Diabetic_poly_neuropathy approach for diagnosis

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1. Dedically related neuropathies BY M HAROUN MD NEUROLOGY

2. Differential diagnosis of polyneuropathy Metabolic Disease Diabetic distal symmetric polyneuropathy Diabetic autonomic neuropathy Diabetic mononeuritis multiplex Diabetic polyradiculopathy Renal Disease Systemic Disease Systemic vasculitis Non-systemic vasculitis Paraproteinemia Amyloidosis Cancer Neoplastic disease Paraneoplastic disease Motor neuron disease syndrome Critical Illness Infectious Human Immunodeficiency Virus (HIV) Hepatitis B Lyme Diphtheria Leprosy Syphylis Parasites Inflammatory Acute motor axonal neuropathy Acute motor and sensory axonal neuropathy Acute inflammatory demyelinating polyradiculoneuropathy Chronic inflammatory demyelinating polyradiculoneuropathy Chronic demyelinating polyradiculoneuropathy with anti-MAG antibodies Miller-Fisher Syndrome Multifocal Motor Neuropathy

3. Nutritional Cobalamin Post- gastroplasty Pyridoxine Strachan’s syndrome Thiamine Tocopheral Industrial Agents , Metals and Drugs Industrial Agents Acrylamide Carbon Disulfide Hexacarbons Organophosphorous Agents Drugs Alcohol Amiodarone Chloramphenicol Colchicine Dapsone Disulfiram Vinka alkaloids Platinum Taxol Metals Arsenic Mercury Thallium Hereditary Hereditary Autonomic and Sensory Neuropathy Hereditary Motor Sensory Neuropathy (Charcot-Marie-Tooth Disease) Types 1, 2 Hereditary Neuropathy with Pressure Palsies Porphyria

4. Metabolic diseases

5. Diabetic neuropathy It is a generic term defined as the presence of symptoms and signs of peripheral nerve dysfunction in individuals with diabetes after the exclusion of other causes . It may coincide with other conditions that cause similar manifestations including CIDP, vitamin B12 deficiency, alcoholic neuropathy, and endocrine neuropathies. Additional causes of polyneuropathy may be present in 10% - 55% of patients with diabetes mellitus

6. Hyperglycemic neuropathy Patients with newly diagnosed diabetes may experience transient pain and paresthesias in the distal lower extremities (hyperglycemic neuropathy). The symptoms will usually resolve when the hyperglycemia is brought under control.

7. Treatment -induced neuropathy An acute painful neuropathy may be precipitated following initiation of treatment of a diabetic patient with insulin ( treatment-induced neuropathy). Burning pain and paresthesias develop in the distal lower extremities shortly after the establishment of glucose control.Pain persists for weeks or up to several months, with spontaneous resolution to follow. Pathological studies demonstrate active axonal regeneration, which may act as generators of spontaneous nerve impulses. This phenomenon is said to be more common in the rare form of diabetes mellitus associated with a mitochondrial tRNA mutation at position 3243 .

8. Impaired glucose tolerance neuropathy Peripheral neuropathy can occur before the onset of clinically diagnosable diabetes mellitus; this is known as impaired glucose tolerance neuropathy Impaired glucose tolerance is determined by oral glucose tolerance testing (OGTT), have been demonstrated to have symptoms, diagnostic abnormalities, and intra-epidermal nerve fiber density reduction consistent with a predominantly small-fiber neuropathy, although with changes less pronounced than in their diabetic counterparts The implication for clinical practice is that patients with undiagnosed painful peripheral neuropathy should undergo OGTT ,early diagnosis followed by improved lifestyle may result in reversal of impaired glucose tolerance and neuropathy.

9. Generalized Symmetrical Polyneuropathies Distal sensory or sensori -motor polyneuropathy Small-fiber neuropathy Autonomic neuropathy Large-fiber sensory neuropathy Focal and Asymmetrical Neuropathies Cranial neuropathy (single or multiple) Truncal neuropathy (thoracic radiculo-pathy ) Limb mono-neuropathy (single or multiple) Proximal motor neuropathy ( lumbosacral radiculo-plexopathy,amyotrophy ) Combinations Poly- radiculoneuropathy Diabetic neuropathic cachexia Classification of Diabetic Neuropathies ------------------------------------------------------------------------------------------

10. The large-fiber neuropathy variant It presents with painless paresthesias beginning at the toes and feet, impairment of vibration and joint position sense, and diminished muscle stretch reflexes . In advanced cases, significant ataxia may develop secondary to sensory deafferentation . Large-fiber involvement is often asymptomatic , but sensory deficit may be detected by careful examination.

11. Common stocking and glove distribution in polyneuropathies

12. Small -fiber neuropathy Frequently presents with pain of a deep, burning, stinging, aching character, often associated with spontaneous shooting pains and allodynia to light touch. Pain and temperature modalities are impaired, with relative preservation of vibration and joint position sensation and muscle stretch reflexes. The small-fiber variant is often accompanied by autonomic neuropathy . At times, a painful small-fiber neuropathy develops soon after the onset of IDDM

13. Diabetic neuropathic cachexia It refers to an acute and severe painful diabetic neuropathy associated with precipitous severe weight loss, depression, insomnia, and impotence in men. . The syndrome is more common in men with poor glucose control. Improved glucose control and weight gain often result in recovery and improvement of EDX abnormalities. The reason for profound weight loss, severe pain, and spontaneous recovery remains obscure.

14. Acrodystrophic neuropathy Sensory loss makes patients with diabetes susceptible to repetitive, often unnoticed injuries that set the stage for foot ulcers and distal joint destruction ( acrodystrophic neuropathy). Chronic foot ulceration is one of the more severe complications of diabetes mellitus, occurring in 4% to 10% of patients, and is due to a combination of unnoticed traumatic tissue damage, vascular insufficiency, and secondary infection. Prevention is better than treatment. Daily inspection and proper foot care can prevent or lessen the severity of this complication .

15. Sensory loss may induce osteous changes with collapse of the small foot bones

16. Neuropathic arthropathy , or a Charcot joint formation , It is a complication seen in patients with diabetes who often have foot ulcers and autonomic impairment. Unlike the Charcot joint seen in syphilis, diabetic arthropathy tends to involve the small joints in the feet . The role of pronounced inflammatory reactions and cytokines following the initial joint insult resulting in increased osteoclastogenesis has recently been emphasized The abundance of osteoclasts causes progressive bone loss, leading to further fractures and potentiation of inflammation and osteoclast formation. The term diabetic pseudotabes is applied to patients having severe lancinating pains, loss of joint sensation, and diabetic pupillary abnormalities ( pseudo-Argyll Robertson pupils ).

17. DIABETIC AUTONOMIC NEUROPATHY

18. DIABETIC AUTONOMIC NEUROPATHY Autonomic neuropathy usually correlates with the severity of somatic neuropathy. The spectrum of autonomic involvement ranges from subclinical functional impairment of cardiovascular reflexes and sudomotor function to severe cardiovascular, gastrointestinal, or genitourinary autonomic dysfunction. Orthostatic hypotension , resting tachycardia, or diminished heart-rate response to respiration are the hallmarks of diabetic cardiac autonomic neuropathy. Orthostatic hypotension occurs mainly because of failure of the sympathetic nervous system to increase systemic vascular resistance in the erect posture and impairment of compensatory cardiac acceleration.

19. It is crucial to exclude confounding effects of medications or coexisting hypovolemia when diagnosing neurogenic postural hypotension. Vagal denervation of the heart results in a high resting pulse rate and loss of sinus arrhythmia. An increased incidence of painless or silent myocardial infarction is reported in diabetic patients with autonomic neuropathy. It is important to investigate the cardiac autonomic neuropathy of diabetes by appropriate noninvasive autonomic function tests, because the presence of such autonomic dysfunction predicts cardiovascular morbidity and mortality .

20. Gastrointestinal motility abnormalities It involving the esophagus, stomach, gallbladder, and bowel, as well as fecal incontinence may occur. Delayed gastric emptying , usually of solids, leads to nausea, early satiety, and postprandial bloating. Diabetic diarrhea due to small-intestinal involvement typically occurs at night and is explosive and paroxysmal. However, constipation due to colonic hypomotility is more common than diarrhea. Associated weight loss or malabsorption is rare. Bacterial overgrowth may occur and can often be successfully treated with small doses of tetracycline (250-500 mg/day in a single dose given at the onset of a diarrheal attack) in adult patients.

21. Impaired bladder sensation It is usually the first symptom of urinary autonomic dysfunction It develop insidiously and progress slowly.. Bladder atony leads to prolonged intervals between voiding, gradually increasing urinary retention, and finally overflow incontinence. Patients with diabetes who have neurogenic bladder should be encouraged to void routinely every few hours to prevent urinary retention.

22. Impotence →the first manifestation of autonomic neuropathy in men with diabetes, occurring in more than 60% and causing serious emotional distress. →both erectile failure and retrograde ejaculation. The majority of diabetic men with impotence have some evidence of associated distal symmetrical polyneuropathy . Other possible causes of impotence in diabetic males ; vasculopathies , hormonal alterations, and psychological issues are equally important.

23. Sudomotor abnormalities → distal anhidrosis , compensatory facial and truncal sweating, and heat intolerance. → gustatory sweating is characterized by profuse sweating in the face and forehead immediately following food intake. This often becomes difficult to treat and socially embarrassing. Oral or topical glycopyrrolate may prove partially effective in some patients.

24. Pupillary abnormalities → constricted pupils with sluggish light reaction, which occurs in 20% of unselected diabetic patients. →Due to early involvement of sympathetic nerves that dilate the iris and an imbalance between parasympathetic and sympathetic function.

25. The most serious sequel of autonomic neuropathy A blunted autonomic response to hypoglycemia produces an inadequate sympathetic and adrenal response and hence an unawareness of hypoglycemia that may seriously complicate intensive insulin

26. PROXIMAL DIABETIC NEUROPATHY

27. PROXIMAL DIABETIC NEUROPATHY (DIABETIC AMYOTROPHY OR LUMBOSACRAL RADICULOPLEXOPATHY) it is emphasizing the proximal motor weakness as a distinguishing clinical feature. Diabetic amyotrophy , thoracic radiculopathy , and proximal or diffuse lower extremity weakness should probably be grouped under the single term, diabetic polyradiculopathy , since these disorders seem to be different presentations of the same basic involvement of multiple nerve roots or proximal nerve segments .

28. Diabetic amyotrophy . Clinically, asymmetrical weakness and wasting of pelvi -femoral muscles may occur either abruptly or in a stepwise progression in individuals with diabetes who are older than 50 years. It is rare in young adults or children The onset is unrelated to the duration of diabetes, and the condition may develop in patients with long-standing NIDDM during periods of poor metabolic control and weight loss, but it can also occur in mild and well-controlled diabetics or be the presenting feature of diabetes.

29. Typically, unilateral severe pain in the lower back, hip, and anterior thigh heralds the onset of neuropathy. Within days to weeks weakness ensues, affecting proximal and, to a lesser extent, distal lower-extremity muscles ( iliopsoas , gluteus, thigh adductor, quadriceps, hamstring, and anterior tibialis ). In some cases, the opposite leg becomes affected after a latency of days to months. Reduction or absence of knee and ankle jerks is the rule. Numbness or paresthesias are minor complaints.

30. Weight loss occurs in more than half of patients and is more pronounced than in individuals with non-diabetic lumbosacral radiculoplexopathy The progression may be steady or stepwise and may continue for many months. The result is often a debilitating, painful, asymmetrical motor neuropathy with profound atrophy of proximal leg muscles. Pain usually recedes spontaneously long before motor strength begins to improve. Recovery takes up to 24 months because of the slow rate of axonal regeneration.

31. Diabetic lumbosacral radiculoplexus neuropathy typically affects older patients with type 2 diabetes. Unlike DSP, DLRPN risk is not related to diabetic control or duration. Indeed, DLRPN patients typically have shorter diabetes duration than those with DSP. Electrodiagnostic studies It demonstrate evidence of a polyradiculoneuropathy . Cerebrospinal fluid examination is characterized by elevated protein concentration without pleocytosis . Nerve biopsies demonstrate a microvasculitis . T these features support an autoimmune etiology.

32. Treatment A retrospective case series reported benefit for neuropathic pain in five DLRPN patients treated with intravenous immunoglobulin ( IVIg ) , but a small randomized trial did not demonstrate significant disease modification with IV methylprednisolone . A recent Cochrane review concluded that definitive studies are lacking, perhaps setting the stage for a carefully designed randomized trial of IVIg in this disorder

33. Diabetic TRUNCAL NEUROPATHY Thoracic radiculopathy It involvs the T4 through T12 spinal nerve roots causes pain or dysesthesias in areas of the chest or abdomen, thereby producing diagnostic confusion. Bulging of the abdominal wall as a result of weakness of abdominal muscles may also occur . Truncal pain is seen in older patients with NIDDM and may occur either in isolation or together with the typical lumbosacral radiculoplexopathy .

34. Truncal pain → may occur either in isolation or together with the typical lumbosacral radiculoplexopathy . →burning, stabbing, boring, beltlike pain . Contact with clothing can be very unpleasant The regions of sensory loss or dysesthesia involve the trunk in a highly variable pattern, affecting either the entire dermatomal distribution of adjacent spinal nerves or, more often, restricted areas limited to the distribution of the dorsal or ventral rami of spinal nerves.

35. Bulging of right lower thoracic abdominal wall at level of umbilicus, associated with diabetic truncal monoradiculopathy .

36. LIMB MONONEUROPATHY it is caused by two basic mechanisms: nerve infarction or entrapment. Due to nerve infarction It has a stereotyped presentation, with abrupt onset of pain followed by variable weakness and atrophy. Because the primary pathological lesion results in acute axonal degeneration, recovery tends to be slow. The median, ulnar , and fibular nerves are most commonly affecte EMG studies demonstrate axonal loss Due to nerve entrapment They are more common than nerve infarctions. Usually gradual in onset EMG & NCS → focal conduction block or focal slowing in entrapment.

37. Compressive mononeuropathies in diabetic

38. Compressive mononeuropathies , Especially ulnar , median, and peroneal , are more common in diabetes. Bilateral and non-dominant median mononeuropathy at the wrist are more common in diabetes ( CTS Diabetics is found in 8% to 12% of patients presenting with CTS; 2 fold higher compared to the general population. ) Subclinical CTS Electrophysiological abnormalities consistent with CTS but without symptoms are found in ¼ of diabetic patients,

39. Hand numbness suggests bilateral median mononeuropathies at the wrist (carpal tunnel syndrome) and/or ulnar mononeuropathy at the elbow ( cubital tunnel syndrome) in preference to advanced DSP. Nerve conduction studies should be performed to confirm compressive ulnar or median mononeuropathies , and to screen for associated axonal injury.

40. Those with pure demyelinating injury may respond to nocturnal neutral wrist splints and a regimen of studious avoidance for positional cubital tunnel compression. Patients with active denervation should be referred for carpal tunnel decompression, which is nearly as effective for diabetes patients as for normo-glycemic controls, improving digital sensation in two-thirds. [5] Ulnar transposition from the cubital tunnel improves symptoms in only 50 to 60% of ulnar mono-neuropathy patients

41. Diabetes predisposition to nerve entrapment (Single / multiple) The Possible reason → aggravation of ischemia in nerves already stressed by chronic endoneurial hypoxia may be one factor. → obesity, rather than diabetes, may be the primary driver of increased carpal tunnel syndrome risk The possibility of occult diabetes should always be kept in mind in every case of entrapment neuropathy.

42. MULTIPLE MONONEUROPATHIES

43. MULTIPLE MONONEUROPATHIES Mononeuritis multiplex The condition refers to the involvement of two or more nerves. As in mononeuropathy , the onset is abrupt in one nerve, and then other nerves are involved sequentially at irregular intervals. Nerve infarction results from occlusion of the vasa nervorum . Because multiple mono-neuropathies occur most frequently in systemic vasculitis , this possibility should always be considered in the differential diagnosis of diabetic multiple mononeuropathies .

44. CRANIAL MONONEUROPATHIES Diabetic third-nerve palsy. it is the most commonly encountered diabetic cranial mono-neuropathy. Pupillary sparing, the hallmark of diabetic third-nerve palsy, results from ischemic infarction of the centrifascicular oculomotor axons due to diabetic vasculopathy of the vasa nervorum . The peripherally located pupillary motor fibers are spared as a result of collateral circulation from the circumferential arteries.

45. With decreasing frequency, the fourth, sixth, and seventh nerves are also affected. Patients with Bell palsy have a significantly higher frequency of diabetes than an age-matched population. Most make a full recovery in 3 to 5 months.

46. Pathology

47. Pathology In proximal nerve Whether ischemic or inflammatory lesions in multiple lumbar roots, plexus, or proximal nerve segments are responsible for this particular diabetic complication still remains to be decided. Postmortem examination of the obturator nerve in a single case of proximal neuropathy showed multiple infarcts due to occlusion of the vasa nervorum.However , lumbar nerve roots were not examined. Studies of peripheral sensory nerves in patients with diabetic lumbo -sacral radiculo-plexopathy reveal micro- angiopathy and evidence of ischemia

48. The pathological lesions of symmetrical distal polyneuropathy The sural nerve →loss of myelinated fibers, acute axonal degeneration, some degree of demyelination, → blood vessel vasculopathy . characterized by narrowing or closure of the endoneurial capillary lumen by hyperplastic endothelial cells, thickening of the capillary wall, and marked redundancy of basement membranes. →Dying-back centripetal axonal degeneration is evident.

49. Type of neuropathy/ pathology Painless distal polyneuropathy affects predominantly the large-nerve fiber populations, whereas Painful distal diabetic polyneuropathy often shows marked depletion of small myelinated and unmyelinated fibers. In the latter condition, active axonal regeneration gives rise to abnormal nerve impulses and neuropathic pain . The reason for demyelinating process →the result of primary progressive axonal atrophy or →direct damage to Schwann cells secondary to ischemia &metabolic disturbances

50. The pathological lesions P roximol neuropathy Nerve fiber loss →distributed multifocally within individual and different fascicles (differential fascicular involvement), a pattern similar to that seen experimentally from injection of microspheres into the peripheral nerve vasculature to cause occlusion of multiple endoneurial blood vessels. Fiber depletion increases from proximal to distal in the nerves. This finding correlates with electrophysiological studies demonstrating a diffuse abnormality of NCVs with proximodistal gradients.

51. A Normal sural nerve showing an abundant and normal distribution of myelinatedfibers . Sural nerve biopsy IN DIABETIC B Sural nerve from a patient with diabetes showing severe loss of axons Normal Diabetic

52. C High magnification view of B showing loss of myelinated fibers, splaying of myelin with early onion bulb form formation

53. Laboratory Findings

54. The revised 2003 American Diabetes Association criteria for diagnosis of diabetes defines a normal fasting plasma glucose as being equal or less than 100 mg/ dL Impaired fasting glucose (IFT) occurs when the glucose level is above 100 mg/ dL but below 126 mg/ dL . An impaired glucose tolerance (IGT) is defined as a 2-hour plasma glucose level between 140 mg/ dL and 199 mg/ dL following ingestion of 75 g of oral glucose. .

55. Diabetes is defined as fasting blood glucose above 126 mg/ dL or the 2 hours level of greater than 200 mg/ dL in the OGTT. Glycosylated hemoglobin (hemoglobin A1c) is a useful indicator of the long-term control of hyperglycemia but is not generally used to diagnose diabetes, IGT, or IFG.

56. Electoneuro -physiology Distal symmetrical polyneuropathy S ensory Absent or decreased amplitudes of the sural nerve potentials and low amplitude or absent tibial H-reflexes are found in almost all patients. MC STUDIES decreased amplitudes of CMAPs, together with mild slowing of conduction velocities in the motor nerves, are found in more than two-thirds of patients. EMG Active denervation in intrinsic foot muscles Abnormalities occur more commonly in sensory than in motor fibers, in the legs more than in the arms, and in distal more than proximal nerve segments.

57. Proximal neuropathy Typical EMG findings low- ampl itude femoral nerve motor , prominent fibrillation potentials in thoracic and lumbar paraspinal muscles, and active denervation in affected muscles Evoked nerve action potential amplitudes reduced in patients with diabetes. NCVs are typically slower in this group than in healthy subjects, although strict criteria for demyelinating neuropathy are not often met.

58. Neuroimaging studies of the lumbar spine, lumbosacral plexus, or both should be considered when lumbar root, cauda equina lesions, or structural lumbosacral plexopathy are suspected . Sural nerve biopsy specimens in these individuals show multifocal nerve fiber loss, suggesting ischemic injury and perivascular infiltrates in small vessels, which implies an immune mechanism infarcts of the proximal nerve trunks and lumbosacral plexus.

59. A vascular pathogenesis of this proximal neuropathy was documented by autopsy, showing

60. Sural nerve biopsy from patient with diabetic lumbar radiculoplexopathy . Perivascular lymphocytic inflammation involves two epineurial arterioles. B, In the same patient, semi-thin transverse section illustrates selective involvement of one fascicle, with marked loss of myelinated fibers, a pattern highly suggestive of nerve ischemia. (

61. Pathogenesis of Diabetic Neuropathy

62. Pathogenesis of Diabetic Neuropathy Metabolic Hyperglycemia has been implicated in many different pathogenic mechanisms in diabetic neuropathy, but there is also a role for insulin deficiency and its effect on neurotrophic factors in the pathogenesis of neuropathy.

63. Hyperglycemia →generates rheological changes that increase endoneurial vascular resistance reduce nerve blood flow. → causes depletion of nerve myoinositol through a competitive uptake mechanism and activates protein kinase C . → activate the polyol pathway in nerve tissue through the enzyme, aldose reductase , which leads to the accumulation of sorbitol and fructose in nerve and enhancement of non-enzymatic glycosylation of structural nerve proteins . → autooxidation of glucose, which results in the generation of toxic reactive oxygen intermediate. →activates protein kinase C Which has been linked to vascular damage in diabetic neuropathy

64. These metabolic changes are likely to cause abnormal neuronal/axonal and Schwann cell metabolism and impaired axonal transport. Direct measurements of sugar alcohols in sural nerves from patients with diabetes confirm the correlation between increased levels of glucose, sorbitol , and fructose and the severity of the neuropathy.

65. Endoneurial hypoxia → is produced by decreased blood flow to the nerve and increased endoneurial vascular resistance from endothelial cell hyperplasia . Once hypoxia is established, a vicious cycle of further capillary damage escalates hypoxia. →impair axonal transport and reduces nerve sodium-potassium- ATPase activity. →axonal atrophy, leading to reduced NCVs.

66. Although the precise mechanisms leading to capillary abnormalities that initiate hypoxia are unknown, the hypoxic hypothesis provides a framework for further research into the pathogenesis of diabetic neuropathy. Autoimmune mechanisms and amino acid, electrolyte, and lipid biochemical abnormalities also play a role in the neuropathies of diabetes mellitus

67. Treatment

68. Potential treatments for DSP are discussed in four broad themes : (1) medication and lifestyle therapy to improve hyperglycemia, insulin resistance, and attendant features of metabolic syndrome, including obesity and dyslipidemia ; (2) pharmacologic therapy to alter neuropathy natural history aimed at rational targets from known pathophysiology ; (3) symptomatic relief of neuropathic pain; and (4) treatment to prevent complications of neuropathy, including stasis ulcers and falls.

69. Metabolic Syndrome Features and Their Role in Diabetic Neuropathy

70. Hyperglycemia does not exist in isolation, and is one component of a broader metabolic syndrome with features initially identified due to their prediction for cardiovascular disease. [11] Metabolic syndrome is defined as the presence of three of the following , increased fasting glucose, hyper- triglyceridemia , decreased high-density lipoprotein-C (HDL-C), ethnicity-specific central obesity, and elevated blood pressure. Active drug treatment for any of these conditions in a given patient also meets criteria. [12]

71. Several metabolic syndrome features have been linked to neuropathy, particularly obesity and dyslipidemia, independent of hyperglycemia. [13] The largest studies have examined metabolic syndrome contribution to neuropathy risk in patients with known diabetes. Hypertriglyceridemia It is significantly more common in those with idiopathic neuropathy, [18] and may be involved in its development and progression The Diabetes Control and Complications Trial (DCCT) Aggressive glycemic control has been shown in large, well-designed clinical trials to reduce the neuropathy risk in type 1 diabetes.

72. Exercise An evolving literature supports a role for exercise in neuropathy prevention and therapy. ] THE BENEFIT through a mechanism other than improvement in glucose control.

73. Generally, however, once DSP is established, it has proved remarkably With neuropathy progression, reversible metabolic factors tend to be supplanted by irreversible structural injury . Even in rodent models, spontaneous reversion to normo-glycemia does not result in significant improvement of chronic diabetic neuropathy. [29] These observations suggest future therapeutic efforts should focus on very early disease or even neuropathy prevention. .

74. . No human clinical trial has demonstrated reversal or improvement of DSP even with complete resolution of diabetes. Patients with type 1 diabetes who underwent pancreatic transplant were compared with matched subjects who received best medical therapy. Compared with medical therapy subjects, who experienced unrelenting decline in clinical measures of peripheral nerve function, transplant recipients showed a stabilization of neuropathy progression, but minimal improvement over many years

75. With neuropathy progression, reversible metabolic factors tend to be supplanted by irreversible structural injury . [ Even in rodent models, spontaneous reversion to normo-glycemia does not result in significant improvement of chronic diabetic neuropathy . [ These observations suggest future therapeutic efforts should focus on very early disease or even neuropathy prevention.

76. Optimal glucose control . Considerable evidence supports the idea that good diabetic control is associated with less frequent and less severe peripheral nerve complications.

77. Successful pancreatic transplantation It is beneficial in preventing the progression of diabetic neuropathy, and the effect may be sustained in longterm follow-up . Unfortunately, once the diabetic neuropathy is established, the existing damage is largely irreversible .

78. Treatment Based on Recognized Steps in Diabetic Pathophysiology

79. Multiple trials of small vessel vasodilatory agents showed no clinical response, [34] nor did a large trial of nerve growth factor (NGF). Trials of aldose reductase inhibitors (ARI), which control entry of excess glucose into the polyol pathway and reduce glucose mediated oxidative stress and microvascular disease in animals, have generally shown no efficacy in humans .

80. Three related potential medications for DSP combine neuropathic pain relief with possible direct effect on neuropathic injury. Alpha lipoic acid , acetyl-L carnitine , and benfotiamine each act to reduce oxidative stress, which has been identified as a key component of neuropathy pathogenesis.

81. Alpha lipoic acid (ALA) The Symptomatic Diabetic Neuropathy (SYDNEY) Study randomized diabetic neuropathy subjects to double-blinded treatment with either placebo or up to 1800 mg of oral ALA. Over the 5-week treatment course, subjects treated with any of the ALA doses reported a significantly greater reduction in neuropathic pain than did the placebo-treated controls. [ Most clinical measures of neuropathy severity did not significantly improve; previous studies had reported modest improvement in neuropathy measures following IV ALA injection . [ ALA may be started at a dose of 300 mg by mouth daily and titrated as high as 600 mg twice daily. ALA may lower blood glucose and thiamine stores, and has unpredictable effects on thyroid function.

82. Acetyl-L carnitine (ALC), Diabetes is associated with reduced serum levels and cellular concentrations of acetyl-L carnitine (ALC), another antioxidant that has been shown to inhibit lipid peroxidation and increase nitric oxide synthase and nitric oxide in experimental models. Two parallel randomized, blinded controlled trials used measures including the Visual Analog Pain Scale (VAS), and morphometric analysis of sural nerves to assess neuropathy severity at baseline and after 52 weeks of treatment; 1257 diabetic neuropathy subjects received either placebo or one of two ALC doses. [41] ALC significantly improved sural morphology and VAS . These also improved significantly with the larger ALC dose. ALC is available as a nutritional supplement, often in combination with ALA, and a target dose of 500 mg daily is best supported

83. Benfotiamine or S- benzoylthiamine O- monophosphate It is a vitamin B1 derivative with antioxidant properties. A phase III study randomized 165 diabetic neuropathy subjects to either placebo or benfotamine . [ Subjects receiving active drug showed significant improvement in the neuropathy-specific Total Symptom Score and its pain subscore over the 6-week trial, with greater benefit in the 600 mg dose group . Taken together, trials of these medications strongly implicate oxidative stress as a contributor to neuropathy pathogenesis

84. Neurotrophin treatments Despite promising preliminary evidence, neurotrophin treatments for diabetic neuropathy, such as nerve growth factor, have been disappointing . .

85. Delivery of a putative therapeutic agent to the target organ (dorsal root ganglia or nerve) THE use of delivery vectors derived from the herpes simplex virus, which has trophism for dorsal root ganglia neurons. A recent phase I study of a replication deficient HSV v ector expressing the gene for pre- proenkephalin i n patients with cancer-related pain demonstrated an apparent dose-related treatment effect. [44] Plasmids (naked DNA) containing growth factor genes to deliver therapy to nerve via intramuscular injection. A small trial of a plasmid containing the gene for vascular endothelial growth factor suggested benefit, and other trials using this delivery system are underway

86. VEGF gene transfer into small mammals has been shown to improve NCVs, increase blood vessel density, and enhance nerve blood flow, giving impetus to pursuing this approach to treating human diabetic neuropathy. Because human C-peptide prevents neuropathy in diabetic rats in a dose-dependent fashion (Zhang et al., 2001), clinical interest has developed for this compound as well

87. Patients with autonomic dysfunction

88. Patients with autonomic dysfunction . Patients with symptomatic orthostatic hypotension The head-up tilt prevents salt and water losses during the night and will combat supine hypertension → advised to sleep with the head of the bed elevated 6 to 10 inches. →Practical suggestions include drinking two cups of strong coffee or tea with meals, eating more frequent small meals rather than a few large ones, and increasing the daily fluid intake (>20 oz/day) and salt ingestion (10-20 g/day). Elastic body stockings may be beneficial by reducing the venous capacitance in bed but are poorly tolerated by many patients.

89. DRUGS fludrocortisone Plasma volume expansion can be achieved by fludrocortisone (0.1-0.6 mg/day). NSAlDs , which inhibit prostaglandin synthesis, represent the next class of drugs to be considered; ibuprofen, 400 mg 4 times a day, is better tolerated than indomethacin . Phenylpropanolamine (25-50 mg 3 times a day), a direct-acting α-agonist, was once used to manage orthostatic hypotension. Although a sustained-release form of phenylpropanolamine can be obtained over the counter (e.g., Dexatrim ), the association of hemorrhagic stroke makes this medication an undesirable option Midodrine , an α1-adrenergic agonist that causes vasoconstriction, is also effective. Similarly, subcutaneous Recombinant human erythropoietin given SC has proved effective in some patients with orthostatic hypotension and anemia. Octreotide may improve orthostatic blood pressure by inducing splanchnic vasoconstriction.

90. Delayed gastric emptying It is often relieved with metoclopramide ; therefore, it is a dopamine antagonist, extrapyramidal symptoms may occur at higher doses. Diabetic diarrhea may be treated with short courses of tetracycline or erythromycin if appropriate. In some cases, clonidine has been reported to reduce the troublesome diarrhea.

91. Genitourinary complications of diabetic autonomic neuropathy Neurogenic bladder Patients with a neurogenic bladder should be encouraged to adhere to a frequent voiding schedule during the day, which helps diminish the amount of residual urine. For more severe involvement, manual abdominal compression or intermittent self-catheterization may be needed.

92. Erectile dysfunction oral treatment with sildenafil or similar drugs, direct injections into the corpora cavernosa , or penile implants. Proper skin care in diabetics with cutaneous sensory loss, impaired sweating, and vascular disease is extremely important to prevent foot ulcers.

93. Treatment of Neuropathic Pain

94. A wide variety of drugs A ntidepressants, Antiepileptic drugs, Opiates, and Serotonin / norepinephrine reuptake inhibitors have been shown to significantly reduce neuropathic pain compared with placebo in randomized controlled trials, but pain relief is incomplete for most patients Tricyclic antidepressants (amitriptyline, nortriptyline , desipramine ) have been mainstays of neuropathic pain treatment, with efficacy proven in several well-designed studies. [53] Tricyclic antidepressants are inexpensive, and because of their long half-life, dosing is simple A typical dose of amitriptyline is 50–200 mg, 2 hours before bedtime.

95. Gabapentin is structurally related to the pain-modulating neurotransmitter, g- aminobutyric acid (GABA), although it acts neither as a GABA agonist or antagonist. Its mechanism is thought to be related to binding to the α 2 delta subunit of voltage gated Ca 2+ channels Dose escalation of gabapentin should begin at 300 mg taken 2 hours before bedtime, increasing in 300 mg increments every 3 to 7 days to 600 mg three times daily.

96. Pregabalin ( Lyrica ®, ) is structurally similar to gabapentin and offers a very similar pharmacokinetic, metabolic, and side-effect profile, with a somewhat faster onset of pain reduction. Pregabalin has been approved by the Food and Drug Administration (FDA) for treatment of neuropathic pain in diabetes, and for treatment of fibromyalgia. Dose escalation of pregabalin can begin at 75 mg twice daily, and increase by 75 mg increments to 150 mg twice daily.

97. Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor FDA-indicated for neuropathic pain associated with diabetic DSP, as well as for depression, anxiety, pain associated with fibromyalgia, and chronic musculoskeletal pain. In two randomized controlled trials, diabetic subjects with painful DSP of less than 6 months duration showed statistically better cumulative pain relief over the 12-week trial period when administered duloxetine 60 mg daily compared with placebo. . Common side effects include nausea, somnolence, dry mouth, and constipation. Appetite suppression is common, but is often regarded as a benefit of the drug.

98. Opiates have a defined role as adjunct treatment in poorly controlled neuropathic pain, but are often overlooked because of concerns for tolerance and addiction. [59] The oral opiate oxycodone improved pain and quality of life in a small diabetic neuropathy cohort, [60] and a larger study (338 subjects) found significantly enhanced pain relief when added in a randomized and double-blinded fashion to optimized gabapentin dosing. [61] However, in a recent study of 62 diabetic neuropathy subjects, randomized addition of low-dose oxycodone did not significantly improve the neuropathic pain effects of pregabalin . [62] The novel mu- opioid receptor binding agent tapentadol has recently been shown superior to placebo in reducing neuropathic pain in a randomized trial cohort of 395 subjects with diabetic neuropathy . [63]

99. Tramadol , It is an agent that binds to opiate receptors and blocks reuptake of serotonin and norepinephrine , was significantly more effective than placebo in treating neuropathic pain in a 42-day double-blind placebo controlled study of 131 diabetic subjects, and in combination with acetaminophen was shown to be significantly more effective than placebo alone in a cohort of 160 subjects. Long-term use of Tramadol in patients with diabetic neuropathy did not result in significant tolerance or dose escalation.

100. Mexiletine It is an orally active local anesthetic agent that showed statistically significant reduction in Visual Analog Pain Scale pain ratings for diabetic neuropathy patients in two small trials at doses of 225–675 mg day . Nausea and other gastrointestinal complaints were the most common side effects.

101. Capsaicin cream it is applied topically, and acts to reduce pain sensation by depleting substance P from proximal terminals of cutaneous nociceptive c-fibers . Capsaicin is practical only for patients with small areas of neuropathic pain . Pragmatically, few patients tolerate capsaicin therapy: the cream must be applied three to four times daily using rubber gloves to avoid affecting non-painful skin or mucosa. Failure to maintain treatment for even one dose allows substance-P regeneration and recrudescence of pain

102. Prevention of Neuropathy Complications: Falls and Ulcers

103. Falls Patients with peripheral neuropathy are at higher risk of falling, and this problem may be particularly acute in diabetes. Among 60 diabetic patients over the age of 55 years old, over one-third had fallen in the prior year. Neuropathy, sensory loss, and distal weakness were major risk factors. Patients with neuropathy often fall when walking on uneven or irregular surfaces, and formal gait evaluation should include these testing conditions. Any DSP patient, or patients with poor lower extremity strength or vibration perception should be counseled regarding fall risk and consideration given to possible gait evaluation and physical therapy intervention.

104. Foot ulceration and consequent digit, foot, or limb amputation It remains a common diabetic complication. Among 248 diabetic patients followed prospectively in tertiary care podiatric clinic, foot ulcers developed in 29% of subjects and 19% of feet over a mean 30-month follow-up. DSP increases the risk of ulceration seven fold and contributes to over 60% of lower extremity amputations in diabetic patients. The increased risk is due to a combination of lack of protective sensation, abnormalities in blood flow that are often compounded by peripheral artery disease, abnormal sweating, and poor wound healing.

105. Ulceration and amputation risk is also related to duration of neuropathy and severity of hyperglycemia. Care of the foot Daily self-examination, with a foot mirror if necessary; podiatric consultation and maintenance for toenails and bunions; orthotic foot support, and use of protective, wide-based shoes with adequate toe box and ankle support are recommended for patients at risk for ulcers. If stasis ulcers develop, nonsurgical debridement, application of hydrogels , and empiric antibiotic coverage for wound flora are appropriate therapy

106. Diabetic neuropathy. Pes planus

107. Distal symmetric polyneuropathy of renal disease

108. Clinical syndrome/SIGNS This neuropathy commonly occurs in patients with end-stage renal disease on dialysis; 60% of patients on dialysis have some degree of neuropathy. Neuropathy secondary to renal disease is 2 times more common in men. Examination reveals a symmetric stocking-glove loss to all sensory modalities with distal weakness, absent ankle and depressed knee reflexes. While the definitive cause is unknown, the neuropathy may be due to accumulation of metabolites or loss of unknown renal factors

109. Laboratory: Serum BUN and Cr and 24 hour urine collection all indicate renal failure. Electrophysiology: Early in neuropathy there are prolonged distal latencies, slowed motor conduction velocities and prolonged F waves. The relationship between conduction slowing and renal failure is well established. Lowered sensory and motor amplitudes are present, and in severe cases, are absent. There is evidence of denervation by EMG in distal foot muscles.

110. Nerve Biopsy: There is evidence of axonal degeneration , with loss of large and small axons in the absence of inflammation. Nerve biopsy is usually not required for the diagnosis. . Therapy consists of pain management and physical therapy. Optimizing renal function may improve the neuropathy. The neuropathy progresses over a period of months and is rarely fulminant . Prognosis it is improved following renal transplant, and sometimes with more intensive dialysis.

111. Systemic disease Vasculitic neuropathy,

112. Sural nerve biopsy from a patient with isolated peripheral nerve vasculitis . A Infiltration of a perineurial vessel wall by multiple inflammatory cells including lymphocytes and Macrophages (black arrows). There is also evidence of pink fibrin deposits consistent with the presence of fibrinoid necrosis.

113. B Teased fiber preparations showing multiple axon balls (white arrows) and evidence of empty strands consistent with axonal degeneration

114. Hand in a patient with vasculitis . Atrophy of the small hand muscles and vasculitic changes at the nailbed

115. Anatomy/distribution Nerve and muscle pathology relates to destruction of blood vessels. Symptoms Proximal and distal weakness, pain, and sensory loss occur in a multifocal distribution. Clinical syndrome/signs May affect isolated nerves (45% of cases), overlapping nerves (40%), or cause symmetric neuropathy (15%). Patients typically present with a mixture of motor and sensory signs. Associated signs of systemic vasculitic disease include: fever, weight loss, anorexia, rash, arthralgia , GI, lung, or renal disease. Usually the neuropathy presents in patients that have already been diagnosed with a specific vasculitic disease .

116. B Vasculitic neuropathy was heralded by vasculitic skin changes

117. Several immune-mediated mechanisms have been identified that lead to destruction of vessel walls. The various mechanisms result in ischemic necrosis of axons Systemic disease that can involve vasculitic neuropathy can be divided into the following categories: Immune/Inflammatory mediated: Wegener’s granulomatosis Polyarteritis nodosa , Churg -Strauss syndrome, Hypersensitivity reaction Paraneoplastic : Various cancers (rare) Infectious: Hepatitis B or C, HIV-1, Lyme disease Other: Collagen vascular diseases

118. DIAGNOSIS Laboratory: Findings in conjunction with systemic disease could include elevated ESR, anemia, ANA, ENA, cryoglobulins , P-ANCA, hepatitis B or C antibodies, HIV-1, or Lyme serologies . EMG and NCV they are abnormal, and are important for identifying which nerves are involved. SNAPs and CMAPs are reduced reflecting axonal damage. Muscle and nerve biopsies should be taken, and show T-cell and macrophage invasion, with necrosis of blood vessels.

119. DIFFRENTIAL DIAGNOSIS Diabetic neuropathy, HNPP, CIDP, multifocal neuropathy with conduction block, plexopathies , porphyria , multiple entrapment neuropathies, Lyme disease, sarcoidosis . THERAPY Prednisolone and cyclophosphamide are frequently used in the treatment of systemic vasculitic diseases. Aggressive pain management should be a special concern of the neurologist. PROGNOSIS Therapy leads to improvement in most cases, but residual impairments and relapses are possible. Pain symptoms often respond quickly, but this should not be taken as an indication that the vasculitis is under control. Other symptoms may take some time to improve.

120. Vasculitic neuropathy, non-systemic

121. Anatomy/distribution Both sensory and motor fibers are affected in individual peripheral and cranial nerves. Symptoms The symptoms in vasculitis neuropathy are dependent on which nerve(s) and/or root(s) are affected. As a class, this neuropathy is usually painful and patients experience both sensory loss and weakness in multiple named nerves (85% of cases). 15% of patients present as a symmetric polyneuropathy .

122. Clinical syndrome/signs Pure peripheral nervous system vasculitic neuropathies are very rare. Examination reveals sensory loss and weakness in named affected peripheral or cranial nerves (multiple mononeuropathies ), and rarely, a stocking-glove pattern of sensory loss and weakness.

123. DIAGNOSIS Laboratory: The serological markers of vasculitis should be normal. Vitamin levels, glucose, hepatic and renal function are normal. There is no monoclonal gammopathy . Cerebrospinal fluid analysis is normal. Electrophysiology: Multiple axonal mononeuropathies with low or absent sensory and motor amplitudes and denervation in innervated myotomes are present. Imaging: None. Nerve Biopsy: There is evidence of epineurial arteriole or venule inflammation and necrosis in multiple sites, producing axonal loss, frequently in a central fascicular pattern.

124. THERAPY Patients may respond to prednisone alone or in conjunction with cyclophosphamide therapy for 6 months. Prognosis is fair to good, and 80% of patients go on to near full recovery

125. Neuropathies associated with paraproteinemias

126. Neuropathies associated with paraproteinemias

127. Neuropathy in conjunction with multiple myeloma IT IS A Axonal neuropathy occurs with amyloid deposits. SYMPTOMS Patients experience distal symmetric motor and sensory dysfunction. Signs Exam shows proximal and distal weakness and sensory loss, mononeuropathies and autonomic dysfunction. Diagnosis . Serum electrophoresis can show IgA or IgG monoclonal gammopathy . Bone marrow studies reveal myeloma, and examination of the skeletal system can show osteolysis

128. Neuropathies associated with monoclonal gammopathies : monoclonal gammopathy of undetermined significance (MGUS ) Symptoms Symptoms may be motor, sensory, or sensorimotor depending on IgM antibody specificity. Clinical syndrome/signs shows distal greater than proximal weakness and sensory loss. Pathogenesis Disease is primarily associated with IgM , IgA and IgG gammopathy .

129. Diagnosis NCV maybe slowed (LIKE CIDP). Serum electrophoresis reveals a monoclonal gammopathy . Bone marrow studies and skeletal examination should be normal, confirming that the gammopathy is of “unknown significance.” Therapy Immunosuppression (prednisone) plus plasma exchange is effective in patient’s with IgG and IgA gammopathies and a CIDP like picture. Patients who present with an axonal neuropathy are less responsive to treatment.

130. IgM paraproteinemia with anti-MAG antibodies Half of patients with MGUS develop antibodies against MAG (myelin associated glycoprotein). Patients have a moderate to severe sensory loss with distal weakness. Nerve conduction velocities are significantly slowed with temporal dispersion and conduction block. These patients do not respond to therapy, but the disorder itself is usually indolent Clinical syndrome /SIGNS Large fiber sensory function is lost, and there may be tremor. The disease presents as a sensorimotor neuropathy with predilection of large fiber dysfunction. It is difficult to distinguish from MGUS( likely an auto-immune attack against peripheral nerves .) THERAPY Chemotherapy, intravenous gammaglobulin or plasmapheresis are usually not effective. PROGNOSIS Neuropathy is usually not improved with treatment.

131. Amyloidosis (primary)

132. ANATOMY DISTRIBUTION Primary amyloidosis (AL) is a multi-organ systemic disease affecting the peripheral and autonomic nervous systems. Axonal degeneration, particularly of small myelinated and unmyelinated fibers is present with diffuse amyloid deposits infiltrating epineurial and endoneurial connective tissue Symptoms Initial neuropathic symptoms are most commonly burning pain and loss of sensation in the feet. These symptoms may precede development of multiorgan involvement by 1 year. With disease progression, patients experience distal muscle weakness and in advance cases autonomic symptoms of postural hypotension, syncope and impotence.

133. Clinical syndrome/signs AL is a disorder of older men. Approximately 70% of affected patients are men with a median age of 65 who experience weight loss, hepatomegaly , macroglossia , purpura and ankle edema. Early in the disease examination reveals a stocking/glove loss of all sensory modalities and depressed ankle reflexes. Approximately 25% of patients will have signs of a median mononeuropathy with paresthesias in the first 3 fingers with variable weakness of thenar muscles. As AL progresses, distal weakness, absent reflexes and autonomic signs are present, including orthostatic hypotension and abnormal sweating.

134. Diagnosis Laboratory: A serum or urine monoclonal protein is present in 90% of patients with AL. An IgG monoclonal gammopathy occurs in 30% of patients; 20% have free monoclonal light chains in their sera. 80% have proteinuria and of these patients two-thirds have a urine monoclonal light chain. Electro physiology: Sensory nerve amplitudes are absent, motor amplitudes are decreased or absent but motor latencies and conduction velocities are normal or only mildly decreased. Needle exam reveals fibrillations and positive sharp waves in distal musculature.

135. Nerve Biopsy: Congo red positive amyloid deposits are present in the abdominal fat aspirates of 70% of affected patients and in bone marrow aspirates in 50%. If these sites are negative, sural nerve biopsy is indicated and is positive in 85% of AL patients with neuropathy

136. Therapy While nephropathy is partially responsive to melphalan and prednisone, Antiinflammatory and alkylating agents ( cyclophosphamide ) have no affect on the course of neuropathy. Amyloid deposits are permanent. Prognosis Neuropathy continues to progress unabated, and most patients die from multiorgan failure within 4 years of diagnosis.

137. Neoplastic neuropathy

138. A Infiltration of the peripheral nerve by collections of B cells, with disruption of normal sural nerve architecture. B Disruption of myelin, with myelin splaying, and partial loss of axons Sural nerve biopsy from a patient with lymphoma

139. Anatomy/distribution There is diffuse infiltration of peripheral nerves or nerve roots in neoplastic neuropathy. Symptoms The symptoms in neoplastic neuropathy are dependent on which nerve(s) and/ or root(s) are affected. As a class, neoplastic neuropathy is usually painful and patients experience both sensory loss and weakness. Clinical syndrome/signs Neoplastic neuropathies are very rare, and occur almost exclusively in patients with lymphoma, chronic lymphocytic leukemia, and breast and ovarian carcinomas . Infiltration of specific peripheral nerves by lymphoma is known as neurolymphomatosis . Leukemia can affect multiple nerve roots, especially myelomonocytic leukemia. .

140. Meningeal arcinomatosis with polyradicular nerve root involvement can occur in leukemia, Lymphoma and in both breast and ovarian carcinoma. Examination reveals sensory loss and weakness in named affected nerves (multiple mononeuropathies ) or alternatively a Polyradiculopathy . Since there is direct nerve and root infiltration, both sensation loss and motor weakness are present in affected patients.

141. Diagnosis Electrophysiology: Multiple axonal mononeuropathies with low or absent sensory and motor amplitudes and denervation in innervated myotomes are present. If there is primarily nerve root infiltration, needle examination reveals anterior and posterior myotome denervation .

142. Imaging: MRI imaging of the craniospinal axis is required in suspected cases of neoplastic polyradiculopathy . Positron emission tomography (PET) scanning of the plexus and peripheral nerves can reveal areas of tumor deposition. Differential diagnosis Disorders that can affect multiple named nerves or nerve roots, such as vasculitis or infectious neuropathies, need to be excluded.

143. Paraneoplastic neuropathy

144. Dorsal root ganglion pathology: A and B show an example of an inflammatory paraneoplastic ganglionitis . B shows an infiltrate that is immunostained for T cells. C is a rare example of neoplastic infiltration of a DRG by lymphoma cells of a Burkittlike lymphoma. This patient had additional meningeal infiltration

145. Paraneoplastic ganglionopathy in a patient with a nonsmall cell carcinoma of the lung. A CT chest showing enlargement of the mediastinal lymph nodes. B Single dorsal root ganglion (DRG) neuron (large arrow) and evidence of inflammatory cell infiltrates (white arrows). Most of the DRG have degenerated

146. Paraneoplastic neuropathies They are heterogeneous and can affect the peripheral nerve (sensory, sensory/motor), cause ganglionopathies [dorsal root ganglion neuron (DRG) loss], and can be associated with posterior column degeneration. Some are associated with anti-neuronal antibodies. Peripheral neuropathies in cancer patients can also be part of a multifocal paraneoplastic encephalomyelitis (PEM). Anatomy/distribution Demyelination and nerve vasculitis are rarely associated with paraneoplastic syndromes. Typically, there is axonal loss of distal sensory and motor nerves The ganglionopathy sub-type is secondary to inflammation with DRG loss and possible posterior column degeneration

147. Symptoms – Autonomic neuropathies can cause gastrointestinal symptoms (e.g., seudoobstruction ), sexual dysfunction and orthostatic hypotension. – Demyelinating neuropathy like AIDP or CIDP have been described on rare occasions and have no special characteristics. – Rare cases of vasculitic neuropathy are characterized by painful mononeuritis multiplex. – Sensorimotor type: distal symmetric polyneuropathy , sometimes as a subclincal finding. Sensory neuropathies can be painful. – Sensory neuronopathy (“Denny Brown Syndrome”) is rare with subacute development of sensory neuropathy, with ataxia, and pseudoathetoid movements of the upper extremities. In the full-blown disease motor force can persist, but deafferentation prevents the patient from coordinated movements.

148. Clinical syndrome/SIGNS – Demyelinating neuropathy cannot be distinguished from AIDP or CIDP. – Sensorimotor type shows distal symmetric polyneuropathy , glove and stocking distribution, with sensory and motor signs often mild. This is the most common araneoplastic neuropathy and often occurs late in the disease in patients with severe weight loss. – Sensory neuronopathy (“Denny Brown syndrome”) shows areflexia , dysesthesias , ataxia, pseudoathetoid movements, and is often painful and asymmetric.

149. PATHOGENESIS Pathogenesis of paraneoplastic neuropathies is unclear, but is believed to be the result of numerous auto-antibodies associated with cancer. The sensorimotor type has been associated with anti-CV2 antibodies . Demyelinating forms are more highly associated with lymphoma and Hodgkin’s disease. Sensory neuronopathy is related to anti- Hu and other anti-neuronal antibodies, in the context of small cell lung cancer.

150. Therapy No treatments are available for the sensory/motor, demyelinating , and autonomic syndromes. For sensory neuropathies and neuronopathies immunmodulatory therapies have been suggested and range from steroids to intravenous gammaglobulin , plasmapheresis , and immunosuppression . Vasculitic neuropathy can be treated with steroids and immunosuppression (which may be part of the cancer therapy).

151. Motor neuropathy or motor neuron disease syndrome

152. Anatomy/distribution Anterior horn cells degenerate, which leads to concomitant degeneration of long tracts. . Clinical syndrome/signs Motor neuron disease syndrome is associated with several cancer conditions and can exhibit different combinations of lower and upper motor neuron signs. One type associated with anti- Hu antibodies is relentlessly progressive and involves mostly lower motor neurons and encephalopathy. Another lower motor neuron syndrome is associated with lymphoma . A syndrome of upper and lower motor neuron signs resembling ALS is linked to numerous tumors(lymphoma, ovarian, uterine, breast, non-small cell lung cancer). Finally, an upper motor neuron syndrome has been reported with breast cancer

153. Pathogenesis The existence of paraneoplastic motor neuron disease is controversial. Some feel that this is an occurrence of two separate common disorders in one patient. Evidence for the existence of paraneoplastic motor neuron disease is based on the presence of antibodies to antigens shared by neurons and tumors, the responsiveness of some motor neuron disease to successful cancer treatment, and occurrence of motor neuron disease in patients exhibiting other well characterized paraneoplastic syndromes.

154. Diagnosis Diagnosis of a paraneoplastic motor neuron disease can be suggested by a lower motor neuron syndrome in association with cancer. Anti- Hu antibodies may be detected. Therapy While some have reported regression of nervous system disease with treatment of cancer and immune therapy, generally treatments are not effective.

155. Infectious neuropathies

156. Human immunodeficiency virus-1 neuropathy

157. HIV-1 AIDP HIV-1 AIDP occurs early in disease and may be the first manifestation of disease, preceding any other signs and symptoms. HIV AIDP is immunemediated and resembles AIDP in the general population.

158. Clinical syndrome/signs Distal weakness in two or more limbs that is rapidly progressive, with areflexia . Sensory symptoms may be absent. Respiratory impairment and autonomic dysfunction may pose serious threats. Diagnosis Serology is used to detect HIV infection. EMG and NCV results resemble AIDP. Therapy IVIG protocol as per AIDP.

159. Prognosis AIDP usually lasts for several weeks and then remits, with good prognosis. HIV-1 CIDP usually occurs later in disease and is immune mediated. Clinical syndrome/signs Similar to AIDP, except the course is relapsing-remitting. Disability may become chronic, and sensory complaints are more common than with AIDP. Diagnosis CSF analysis shows pleocytosis and elevated protein. EMG and NCV resemble AIDP, but abnormalities are generally more pronounced. Therapy Plasmapheresis , IVIG (often transient and needs frequent administration), immunomodulatory agents, ganciclovir , foscarnet , cidofovir Prognosis Good.

160. Mononeuropathy multiplex MM affects one or more nerves, and causes motor and sensory dysfunction. It usually occurs late in disease and is associated with vasculitis , CMV infection, lymphocytosis or lymphoma. Clinical syndrome/signs Weakness and sensory abnormalities in a nerve or root distribution pattern are typical. Cranial nerve involvement is common. Diagnosis Nerve biopsy may show signs of vasculitis . PCR can be used to detect associated CMV infection in the CSF.

161. Therapy Immunomodulatory agents, anti-HIV and anti-CMV drugs can be used. The efficacy of antivirals in abating peripheral nerve disease is not clear. Prognosis MM that occurs early in disease is often self-limiting over the course of a year. Otherwise, the prognosis is poor. Distal sensory or sensorimotor is the most common neuropathy in HIV. Its cause is unknown, but may be the result of cytokine release or treatment toxicity

162. Distal sensory or Sensorimotor Distal sensory or sensorimotor is the most common neuropathy in HIV. Its cause is unknown, but may be the result of cytokine release or treatment toxicity Clinical syndrome/signs Pain is the most common feature, in a stocking glove distribution. Foot pain may be so severe that patients cannot walk or tolerate contact with bedding. Often, the only signs are abnormal ankle reflexes. Signs may seem mild to the degree of pain experienced by the patient. Weakness is not common, and distal if present.

163. Diagnosis Diminished or absent SNAPs are found with NCV studies. Other treatable causes should be explored, such as vitamin B12 deficiency, alcoholism, therapy-related toxicity from nucleoside analogues Therapy .Treatment for neuralgia is selected depending upon the severity of pain:NSAIDs , anti-depressants, anti- convulsants , topical lidocaine or capsaicin,opioids . Prognosis The pain is chronic and poorly treatable.

164. Autonomic neuropathy Autonomic neuropathy is a late occurrence of unknown cause. It is characterized by orthostatic hypotension and diarrhea. Studies have found decreased intestinal innervation in late-stage HIV. Diagnosis Autonomic testing is not always conclusive, as cardiac dysfunction, anemia, and dehydration may cause signs and symptoms similar to autonomic neuropathy. Therapy Symptomatic care is all that can be offered. PROGNOSIS Poor.

165. Herpes neuropathy

166. Herpes virus remains in a latent state in the dorsal root ganglion or trigeminal ganglion. SYMPTOMS Sensory disturbances occur with cutaneous eruptions. Post-herpetic neuralgia can involve three distinct pain situations: lancinating , shock-like pain, a continuous burning or aching pain, or pain caused by innocuous stimuli ( allodynia ). All of these occur in a dermatomal distribution.

167. CLINICAL SYNDROME &SIGNS Motor signs are infrequent (herpes zoster), and are caused by radiculopathy . Motor impairment occurs in the corresponding myotome to the sensory distribution. Long standing radicular pain that resembles diabetic neuropathy or infiltrative radiculopathy may be caused by herpes reactivation without the distinctive rash (zoster sine herpete ). Cranial nerve palsies are also common, include oculomotor and facial nerve palsies, and optic neuritis or vestibulocochlear impairment (Ramsay-Hunt syndrome). .

168. PATHOGENESIS Herpes simplex or Herpes zoster (chicken pox) infection can come out of latency in a sensory ganglion. Herpes zoster occurs frequently in HIV patients and patients recovering from chemotherapy. The virus migrates down the sensory nerve fibers to the skin, causing tissue damage and inflammation. The pain syndromes associated with post-herpetic neuralgia may result from altered CNS pain pathways, aberrant reinnervation following infection, or changes in receptor sensitivity.

169. Diagnosis Vesicle smear and PCR may be used to confirm infection. Therapy Acyclovir and other antivirals may be used both acutely and prophylactically . Pain can be managed by tricyclic antidepressants or opiates. Nerve block or lidocaine treatment may also be used. Prognosis Herpes simplex is recurrent and may be implicated in Bell’s palsy. Herpes zoster neuropathy increases in frequency with age and may lead to residual neuralgia, although recovery is generally good .

170. Hepatitis B neuropathy

171. Anatomy/distribution There is acute demyelination of peripheral nerves or nerve roots in neuropathy due to Hepatitis B. Symptoms most commonly similar to those of an inflammatory demyelinating polyneuropathy, either acute (AIDP) or chronic (CIDP ). Patients experience both sensory loss and weakness, which can be rapid, is usually symmetrical and progressive. Less commonly, patients experience multiple mononeuropathies . Clinical syndrome/ signs Hepatitis B neuropathy is very rare and, when present, occurs in the setting of chronic active or chronic persistent Hepatitis B. Examination reveals symmetrical sensory loss and weakness with areflexia . The weakness can be profound affecting all 4 extremities. In rare cases, patients have weakness and sensory loss in multiple named nerves.

172. Diagnosis There is hematologic evidence of chronic active or chronic persistent hepatitis B and abnormal liver function tests while vitamin levels, glucose, and serological markers of vasculitis are normal. Cerebrospinal fluid analysis reveals an elevated protein. Electrophysiology: Demyelination with prolonged distal motor latencies, slowed motor conduction velocities, prolonged or absent F waves and temporal dispersion and conduction block of motor evoked amplitudes. Sensory responses are usually absent. Needle examination shows decreased recruitment early in the disorder and only later is there evidence of denervation in affected muscles. In rare cases, rather than demyelination , there are multiple mononeuropathies present on nerve conduction studies.

173. Nerve biopsy: According to one report, there are deposits of Hepatitis B surface antigen, Immunoglobulin and complement in the vasa nervorum .

174. Therapy Treatment is of the Hepatitis B itself (e.g. interferon or ribavirin treatment) and supportive neurological care. Plasma exchange has been suggested, but may be difficult if the patient’s coagulation status is impaired due to liver failure. Prognosis The prognosis is good in cases of acute viral infection but less certain if the neuropathy is associated with chronic persistent Hepatitis B.

175. Mycobacterium leprae (Leprosy)

176. this patient served with the foreign legion in North Africa. He has mutilated hands and toes and an ulcer Leprosy:

177. Clinical syndrome/ signs Leprous neuropathy is characterized by sensory loss in a patchy distribution. “ Tuberculoid ” leprosy involves only a few skin lesions with accompanying local sensory loss. “ Lepromatous ” disease is more extensive, with loss of temperature and pain occurring first on the forearms, legs, ears, and dorsum of hands and feet Cranial nerve damage can lead to facial damage, including iritis , alopecia, and changes in eyelid and forehead skin. Some patients with intermediate disease may be classified as “borderline”. This group is most susceptible to therapy-induced reactions that cause disease to worsen for the first year of treatment

178. Pathogenesis Infection with Mycobacterium leprae causes severe disease in patients with an impaired cell-mediated immunity ( lepromatous cases) or benign disease in patients with intact immunity ( tuberculoid cases). Early lepromatous disease involves infection of Schwann cells with minimal inflammatory response. Later, increased inflammation may lead to axon damage, and scarring and onion bulb formation from episodes of demyelination and remyelination . Nerve damage from tuberculoid and borderline disease results from granuloma formation. therapy-related toxicity from nucleoside analogues.Treatment

179. Diagnosis Patients can be classified as lepromatous or tuberculoid by a skin reaction to injected lepromin antigen. Tuberculoid and borderline cases will have an indurated reaction at the injection site. Skin biopsy can show granulomas . Nerve biopsy is used when other causes need to be excluded. EMG shows segmental demyelination , axon damage, slowed NCV, and low amplitude SNAPs.

180. Therapy Lepromatous patients are treated with dapsone for a minimum of 2 years. Tuberculoid and borderline patients are treated with dapsone and rifampin for 6 months. Cases of treatment-induced reactions require quick diagnosis and treatment with high-dose steroids until the reaction subsides. Attention must be given to areas of the body that have lost sensation. Prognosis Progression can be arrested by treatment, but outcomes are dependent upon the severity and duration of disease, and the response to treatment.

181. Cobalamin neuropathy

182. Anatomy distribution Vitamin B12 deficiency can cause a mild peripheral axonal degeneration, but it also causes a more pronounced myelopathy (vacuolization of the posterior columns and corticospinal tracts). Symptoms The symptoms of neuropathy include paresthesias , with burning in the feet and hands. Weakness may occur later. Symptoms may ascend. Clinical syndrome/signs Loss of vibratory and position sense are common sensory signs. Neuropathy is difficult to separate from myelopathy , which involves spasticity, posterior column dysfunction and ataxia. There is also memory loss and confusion. Loss of ankle reflexes may be the most diagnostic sign of neuropathy. Psychosis has also been described.

183. Pathogenesis Malabsorption of vitamin B12 is most often a result of an autoimmune-induced deficiency of intrinsic factor (pernicious anemia), but can also be caused by a vegan diet, inflammatory bowel disease, gastric or ileal resection, and nitrous oxide anesthetic. Cobalamin is required for methionine synthase and methylmalonyl CoA reductase , which influence myelin basic protein and sphingomyelin production.

184. Diagnosis CMAPs and SNAPs are reduced or absent, with slowed conduction. SEPs and VEPs are often abnormal, but BAERS are usually spared. Laboratory tests can indicate low serum B12, intrinsic factor or parietal cell antibodies, and elevated homocysteine and methylmalonic acid (intermediates in biosynthetic reactions that build up in the absence of B12).

185. Therapy 1000 ug crystalline vitamin B12 is injected intramuscularly daily for 5 days, then 500–1000 ug is given IM once a month for life for maintanence . Oral B12(1000 ug daily) can also be considered for maintenance after the initial 5 day IM load. Prognosis Loss of vibratory sensation is the least responsive symptom. Paresthesias may respond if treated early. If treatment begins within 6 months of onset, the prognosis can be very good

186. Pyridoxine neuropathy

187. Anatomy Pyridoxine deficiency causes injury of motor and sensory axons, whereas an overdose of pyridoxine causes a pure sensory neuropathy. Clinical syndrome/signs Distal burning paresthesias in hands and feet. Pyridoxine is unusual in that both deficiency and overdose cause neuropathies. Deficiency causes a syndrome of motor and sensory neuropathy. Toxicity from high doses causes a sensory neuropathy with prominent sensory ataxia.

188. Pathogenesis How pyridoxine deficiency and overdose cause neuropathy is unclear. Deficiency results from polynutritional deficiency, chronic alcoholism, and from treatment with isoniazid and hydralazine . Isoniazid inhibits conversion of pyridoxine to pyridoxal phosphate. Increased pyridoxine can be detected in the urine, but this is not important for diagnosis. Pyridoxine is toxic at doses over 200 mg/day.

189. Diagnosis can be easily diagnosed by checking blood levels of pyridoxine. EMG shows predominantly sensory abnormality in pyridoxine toxicity, but can show some mild motor involvement as well. Pyridoxine deficiency looks like other nutritional and metabolic sensory/motor axonal neuropathies. Therapy 100–1000 mg pyridoxine given daily during isoniazid or hydralazine treatment is effective. Deficiency caused by alcoholism or other states of malnutrition should be treated with pyridoxine and other vitamins, since other deficiencies are likely concurrent. Prognosis The deficiency neuropathy may improve with pyridoxine replacement or when INH is stopped. The sensory neuropathy caused by overdose shows little improvement.

190. Thiamine neuropathy

191. Anatomy/distribution Thiamine deficiency causes degeneration of sensory and motor nerves, vagus , recurrent laryngeal nerve, and brainstem nuclei. Lactate accumulates in axons due to the absence of thiamine diphosphate and transketolase . Symptoms The symptoms indicate a sensory and motor neuropathy: distal paresthesias , aches and pains, and limb weakness.

192. Clinical syndrome/signs “Dry Beriberi” is characterized by painful distal paresthesias , ankle areflexia , and motor weakness. “Wet Beriberi” combines the neuropathy with cardiac failure. “Wernicke- Korsakoff Syndrome”, resulting from long-term thiamine deficiency, causes CNS dysfunction that includes confusion, memory loss, oculomotor and gait problems.

193. Pathogenesis Beriberi is caused by states of poor nutrition: starvation, alcoholism, excessive and prolonged vomiting, post-gastric stapling, or unbalanced diets of carbohydrates without vitamins, protein, or fat (polished, milled rice or ramen noodles ). The importance of thiamine to carbohydrate metabolism may be the cause of the nervous system damage

194. Diagnosis CMAPs and SNAPs are reduced or absent, with distal denervation. RBC transketolase , serum lactate, and pyruvate may elevate after glucose loading. Differential diagnosis The sensory motor neuropathy caused by beriberi is similar to other causes of non-specific sensory motor neuropathy. Facial and tongue weakness, and recurrent laryngeal nerve deficiency are uncommon in other causes of sensory motor neuropathy, and should suggest beriberi.

195. Therapy For Wernicke- Korsakoff patients: 100 mg thiamine IV and 100 mg IM immediately, plus 100 mg IM or orally for three days. Without Wernicke- Korsakoff , restore a nutritious diet with additional thiamine. Prognosis Improvement varies with thiamine replacement. The non-neuronal components respond well, but neuropathic beriberi may result in permanent impairmen t

196. Tocopherol neuropathy

197. Anatomy Tocopherol (vitamin E) deficiency causes abnormalities of certain brainstem nuclei, as well as degeneration of the spinocerebellar tracts, posterior columns, and DRG. Neuropathy is related to loss of large sensory fibers. Symptoms Symptoms of sensory neuropathy are extremely slow in onset, and are almost always seen along with CNS dysfunction. Adult-onset disease can take 5–10 years to present, but onset latency is shorter in children. Clinical syndrome/signs The clinical syndrome is characterized by slowly progressive limb ataxia, and signs of posterior column dysfunction: loss of vibratory and joint position sense, head titubation , absent ankle reflexes, and extensor plantar responses

198. Pathogenesis Vitamin E deficiency results from abetalipoproteinemia ( Bassen-Kornzweig Syndrome), fat malabsorption states (cystic fibrosis, biliary atreasia ), or a familial defect of the tocopherol transport protein. Tocopherol is a free radical scavenger and probably functions as an antioxidant to maintain nerve membrane integrity. Diagnosis EMG shows SNAPs absent or reduced, with CMAPs unaffected. Serum tocopherol is undetectable.

199. Differential diagnosis Because of the cerebellar and spinal dysfunction, inherited spinocerebellar ataxias need to be considered. The neuropathy caused by vitamin E deficiency is very nonspecific, and without spinocerebellar disease or evidence of fat malabsorption , it can resemble neuropathies caused by numerous other etiologies. Therapy Patients with isolated vitamin E deficiency can be treated by replacement with 1–4 mg vitamin E daily. Patients with cystic fibrosis can be treated with 5–10 IU/ kg. Abetalipoproteinemia patients can be treated 100–200 mg/kg per day. Prognosis Progression of symptoms can be halted by vitamin E.

200. Drugs

201. Alcohol polyneuropathy

202. Anatomy/distribution Axonal loss of sensory and motor fibers in a distal to proximal distribution, with involvement of autonomic fibers. Symptoms Distal sensory loss, paresthesias and burning feet, with leg pain, aching and burning sensations. Stocking glove distribution. Painful calves, cramps, weakness, and sensory ataxia. Clinical syndrome/signs Exam shows sensory loss of all modalities, distal symmetric, weakness: legs > hands, distal areflexia , and orthostatic hypotension, hyperhydrosis from autonomic involvement.

203. Mononeuropathies due to pressure palsies are common in patients with alcoholic neuropathy and include mononeuropathies of the radial, ulnar , peroneal and sciatic nerves. Brachial plexus neuropathies can also occur. Pathogenesis Difficult to separate from nutritional or vitamin deficiency neuropathy. There is axonal degeneration with loss of large and small myelinated fibers in autonomic and sensory and motor nerves. Incidence is 9–30% of hospitalized alcoholics. Occurs after several years of consuming at least 100 mg alcohol daily. Women are more susceptible

204. Pathogenesis Difficult to separate from nutritional or vitamin deficiency neuropathy. There is axonal degeneration with loss of large and small myelinated fibers in autonomic and sensory and motor nerves. Incidence is 9–30% of hospitalized alcoholics. Occurs after several years of consuming at least 100 mg alcohol daily. Women are more susceptible Diagnosis Laboratory: Frequently elevated liver function tests due to alcohol consumption. Vitamin levels should be normal.

205. Electrophysiology: SNAPs may be absent or reduced, variable involvement of motor nerves; distal degeneration on EMG. Nutritional and vitamin deficiency neuropathies, toxic neuropathies, other axonal neuropathies Prognosis Depends on duration and severity of symptoms. No regeneration seen in nerve biopsies in 17 patients after 2 years. Autonomic neuropathy reduces life expectancy.

206. Amiodarone neuropathy

207. Anatomy/distribution Axonal loss of sensory and motor fibers in a distal to proximal distribution, with involvement of autonomic fibers. Symptoms Burning, dyesthesias particularly in the feet with diffuse aching pain in proximal and distal muscles. Clinical syndrome/signs Exam shows sensory loss of all modalities, distal symmetric, weakness: legs > hands, distal areflexia , and orthostatic hypotension, hyperhydrosis from autonomic involvement. Pathogenesis Class I anti-arrhythmic that is directly toxic to nerves. Neuropathy caused by 400 mg/day for one or more years.

208. Diagnosis Electrophysiology: SNAPs may be reduced or absent, conduction velocities are low normal or slowed with distal degeneration on EMG. Biopsy shows axonal degeneration, segmental demyelination , lipid lysosomal dense bodies in Schwann cells and perineural cells. Therapy Drug withdrawal. Prognosis Good with early detection, partial recovery for established neuropathy.

209. Chloramphenicol neuropathy

210. Anatomy/distribution Prognosis Axonal loss of sensory and motor fibers in a distal to proximal distribution. Symptoms Numbness is greater than burning in the feet with accompanying calf tenderness. Clinical syndrome/signs Diminished distal pain and touch, loss of ankle reflexes. Rare reports of optic neuropathy. Bone marrow suppression. Pathogenesis Occurs in children being treated for cystic fibrosis receiving an average of 255 mg for an average of 10 months. Renal failure may potentiate toxicity, and agranulocytosis is the main dose limiting effect. Thus, neuropathy is very rare today.

211. Diagnosis Pathophysiology is unknown but it is likely due to direct toxic effects on axons. Should also consider critical illness neuropathy. Therapy Chloramphenicol should be stopped if symptoms cannot be ascribed to another cause. High dose vitamin therapy has been used but there is little data to support it. Prognosis Complete recovery can be expected if the drug is stopped soon after the onset of symptoms.

212. Colchicine neuropathy

213. Anatomical distribution Widespread degeneration of myelinated and unmyelinated axons in PNS and CNS, changes in DRG. Symptoms Mild distal sensory loss and parasthesias . Patients may also experience proximal weakness. Clinical syndrome/signs Exam shows sensory loss of all modalities, distal symmetric with decreased or absent tendon reflexes. While there can be mild distal weakness of the lower extremities, the more common presenting sign is proximal weakness due to an accompanying colchicine myopathy .

214. Pathogenesis Colchicine blocks microtubular function and impairs axonal transport. Patients with impaired renal function are more likely to develop a colchicine neuromyopathy than a patient on colchicine who has normal renal function. Diagnosis Electrophysiology: Decreased SNAPs with near normal NCV. Biopsy: Mild axonal loss and disruption of myelin with nerve biopsy. Muscle biopsy shows vacuolar and lysosomal changes. Therapy Discontinue colchicine . Prognosis Neuropathy will improve.

215. Dapsone neuropathy

216. Anatomy distribution Motor axonal loss with relative sparing of sensory neurons and axons. Symptoms Motor neuropathy predominately. Occasionally generalized weakness. Arms greater than legs, especially median nerve. Hand weakness without sensory loss may give impression of motor neuron disease. Pathogenesis Dapsone is used for the treatment of leprosy and other dermatologic conditions, and causes neuropathy after long term, high dose use.

217. Diagnosis Biopsy: Non-specific axonal changes on biopsy. Neuropathy from leprosy is predominantly sensory, and should not be confused with this. Mildly slowed motor NCV and minimal signs of denervation . Therapy Discontinue usage. Prognosis Symptoms may progress after discontinuing use, but will gradually improve.

218. Disulfiram neuropathy

219. Anatomical distribution Primary axonal degeneration. Symptoms Paresthesias of the feet and unsteady gait. Pain, temperature, and vibration sensation are diminished in the feet. Hand involvement occurs later. Absent ankle reflexes, dorsiflexor weakness. Optic neuropathy may occur. Pathogenesis Used infrequently as an adjunct treatment for chronic alcoholism. Occurs after several months of therapy on standard doses.

220. Diagnosis Mild slowing of motor NCV, diminished sensory amplitudes, distal denervation . Biopsy shows loss of all fiber sizes. Therapy Drug withdrawal. Prognosis Most cases improve after several months.

221. Polyneuropathy and chemotherapy

222. Toxic neuropathies caused by chemotherapy are usually dose-dependen t, and have a potential reversibility after termination of the drug treatment. Little is known about the influence of preexisting polyneuropathies in the development of a chemotherapeutically induced neuropathy (except vincristine given in patients with hereditary sensorimotor neuropathy), and the toxicity of only a few drug combinations have been described. This is of importance as chemotherapyis not always used as a single agent therapy , but patients often receive drug combinations or second line therapy. Additionally also biological agents such as antibodies, interferons , cytokines and vaccines are used in cancer therapy and also have a risk of inducing polyneuropathies

223. Clinical distribution: Most neuropathies caused by chemotherapeutic agents are symmetric and length dependent, with a stocking glove distribution of sensory loss . Sensory symptoms and distal weakness ( lower extremities) occur. The development of distal sensory symptoms (numbness or paresthesias ) can be used as a possible sign of neurotoxicity

224. Overview of the most frequently used chemotherapeutic agents causing polyneuropathy

225. Vinca alkaloids Symptoms Paresthesias on fingers and toes, sensory loss for pin prick and light touch. Areflexia . Clinical syndrome/signs Dose dependent mixed sensorimotor polyneuropathy . Muscle weakness in distal muscles. Rarely cranial nerves and autonomic dysfunction. Pathogenesis Vinca alkaloids bind to microtubules and interfere with their assembly. Structural changes account for abnormal axoplasmic transport and are related to axonal degeneration.

226. Diagnosis Electrophysiology : axonal damage with an EMG that shows neurogenic changes. Differential diagnosis Paraneoplastic neuropathy, other chemotherapeutic agents. Therapy Discontinue drug. Prognosis Potentially reversible, sensory symptoms improve within some months

227. Platinum-compounds ( cisplatin , carboplatin , oxaliplatin ) Anatomy Predominantly sensory neuropathy with paresthesias in hands and feet followed by numbness. Rapid onset, often with burning pain, with rare weakness. Hearing loss. Clinical syndrome/signs While cisplatin and carboplatin have a similar spectrum of dose dependent neuropathy, oxaliplatin has two types of toxicity. The acute toxicity of oxaliplatin occurs after infusions. Patients experience dysesthesias and paresthesias , aggravated by cold. The symptoms recur after each chemotherapy cycle with oxaliplatin . Additional symptoms also include eye and jaw pain, leg cramps, and voice changes. The chronic toxicity is a dose dependent polyneuropathy , resembling cis platinum neuropathy.

228. Pathogenesis Proximal and distal weakness and sensory loss, ataxia. Some times Lhermitte’s sign. Large myelinated fiber loss also small fiber loss. Random demyelination may interfere with microtubular transport. Microtubule aggregation in DRG axons Pathogenesis Proximal and distal weakness and sensory loss, ataxia. Some times Lhermitte’s sign. Large myelinated fiber loss also small fiber loss. Random demyelination may interfere with microtubular transport. Microtubule aggregation in DRG axons Diagnosis Electrophysiology: axon loss changes with small sensory and motor evoked responses, denervation on EMG

229. Diagnosis Electrophysiology: axon loss changes with small sensory and motor evoked responses, denervation on EMG Therapy Drug withdrawal. Symptoms may increase after cessation of therapy (“coasting“). Prophylactic treatment with ACTH analogs, glutathione or amisfostine have not been successful. Prognosis Slow reversal of symptoms with variable degrees of residual numbness and reflex changes, motor symptoms if present.The combination with other cytostatic drugs such as taxanes may potentiate the neurotoxicity. Clinically the neuropathy can be confused with ganglionopathies , in particular with paraneoplastic subacute sensory neuronopathy . The individual case history and the evaluation of the cumulative dose of previous treatment is necessary.

230. Taxol Taxanes ( diterpene alkaloids) are used as cytostatic drugs. Docetaxel induces a mild to moderate neuropathy with loss of deep tendon reflexes, vibration sense. Paresthesias may occcur . Severe neuropathies may occur after high cumulative doses. Paclitaxel neuropathy results in paresthesias , numbness, sometimes pain in the feet and hands. Fine motor tasks such as buttoning and writing can be impaired. Unsteadiness of walking can occur. Additionally perioral and tongue numbness can appear. Weakness is mild. Rarely proximal muscle weakness has been observed.

231. Symptoms Predominantly sensory neuropathy with paresthesias in hands and feet followed by numbness. Weakness is rare. Clinical syndrome/signs Proximal and distal weakness and sensory loss. Rapid onset, often with burning pain, with rare weakness. Pathogenesis Large myelinated fiber loss also small fiber loss. Random demyelination may interfere with microtubular transport. Microtubule aggregation in DRG axons. Diagnosis Electrophysiology with small sensory and motor evoked responses, denervation on EMG. Therapy Drug withdrawal. Prognosis Slow reversal of symptoms with variable

232. Metals

233. Arsenic neuropathy Meese lines at the nailbed , in case of arsenic poisoning and polyneuropathy (courtesy Dr. Freymueller , Hermagor , Austria)

234. Anatomy/distribution Massive exposure may demonstrate demyelinating polyradiculoneuropathy , distal axonopathy . Symptoms Painful stocking-glove sensory neuropathy, motor neuropathy usually mild but can be severe. Malaise, nausea, vomiting, mucous membrane irritation. Clinical syndrome/signs Hyperkeratosis, darkened skin, Mee’s lines ), pitting edema. Acute massive exposure leads to vasomotor collapse and death. Chronic exposure leads to aplastic anemia

235. Pathogenesis Arsenic can be encountered in copper and lead smelting, wells near mines with arsenic, accidental or intentional poisoning. Arsenic may inhibit conversion of pyruvate to acetyl CoA . Diagnosis Signs of demyelination . Absent SNAPs and reduced CMAPs, muscle denervation . Arsenic can be detected in hair, nails, and urine in chronic exposure cases. Urine levels greater than 25 mg/24 hrs, unless recent seafood ingestion. Therapy BAL or penicillamine , continued for months if neuropathy is refractory. Neuropathy from less fulminant exposure usually stabilizes over a 2 year period. Prognosis related to severity and duration of symptoms.

236. Mercury neuropathy

237. Anatomy/distribution Axonal degeneration with relative sparing of sensory fibers. Symptoms Mercury metal vapor causes subacute , diffuse, predominantly motor neuropathy that may mimic AIDP. Alkyl mercury causes intense distal limb paresthesias , probably from CNS dysfunction. Elemental mercury may cause sensorimotorneuropathy . Diagnosis Biopsy shows axonal degeneration. CMAPs decreased more than SNAPs. Alkyl mercury shows normal EMG. Therapy Chelation therapy is of limited benefit. Prognosis Degree of CNS recovery determines prognosis

238. Diagnosis Biopsy shows axonal degeneration. CMAPs decreased more than SNAPs. Alkyl mercury shows normal EMG. Therapy Chelation therapy is of limited benefit. Prognosis Degree of CNS recovery determines prognosis

239. Thallium neuropathy

240. Anatomical distribution Distal axonopathy , especially of large diameter fibers. Symptoms Three temporal varieties of neuropathy occur. A massive dose causes acute painful neuropathy with GI distress. May resemble AIDP, and proceed to lethargy, coma, and death. A one week or longer exposure at lesser doses causes neuropathy with alopecia, hyperkeratosis, Mee’s lines, ataxia, chorea, CNS palsies, autonomic dysfunction with tachycardia. Mild distal weakness. Chronic exposure at low levels causes extrapyramidal dysfunction and questionable sensorimotor neuropathy.

241. Pathogenesis Thallium is found in rodenticides and insecticides, and may be ingested in situations of homicide and suicide. Diagnosis Slight decrease in NCV. Diagnosis made by detection of thallium in urine or organs. Therapy Potassium chloride or Prussian blue is used for treatment, but efficacy is questionable. Prognosis Recovery begins six months following discontinuation of exposure, and recovery for subacute cases is good.

242. Thank you