations • Routine • CSF : CSF protein levels usually are within the reference range in patients with Charcot-Marie-Tooth disease type 1B, but they may be elevated above 100 mg/dL. By contrast, CSF protein is elevated in most but not all cases of Dejerine-Sottas syndrome. • Charcot-Marie-Tooth disease type 1 is characterized typically by diffuse and uniform motor conduction velocity slowing in virtually all the nerves tested. • Motor NCVs are near normal or normal in patients with HMSN 2. Sensory nerve action potentials (SNAPs) are reduced uniformly or are absent. • Motor conduction velocities are reduced markedly, usually below 10 m/s in patients with HMSN 3 (ie, Dejerine-Sottas syndrome). • Nerve biopsies from patients with CharcotMarie-Tooth disease show evidence of a hypertrophic demyelinating neuropathy, with onion bulbs as evidence of chronic remyelination and loss of myelinated fibers, preferentially those of large diameter. • Focally sausagelike thickenings of myelin sheath (tomacula) have been described in patients with Charcot-Marie-Tooth disease • Dejerine-Sottas syndrome and congenital hypomyelination neuropathy are characterized by more severe hypomyelination and demyelination and axonal loss. Management • Prevention, recognition, and treatment of acquired neuropathies are particularly important if compression neuropathies are to be avoided. • This may require adjustments in lifestyle and avoidance of job-related nerve injury. Patients, family members, and physicians must be aware of drugs that can affect the peripheral nervous system. • Physical therapy is often required to prevent and treat joint deformities. • Pain may result from joint deformities or compensatory overuse of certain muscle groups. – (NSAIDs). – Dysesthetic pain may occur but is not typical; it responds to antidepressants, such as amitriptyline, desipramine, or paroxetine, and to anticonvulsants, such as gabapentin or carbamazepine • Surgical Care: Depending on the degree of foot deformities, patients may benefit from Achilles tendon lengthening, tendon transfers, hammertoe correction, and release of the plantar fascia. Entrapment neuropathy • Repetitive motion, force, posture, and vibratory influences on the peripheral nerves of the upper extremity are blamed as contributing factors to the development of neuropathic symptoms. Pathophysiology • The phrase compressive neuropathy implies that the peripheral nerves are being impinged upon by adjacent anatomic structures. The resultant injury is assumed to be related to reduced epineural blood flow • The relative ischemia decreases axonal transport and, in turn, the nerve's ability to conduct impulses. • Long-standing disease can produce irreversible damage, in the form of scarring or fibrosis, and loss of motor endplates, causing muscle atrophy. • The double-crush theory predicts that a compressive lesion at one point along a peripheral nerve lowers the threshold for occurrence of compression at another site secondary to internal derangement of nerve cell metabolism • Vascular - Diabetes, microcirculatory disease • Inflammatory - Synovitis, rheumatoid arthritis • Trauma - Supracondylar humerus fracture, lunate dislocation • Anatomical - Anomalous muscles, vascular plexus, fascial bands • Metabolic - Pregnancy, hypothyroidism • Iatrogenic - Injections, hematomas • Neoplastic - Ganglion, lipoma, sarcoma Common neuropathies • Median nerve  Pronator syndrome  Anterior interosseous syndrome  Carpal tunnel syndrome • Ulnar nerve  Cubital tunnel syndrome  Ulnar tunnel syndrome • Radial nerve  Radial tunnel syndrome  Posterior interosseous syndrome  Superficial radial nerve syndrome Median nerve syndromes • Pronator syndrome  Sites of compression: These include the lacertus fibrosus (bicipital aponeurosis, superficial forearm fascia), the Struthers ligament (thickened or aberrant origin of pronator teres from distal humerus), the pronator teres (musculofascial band or compression between 2 muscular heads), and the FDS proximal arch or the flexor digitorum superficialis.  Signs and symptoms:  pain in the volar forearm that is exacerbated with activity and relieved by rest;  decreased sensation in the thumb, index finger, long finger, and radial side of the ring finger; weakness of thenar muscles; and a positive Tinel or Phalen sign in the proximal forearm.  Treatment:  Nonsurgical or conservative treatment includes rest and anti-inflammatory medications.  Surgical treatment includes exploration of the median nerve in the proximal forearm, an incision distal and more or less proximal to the antecubital fossa in a zigzag fashion across the joint, and the release of all sites of possible compression Anterior interosseous syndrome  Nerve anatomy: The anatomy includes the branch of the median nerve arising approximately 6 cm below the elbow and supplying motor function from the FPL, pronator quadratus, and FDP to the index finger.  Etiology: Causative factors include tendinous bands, a deep head of the pronator teres, accessory muscles (including the Gantzer muscle, which is the accessory head of the FPL), aberrant radial artery branches, and fractures. • Symptoms: – vague pain in the proximal forearm – weakness of the FPL and FDP to the index finger. – Affected persons cannot form a circle by pinching their thumb and index finger (ie, hyperextension of index distal interphalangeal joint and thumb interphalangeal joint). – Sensory involvement is not described  Treatment:  Nonsurgical treatment includes rest, antiinflammatory medications, and splints.  Surgical treatment includes exploration of the median nerve through an approach similar to that for pronator syndrome, release of the lacertus fibrosus and division superficially more or less to the deep heads of the pronator teres, and ligation of crossing vessels. Carpal Tunnel Syndrome • Anatomy: The carpal tunnel is formed by carpal bones (floor), the transverse carpal ligament (roof), the scaphoid and trapezium (radial aspect), and the pisiform and hook of the hamate (ulnar aspect). The tunnel contains 4 FDS muscles, 4 FDP muscles, the FPL, and the median nerve. • Etiology: Causative factors may include accessory muscles (manus)/lumbricals, tenosynovitis, rheumatoid arthritis, type 1 diabetes mellitus, pregnancy, a ganglion, foreign or loose bodies, repetitive motion, carpal fractures or dislocations, or a persistent median artery. • Symptoms: – decreased sensation, paresthesias, and tingling in the distribution of the median nerve; – worsened symptoms with repetitive use; – night awakening with tingling or numbness; – radiation of pain up the forearm; – a positive Tinel or Phalen sign or compression at the wrist; and – possible thenar muscle wasting with advanced cases. • Studies: – EMG or a nerve conduction velocity study can be used in difficult cases or with polyneuropathy. – radiographs help rule out occult fractures, a foreign body, or tumors. – Laboratory studies may include an erythrocyte sedimentation rate, blood glucose value, thyroid evaluation, and rheumatoid factor • Treatment: – Nonsurgical: • wrist splinting in a neutral position to minimize intratunnel pressures at night due to posture; • anti-inflammatory medications; • steroid injections for transient relief; and an • alteration of work station arrangement or the amount of repetitious motion, with breaks or a total change in work activities. – Surgical therapy • in refractory cases or • those not responsive to nonsurgical measures. • All surgical techniques focus on release of the volar transverse carpal ligament. • The main goal is complete release of the ligament without injury to the palmar cutaneous, thenar, and main branch of the median nerve. • Risks: These may include bleeding, infection, and a tender scar; injury to nerves, palmar arch vessels, or tendons; failure to completely release the ligament; and recurrence. • Recovery: Some advocate short-term (3-5 d) wrist immobilization. Others advocate immediate movement to prevent scar formation. Sutures are removed in 2 weeks. Ulnar nerve entrapment • Cubital tunnel syndrome  Anatomy: The ulnar nerve runs adjacent to the medial head of the triceps into the groove behind the medial epicondyle of the humerus. It passes beneath the fascia joining the 2 heads of the FCU and lies on the superficial surface of the FDP • Sites of compression: These include the Struthers arcade, the anconeus epitrochlearis, the intermuscular septum, and the aponeurosis of the FCU. • Signs and symptoms: – pain in the forearm, which radiates in the distribution of the ulnar nerve; – numbness; tingling in the 1.5 fingers of the ulnar aspect; – wasting or weakness of intrinsic hand muscles; – recurrent subluxation of the nerve over the epicondyle; – and the reproduction of symptoms with elbow flexion, with or without wrist extension. • Treatment: – Nonsurgical:nighttime pillow splints to keep the elbow extended. Rest and antiinflammatory medications are also useful. – Surgical methods focus on releasing the nerve along its course at sites of compression, preventing subluxation over the medial epicondyle, and preventing traction or tension on the nerve with elbow motion. – Most commonly, decompression, medial epicondylectomy, anterior transposition (subcutaneous vs submuscular), or a combination of these is used. Ulnar tunnel syndrome (Guyon canal)  Anatomy: This is the triangular canal at the base of the ulnar side of the palm.  It is bordered laterally by the hook of the hamate and the transverse carpal ligament. The medial wall is formed by the pisiform and the attachments of the pisohamate ligament. • Both the ulnar nerve and artery traverse the canal to enter the hand. • The dorsal cutaneous branch of the ulnar nerve branches before the nerve enters the Guyon canal • Etiology: – repeated blunt trauma from power tools and gripping or hammering with the palm of the hand. – Fractures of the hook of the hamate can impinge on the nerve. – tumors such as ganglia or lipomas, anomalous muscle bellies, or hypertrophy of the palmaris brevis. Thrombosis or aneurysm of the artery may compress the nerve • Symptoms: – numbness and tingling, paresthesias and pain in an ulnar distribution of the palm and the 1.5 digits of the ulnar aspect, – cold intolerance in the ring and small fingers, – normal sensation in the dorsal sensory cutaneous branch of the ulnar nerve, and – a positive Tinel or Phalen sign.  Treatment:  Nonsurgical treatment:  rest and avoidance of provocative activities.  Immobilization with a splint and corticosteroid injections are also effective.  Surgical treatment : surgical decompression of the Guyon canal through the carpal tunnel or through a zigzag wrist crease–traversing incision.  Complete exploration should be performed to help exclude a mass or aneurysm that requires repair. Radial nerve entrapment • Radial tunnel syndrome  Anatomy: Compression neuropathy of the radial nerve is considered somewhat more rare than the other compression neuropathies of the upper extremity.  The radial tunnel proper is somewhat ill defined, but it is usually considered the area where the radial nerve exits between the brachioradialis and the brachialis muscles to where it derives below the supinator muscle (Frohse arcade). • Etiology: 5 structures within the radial tunnel. – The most common site of compression is at the proximal fibrous edge of the supinator muscle, known as the arcade of Frohse. – The most proximal structure causing compression is fibrous fascia over the radiocapitellar joint. – radial recurrent artery and the venae comitantes, known as the leash of Henry. – distal edge of the supinator muscle, which is known to be fibrous in 50-70% of patients • Symptoms: These may include pain in the upper extensor forearm; dysesthesia in a superficial radial nerve distribution; and weakening of the extension of the fingers, thumb, or wrist • Treatment: Surgical treatment includes release of the muscle and superficial slip of the supinator ligation and transection of the vascular leash or release of the fascial bands. The supinator muscle should also be released. Posterior interosseous syndrome  Etiology: Causes may include entrapment of the nerve in a supinator, fracture or dislocation of the radial head, tumors (eg, ganglion, lipoma), and iatrogenic causes resulting from open reduction/internal fixation of proximal radius fractures.  Symptoms:  proximal forearm pain.  No sensory deficit is described,  partial-to-complete motor paralysis of the extensors . Often, the brachioradialis and extensor carpi radialis brevis/extensor carpi radialis longus, which are innervated by more proximal branches, are spared. Therefore, any remaining wrist extension also displays radial deviation.  Treatment: Surgical exploration and decompression through an approach similar to that for radial tunnel syndrome Superficial radial nerve syndrome (Wartenberg syndrome)  Anatomy: The superficial radial nerve exits between the brachioradialis and the extensor carpi radialis longus tendons at the junction of the proximal two thirds to distal one third of the forearm. The superficial radial nerve then courses in a superficial subcutaneous plane to provide sensation to the dorsal aspect of the hand from the thumb to the junction of the ring and long fingers. Sensation to the digits is provided up to the area of approximately the dorsal proximal interphalangeal joint • Sites of compression: Fascial bands in the subcutaneous plane at its exit site, the tendons of the brachioradialis, and the extensor carpi radialis longus tendons compress the nerve • . • Symptoms: decreased sensation, paresthesia, and tingling in the distribution of the superficial radial nerve. • A positive Tinel and compression sign is present at the site of exit of the superficial radial nerve. The symptoms are often provoked by extreme pronation of the wrist • Treatment: – Nonsurgical treatment includes wrist splinting in a neutral position and anti-inflammatory medication, which may decrease symptoms in the early stages. – Surgical treatment includes surgical resection of part of the brachioradialis tendon to allow for an easy glide motion of the superficial radial nerve at its exit point. Reflex sympathetic dystrophy • Reflex sympathetic dystrophy (RSD) is a clinical syndrome of variable course and unknown cause characterized by pain, swelling, and vasomotor dysfunction of an extremity. This condition is often the result of trauma or surgery • A type of complex regional pain syndrome (CRPS), which may develop after an initiating event, such as trauma or surgery or may occur spontaneously. • Under this classification, causalgia is a type of CRPS that develops after nerve injury. Pathophysiology • Three conditions are deemed important in the development of RSD. – persistent painful lesion, – a predisposition or susceptibility to developing RSD, – abnormal sympathetic reflex. • Susceptibility factors are unknown and may include genetic predisposition (HLA typing) and, in some patients, a tendency toward increased sympathetic activity. This includes cold hands, hyperhidrosis, or a history of fainting. • In healthy patients, a sympathetic response to injury occurs, with vasoconstriction designed to prevent blood loss and swelling. • This initial response soon subsides and gives way to vasodilatation and increased capillary permeability, allowing tissue repair. • In patients with RSD, this sympathetic response continues unabated. • The reasons for the perpetuation of the response is not known but may be related to central dysregulation of nociceptive impulses. • This dysregulation may be mediated by wide dynamic range neurons in the spinal cord • Prolonged ischemia from the vasoconstriction produces more pain, establishing a reflex arc that promotes further sympathetic discharge and vasospasm. • This is compounded by the local response to trauma, with liberation of substantial amounts of proinflammatory mediators, such as histamine, serotonin, and bradykinin. • The result is a swollen, painful, stiff, nonfunctioning extremity Age:  Most patients are aged 30-60 years, and the mean age is 49 years.  RSD occurs in children and has a much better prognosis than in adults Clinical features • The 3 clinical stages of disease are acute, subacute, and chronic • Acute: lasts approximately 3 months. – Pain, often burning in nature, is one of the first symptoms. – Swelling, redness with vasomotor instability that worsens with dependency, hyperhidrosis, and coolness to the touch are common physical findings. – Demineralization of the underlying bony skeleton begins because of disuse. • Subacute stage: can last for up to 9 months. – persistent severe pain in the extremity and fixed edema that was reversible with elevation during the acute phase. – The redness of the acute stage gives way to cyanosis or pallor and hyperhidrosis to dry skin. – Loss of function progresses, both because of increased pain and also because chronic inflammation begins to cause fibrosis of the joints. In the hand, this leads to flexion deformity of the fingers. – The skin and subcutaneous tissues begin to atrophy. – Demineralization of the underlying bony skeleton becomes quite pronounced • • Chronic phase: 1 year after the onset of disease. – Pain may continue undiminished or abate. – Edema tends to subside over time, leaving fibrosis around the involved joints. – The skin is dry, pale, cool, and shiny. – Flexion and extension creases are absent. – Loss of function and stiffness are marked, – osteoporosis is extreme. – In the upper extremity, this can manifest as a frozen shoulder and claw hand. • Reflex sympathetic dystrophy (RSD) commonly involves only one extremity. It is bilateral in approximately 25% of cases but usually is more prominent on one side.  Pain  constant and disproportionate to the precipitant injury  exacerbated by ambient factors such as loud noises and emotional factors (eg, stress, light touch, active motion, passive motion)  burning, cutting, searing, pressure, or tearing  Usually begins locally but may progress to involve the entire extremity  Historical evidence of prior increased sympathetic activity may be present.  Hyperhidrosis  Cold hands  Fainting  Prior trauma, which may be trivial or significant (eg, Colles fracture), with or without diagnosable nerve injury  Prior surgery  Recent limb immobilization due to hemiplegic stroke, myocardial infarction  Systemic disease such as diabetes Examination  Edema  Edema is the most constant physical finding and is always disproportionate to the severity of the precipitant injury or event.  Stiffness.  Discoloration • Abnormal skin moisture • Tenderness initially is localized but may progress to generalized  Atrophy of the skin and subcutaneous fat pads  Fibrosis of the palmar fascia  Absence of extensor and flexor creases over joints  Frozen shoulder, flexion deformities of the fingers, claw hand Causes  RSD usually is posttraumatic or postsurgical; however, it can occur in a previously healthy extremity with no known trigger.  Trauma  Penetrating wounds  Lacerations  Abrasions  Venipuncture  Intramuscular (IM) injection of medication or illicit drugs  Crush injuries and blunt trauma  Neck or shoulder injuries  Acute traumatic carpal tunnel syndrome  Chest trauma  Sprain, fracture, or dislocation  Postsurgery  Carpal tunnel release  Dental extractions  Cervical rib resection  Fracture repair (Colles fracture)  Postarthroscopy  Local disease  Nerve compression syndromes  Arthritis  Tissue ischemia  Stenosing tenosynovitis  Systemic disease  Myocardial infarction  Stroke  Pancoast tumor  Pancreatic cancer  Herpes zoster Investigations • Routine: acute phase reactants may increase • X-ray : show demineralization • Radionuclide imaging: Findings on 3phase bone scan are positive in 50-90% of patients, and this study is most useful in early disease Management • Aggressive mobilization of the involved extremity as soon as possible, with passive and then active range of motion exercises • Two major approaches to the medical treatment of early RSD exist: sympathetic blockade and anti-inflammatory therapy • Sympathetic block (upper extremity, stellate; lower extremity, lumbar) • Use 1-2 blocks per week. An average of 45 blocks is required to establish permanent relief of symptoms. • For symptoms that are not adequately relieved after 4-5 blocks, institute a continuous stellate blockade via a subcutaneously placed catheter or conduct an operative sympathectomy. • Sympatholytic drugs • Baclofen, a GABA-receptor agonist • Anti-inflammatory medications (corticosteroids, calcitonin) Surgery • Upper thoracic or lumbar sympathectomy  Indications  Duration of disease for longer than 6 months  Failure of permanent resolution after 5 percutaneous sympathetic blocks are performed  Spinal cord stimulation: A recent controlled trial demonstrated the efficacy of epidural implantation of a spinal cord stimulator to relieve pain and function in RSD (hand or foot) compared to physical therapy alone. Radiation induced neuropathy • Radiation-induced brachial plexopathy can occur when radiotherapy is directed at the chest, axillary region, thoracic outlet, or neck. Pathophysiology • The mechanism is believed to be a combination of localized ischemia and failure of cellular proliferation. The net result is fibrosis of the neural and perineural soft tissues secondary to microvascular insufficiency. C/F  The interval from the last dose of radiation to the first symptom of plexus disorder varies widely.  The average interval range reported is 7.5 months to 6 years.  Sensory symptoms, such as numbness, paresthesia, and dysesthesia, along with swelling and weakness of the arm, are the predominant presenting symptoms.  These neurologic symptoms can be progressive and may lead to a weak and edematous arm.  Pain • Neurologic findings are most prominent in the C5-C6 myotomes and dermatomes, as well as diminished deep tendon reflexes supplied by C5-C6. Management • Rehabilitation : – Physical therapy – occupational therapy • Surgical Intervention:  Glenohumeral joint arthrodesis rarely is indicated.  Lymphatic bypass surgery interventions to divert or to redirect lymphatic flow rarely are required. • Deterrence/Prevention:  Use radiotherapy doses below 60 cGy. • Complications:  Lymphangitis  Cellulitis  Complex regional pain syndrome, type 2  Glenohumeral joint subluxation  Contractures in the involved upper extremity • Prognosis:  One third of patients experience significant progression of their radiation-induced plexopathy, whereas the remainder of patients demonstrate gradual progression. Toxic neuropathy • Patients with toxic etiologies for neuropathy are less common than patients with other neuropathies such as those due to hereditary, metabolic, or inflammatory causes. • Drug-related neuropathies are among the most common toxic neuropathies. Pathophysiology • Divided into 3 groups based on the presumed site of cellular involvement: • (1) neuropathy affecting the cell body, especially those of the dorsal root ganglion, (2) myelinopathy or schwannopathy with primary segmental demyelination, and • (3) distal axonopathy causing dying back axonal degeneration.(most common form), C/F • symptoms of pain, tingling, or numbness in their feet, consistent with dysfunction affecting the longest and largest fibers of the PNS.  In some cases, they may have weakness (distal more than proximal) or difficulty with gait  Pain  Autonomic symptoms • ―triad of sensory changes in a glove and stocking distribution, distal weakness, and hyporeflexia.‖ • Slow recovery. Recovery proceeds at a rate of 2 mm/day and may take months or several years, or may never be complete. Function is restored in reverse order to the sequence of loss. • Signs of CNS disease • Alopecia is a clinical hallmark of thallium toxicity that may develop weeks after intoxication. Causes • Drugs – amiodarone, – chloramphenicol, – dapsone, – diphenylhydantoin, – disulfiram, – gold, – isoniazid, – lithium, – metronidazole,  Industrial chemicals  acrylamide, carbon disulfide, inorganic mercury, methyl n-butyl ketone,  organophosphate parathion, polychlorinated biphenyl, thallium, triorthocresyl phosphate, and vinyl chloride  heavy metals arsenic and lead, as well as the solvents n-hexane, perchloroethylene (PERC) – ethylene oxide (EtO), styrene, toluene, and mixed solvents. Management  Advise removal from occupational or environmental exposure.  Advise discontinuation of medication or recreational drug habit. Also provide information regarding how alcohols affect those with exposures.  Acute care for those intoxicated with recreational, industrial, or other agents is discussed in other articles on this web site.  Preventive care and supportive care should include consideration of life stressors, diet, and overall behavior Medical • lipoic acid, evening primrose, and vitamin E. Vasculitic Neuropathy • Peripheral neuropathy is common in many vasculitic syndromes and may be the only manifestation of the underlying vasculitic disease. • Vasculitic neuropathy can be a part of systemic vasculitis. • It also can present as a nonsystemic vasculitic neuropathy, without any constitutional symptoms or serologic abnormalities. • The clinical and pathologic features are those of an ischemic neuropathy caused by a necrotizing vasculitis of small arterioles. • Patients with vasculitic neuropathy may present with either mononeuritis multiplex or asymmetric sensorimotor neuropathy. Symmetric neuropathy is rare. • It can present as acute/subacute relapsing, progressive, or relapsing progressive neuropathy. • Asymmetric or multifocal painful sensorimotor neuropathy is the most common presentation. • Asymmetry and length-independent involvement are the hallmarks of mononeuritis multiplex, which is the most common presenting feature of vasculitic neuropathy Pathophysiology • Wallerian degeneration of nerves results from ischemic infarction caused by inflammatory occlusion of the blood vessels. • Segmental fibrinoid necrosis of a vessel wall and transmural inflammatory cell infiltration are the main pathologic features of vasculitis. • Immune complexes are formed as a result of antibodies reacting with antigen found within the blood vessel walls. • These immune complexes within the circulation activate the complement cascade, generating chemotactic factors responsible for recruitment of polymorphonuclear leukocytes at the local site of deposition of the complex • Necrotizing vasculitis causes neuropathy through ischemic injury to the vessels supplying the nerve • Cranial nerve involvement also has been reported in systemic vasculitis. • Facial nerve neuropathy is observed most commonly, occasionally accompanied by abnormalities in cranial nerve III, VI, or X. C/F  Asymmetric or multifocal painful sensorimotor neuropathy is the most common presentation.  Duration of neuropathy symptoms before biopsy or diagnosis ranges from 3 weeks to 5 years (mean 8 ± 11 mo).  Constitutional symptoms, including weight loss, anorexia, fatigue, arthralgias, myalgias, and fevers, occur in about two thirds of patients.  Neuropathies are painful in more than 80% of patients.  Most patients, about 75%, experience at least one acute attack, but about 25% have an indolent slowly progressive course from onset. In about half of all patients, the neuropathy follows an acute relapsing course.  Typically, the initial symptom of vasculitic neuropathy is acute pain poorly localized in the affected area or limb. Deep aching and burning pain or tingling in the affected nerve distribution appears a few days later. This is followed by weakness in the distribution of the involved nerve. • Weakness in vasculitic neuropathy is mostly focal and presents acutely. On examination, about three quarters of patients have an asymmetric polyneuropathy, either as a multiple mononeuropathy or, less commonly, as an asymmetric polyneuropathy Causes • Systemic vasculitis  Polyarteritis nodosa  Churg-Strauss syndrome  Wegener granulomatosis  Overlap syndrome  Cryoglobulinemia • Hypersensitivity vasculitis  Henoch-Schönlein purpura  Serum sickness  Infectious vasculitis (eg, HIV, hepatitis B)  Drug-induced vasculitis (eg, cocaine, heroin)  Neoplasm (eg, chronic lymphocytic leukemia)  Cryoglobulinemia  Behçet syndrome • Giant cell arteritis – Temporal arteritis – Takayasu arteritis  Collagen vascular  Rheumatoid arteritis  Systemic lupus erythematous  Sjögren syndrome  Systemic sclerosis • Early use of an aggressive immunosuppressive agent is indicated to treat vasculitic neuropathy. • Combination therapy with corticosteroids and cyclophosphamide is reported to be more effective than monotherapy in inducing remission and improving disability and in reducing relapse rate and chronic pain. Prognosis • The long-term outlook for such patients is poor, with a 5-year survival rate of approximately 50%; most excess deaths are due to vascular disease. • The prognosis in nonsystemic vasculitic neuropathy is substantially better than in systemic vasculitis. Traumatic nerve injuries  Complete and incomplete  Complete injuries disrupt all the neurons traversing the injured segment, causing total loss of distal motor or sensory function.  Incomplete lesions disrupt some neurons but leave others unaffected, with some sparing of distal motor or sensory function.  An incomplete nerve injury implies that at least part of the nerve remains in continuity; this has important therapeutic implications • Pathophysiologic responses to trauma at the neuronal level comprise only 2— demyelination and axonal loss. • Segmental demyelination (ie, neurapraxia): mild stretch or compression injury may disrupt or distort the myelin sheath at the injury site, resulting in focal demyelination and leaving the axons intact. • This causes a transient state of disrupted conduction along the injured segment— conduction slowing or block. • Because the axons remain intact, function can be restored by focal remyelination, • Axonal injury and wallerian degeneration: Axonal function is disrupted immediately after the injury, although the disconnected distal segment initially survives and conducts externally applied stimuli; • over the course of the next 5-7 days, however, the distal axonal segment slowly degenerates in a centrifugal fashion and eventually becomes inexcitable. • The neuron may recover subsequently by axonal regeneration from the intact cell body, which is a slow process occurring at a rate of about 1 mm/day. • Axonal injuries that spare the supporting perineural connective tissue sheath are known as axonotmetic. • The intact perineural connective tissue sheaths provide a conduit for axonal regeneration from the cell body to the target muscle, facilitating recovery. • Injuries that disrupt the whole nerve, affecting both the axon and supporting connective tissue, are known as neurotmetic. • These injuries are less likely to recover by axonal regeneration; they more often require surgical repair. • Mixed injuries Management  Incomplete injuries  Incompletely injured nerves remain in (at least partial) continuity; therefore, they are likely to recover spontaneously.  In general, patients with incomplete nerve injuries should be treated conservatively.  Lesions are judged to be partial when some residual motor or sensory function is noted in the distribution of the injured nerve segment.  Complete injuries  Complete nerve lesions caused by lacerations or penetrating injuries should be referred for early surgical exploration and direct end-toend repair.  Management of other complete nerve injuries depends on whether the pathophysiology of injury is thought to be neurapraxic, axonotmetic, or neurotmetic • Complete nerve injuries that are predominantly neurapraxic can be expected to recover favorably over the course of weeks to months. • Axonotmetic injuries are more likely to recover spontaneously. • Neurotmetic injuries often require surgical repair for adequate recovery. • The only way to differentiate these injury types noninvasively is to monitor the patient for signs of recovery. • the chances of successful surgical repair begin to decline by 6 months after the injury. • By 18-24 months, the denervated muscles usually are replaced by fatty connective tissue, making functional recovery impossible. • close clinical observation is warranted for 3-6 months after this type of nerve injury. • If no clinical or electrophysiologic evidence of recovery is noted during this period, these patients should be referred for surgical exploration. Nerve repairs • In the seventh century, Paulus Aegineta was the first to report the use of suture and agglutination to repair nerves. • Other physicians who performed early work with nerves and their repair include Rhazes and Avicenna in the ninth century, Ali Abu Ibn Sina in Persia during the 10th century, and Ferrara in Italy in the 17th century • The questions involved with nerve repair involve 2 main areas, namely, (1) when to do the repair and (2) what type of repair to perform. • Primary repair is generally considered within the first few days, • delayed primary by the end of the first week, and • secondary closure beyond that Selection of Operative Procedure Surgery ECA VB GP PPI DPI End-to-end closure Nerve graft Yes No Yes Yes Yes Yes Yes Yes Yes Yes Vascularized graftNo Conduit Nerve transfer No No No Yes No No Yes No No Yes Yes No Yes Yes ECA VB GP PPI Ends can approximate Vascularized Bed Graft Possible Proximal Portion Intact DPI Distal Portion Intact • Primary closure has been found to be superior to secondary closure • Surgically, the most favorable form of repair is the end-to-end approximation • Contraindications: – Medically unstable patient from other injuries and/or illnesses  Presence of a grossly contaminated wound bed  Active soft tissue infection in the region of the nerve injury  Severely compromised nutrition  Patient unable and/or unwilling to comply with required activity restrictions  Patient with unrealistic expectations  Presence of underlying skeletal instability  Uncertain delineation of zone of injury (requires waiting period) Common Donor Sites Graft Donor Site Distal posterior interosseous nerve Length Obtained 15-20 cm Sensory Deficit Dorsal wrist joint Lateral antebrachial cutaneous nerve Medial antebrachial cutaneous Superficial radial Lateral femoral cutaneous 15 cm 20 cm 25 cm 30 cm ateral forearm surface Medial and anterior surface of FA Dorsal radial hand surface Lateral and thigh Anterior femoral cutaneous Sural 40 cm 40 cm Medial and anterior thigh Lateral foot surface and a portion of the heel Saphenous 5-40 cm Medial foot surface Potential complications  Hematoma of large or small vessels  Failure of sutures or grafted structures  Traction due to adhesions or repair using joint repositioning  Fibrosis of the nerve or nerve graft if no profusion occurs for long periods (This is especially common if the repair is placed under tension or in an unvascularized bed.)  Neuroma formation following incomplete repair  Entrapment of the nerve following the repair due to excessive scar tissue formation or pressure from associated wounds Prognosis • Timing • Better results have been demonstrated when the repair is performed sooner. Good results can be expected if the repair is performed before the 6-month mark. Muscle neuromuscular junctions are usually absent after 15-18 months of inactivity; thus, sooner reinnervation is better. • Patient age • Young patients tend to achieve much better results than older patients, probably due to the elasticity of the CNS and the increased ability to heal. • Condition of the wound • A clean, small, noninfected wound fares much better than a wound full of debris or infection or one that is missing a great deal of tissue. • Level of injury • The chances of regeneration are better for injuries that are more distal. Proximal injuries are less likely to regenerate because the distance required for reinnervation is much greater and the percentage of cells lost in the distal portion of the nerve is greater. Also, if the proximal injury is a traction-type injury, it can pull the cell body out of the anterior horn, resulting in neuron death and no regeneration. • Gap size • Gap size is different from the amount of tissue loss. The gap size is simply the distance between ends that must be closed. If the nerve is left in the severed condition, it retracts over time, increasing the gap size due to the elastic properties of the epineurium. When the gap size is larger, more of a bridge must be filled and the prognosis is worse. • Tension of the repair • Tension tends to increase the fibrotic and scar tissue found within the nerve and the repair site, hindering proper axon regrowth. • Mechanism • The manner in which the nerve was injured is also involved in healing, largely because it affects so many of the other categories. From a surgical point of view, a sharp laceration, such as a knife wound, has a good prognosis, can be closed early, and should do fairly well. Nerve tumours Introduction • Primary tumours are derived from components of the nerve sheath ( Schwann cells, perineural cells, fibroblasts) or from neurons. • Neoplastic and Non neoplastic tumours Benign or malignant Classification • Non neoplastic – Traumatic neuroma – Lipofibromatous hamartomas – Intraneural lesions : Ganglioma, Hemangioma, Lipoma • Neoplastic – Nerve sheath origin • Benign – – – – Schwannoma Neurofibroma Granular cell tumour Neurothekeoma • Malignant – Malignant nerve sheath tumour (MNST) • Nerve cell origin – Priminitive Neuroectodermal tumours – Neuroblastoma – Ganglioneuroma – Ganglioneuroblastoma – Chemodectoma – Pheochromocytoma • Tumours metastatic to nerve Benign Nerve Sheath Tumours • Neurofibroma – most common benign peripheral nerve neoplasm – More frequently seen as a part of neurofibromatosis – Genetic phakomatosis disorder associated with multiple neurofibroma – Transmitted through autosomal dominant gene. – Type- I -- Chromosome 17 - 1 in 3000 – Type II -- Chromosome 22- 1 in 50000 – Trauma also can trigger the formation of Diagnostic Criteria for Neurofibromatosis I and II • Neurofibromatosis I : 2 or more : • Six or more café au lait macules over 5mm in greatest diameter in prepubertal persons and over 15mm in greatest diameter in post pubertal persons • Two or more neurofibromas of any type • Freckling in the axillary or inguinal regions • Optic glioma • Two or more Lisch nodules( iris • Osseous lesion, such as sphenoid dysplasia or thinning of long bone cortex • A first degree relative with neurofibromatosis I Neurofibromatosis II • Either of the following : – Bilateral eighth nerve masses – First degree relative with neurofibromatosis II and either unilateral eighth nerve mass or two of the following : – Neurofibroma – Meningioma – Glioma – Schwannoma – Juvenile posterior subcapsular lenticular opacity Pathology • Can be involving – Large segments of nerve (plexiform) – Localized mass ( globular,Solitary) • Composed of a mixture of proliferating nerve sheath cells likely arising from the peripheral neural fibroblast, and are intimately associated with nerve fibres. • Proliferating cells expand the nerve and envelop the axonal process • Tumour involves the entire cross section of the nerve.Expands the fascicle.Plane of dissection not available Symptomatology • Globular neurofibroma usually present as slowly enlarging, painless,soft ,mobile cutaneous masses. • Plexiform neurofibromas usually develop in deep large nerves and may remain encapsulated by the epineurium. Symptoms arise from axonal compression. Imaging • MRI - Target pattern of increased peripheral signal intensity and decreased central signal intensity on T2 weighted images. Management • Indications of exploration and excision : – Diagnosis – Pain - most common indication – Cosmetic consideration – Progressive neurological deficit – Compression of adjacent tissue – Suspicion of malignancy • Globular neurofibroma can be removed without serious neurological sequelae as they involve small fascicles of cutaneous nerves • Plexiform nerofibroma may extend the length of the nerve and may involve the bulk of the nerve and its branchesremoval may induce neurological deficit. • External Neurolysis can be done for pain. Schwannoma • Neurilemoma was introduced by Stout in 1935 • Replaced by Schwannoma by Ehrlich and Martin in 1943 • Benign slow growing nerve sheath tumours. • Most often are solitary, may be multiple occasionally. • Arise from any peripheral nerve containing schwann cells including distal portions of cranial nerves. • VIIIth nerve -most common cranial Pathology • Presence of only schwann cells ; perineural cells , fibroblasts not present. • Cells arranged in alternating hypercellular palisading ( Antoni A) regions and hypocellular loosely meshed (Antoni B) regions. • Fascicles distinct from tumour, plane of dissection present Management • Symptomatic lesions - surgical excision • Asymptomatic lesions - surgical excision Neurothekoma • Benign tumor of nerve sheath • Also known as nerve sheath myxoma, pacinian neurofibroma and cutaneous neurofibroma • Derives either from a perineural cell line or from the schwann cell line. • More common in females , occurs within the first three decades • Soft , mobile, occasionally tender. • Treatment - Surgical excision • Previously known as malignant schwannoma, malignant neurofibroma, fibrosarcoma etc • 10% of soft tissue sarcomas • 40-60% of MNST arise in the sitting of Von recklinghausen’s disease and about 5% of VRD will develop MNST • Previous irradiation of benign and malignant conditions - 10% risk of MNST Malignant Nerve Sheath Tumour (MNST) • Pain is hallmark of MNST • Mass larger than 2-6cm, irregular borders, rapid expansion, nerulogical deficit. • Gallium -67 citrate scintigraphy used to differentiate malignant from benign tumours in NF . • Treatment - Tumour resection with wide margin,preservation of important vessels followed by radiation /chemotherapy Tumours of nerve cell origin • Priminitive Neuroectodermal Tumor (PNET) – Ewing’s sarcoma,neuroepithelioma, neuroblastoma. – Soft tissues, skeletons, Viscera – Resemble medulloblastoma histologically – Occur in older children/young adults – Aggressive clinical course,poor prognosis – Dissemination to bone -very poor prognosis Others – Neuroblastoma – Ganglioneuroma – Ganglioneuroblastoma – Chemodectoma – Pheochromocytoma Thanks