Peripheral neuropathy in systemic disease children

Peripheral neuropathy in systemic disease children

1. SYSTEMIC DISEASE AND PERIPHERAL NEUROPATHIES IN CHILDREN DR SWAPNIL SAMADHIYA SR NEUROLOGY GMC KOTA

2. GLOBAL BURDEN Overall prevalence – 2 to 4 % Among several sudies , around 20 to 50 % patients remain undiagnosed

3. SYSTEMIC DISEASES ASSOCIATED WITH PERIPHERAL NEUROPATHIES IN CHILDREN Hepatic disorders Endocrinopathies Uremia Amyloidosis Celiac disease Porphyria Mitochondrial disorders(Leigh ,NARP) Disorders of lipid or glycolipid metabolism ( eg ,  Refsum disease,  Fabry disease, abetalipoproteinemia , hypobetalipoproteinemia , Tangier disease) Leukodystrophies with peripheral nerve involvement ( adrenomyeloneuropathy , adrenoleukodystrophy , Krabbe disease ) Connective tissue disorders Neoplasms Infections

4. CLINICAL FEATURES Symptoms generally- paresthesias in the feet in the early stage with progression in a classic stocking-glove distribution. Hand involvement usually begins once sensory loss progresses to the mid-calf or knee. Weakness-same pattern of progression,patient complaints, including foot drop and hand intrinsic weakness. Autonomic sympt - gastroparesis , erectile dysfunction, and orthostatic hypotension Donofrio , Peter D. Textbook of Perhipheral Neuropathies . New York (NY): Demos Medical; 2012.

5. General Examination Purpura, Livodereticularis – Vasculitis , Cryoglobulinemia Fabry’s disease – Angiokeratomas Skin pigmentation – Leprosy, POEMS , adrenoleukodystrophy Icthyosis – Refsum’s Disease Alopecia – Hypothyroidism , SLE Maculoanaesthetic patches with thickened nerves – Leprosy Orange Tonsils – Tangier’s disease Macroglossia – Amyloidosis Chelosis/Glossitis – Multivitamin deficiency

6. Livedo reticularis

7. Purp u r a

8. Angiokeratomas

9. Skin Pigmentation

10. Icthyosis

11. Mee’s lines

12. Thickenend Nerves in Neuropathy Leprosy Neurofibromatosis Roussy Levy Syndrome Refsum’s disease Amyloidosis

13. SYSTEMIC EXAMINATION CENTRAL NERVOUS SYSTEM EXAMINATION Higher Functions Altered in Porphyria, HIV, Lead and other toxins Nutritional: Megaloblastic Madness Cranial Nerve affection CN III, IV, VI: Diabetes, MFS, Diphtheria CN V: Sjogren’s Syndrome, Arsenic, Lyme, Amyloidosis, Leprosy CN VIII, IX, X - Diptheria

14. Motor System Axonal Neuropathy & Hereditary Neuropathies Prominent and early wasting and atrophy Demyelinating Neuropathy Less and disuse wasting as compared to axonal type Deformitity Claw Hand: Leprosy, Diabetes, Amyloidosis Trophic Changes: Diabetes , Leprosy

15. Sensory Examination : Reflexes Usually diminished or absent; especially ankle jerk Exaggerated Knee with ankle absent – Vit B12 deficiecny, HIV myeloneuropathy, Friedrich’s ataxia Gait Disturbances : Ataxias, high stepping gaits, etc

16. RESPIRATORY SYSTEM EXAMINATION Asthma – Churg-Strauss Syndrome Tuberculosis – HIV Connective Tissue Disorder CARDIOVASCULAR SYSTEM Cardiomyopathy: Diptheria , Amyloidosis Pericarditis: Connective Tissue disorder

17. PER ABDOMEN EXAMINATION Hepatosplenomegaly HIV, lymphoma, connective tissue disorder, paraneoplastic, amyloidosis Tenderness: Porphyrias, toxins: lead, thallium OPHTHALMIC EXAMINATION Cataracts: Diabetes Microaneurysms: Diabetes Optic disc edema: AIDP, CIDP, POEMS Xerophthalmia: Sjogren’s Syndrome, Sarcoidosis

18. Liver disease Hepatitis C: Incidence around 5%-10% develop PN or mononeuritis multiplex. Chaudhry V, Corse AM, O’Brian R, Cornblath DR, Klein AS, Thuluvath PJ. Autonomic and peripheral ( sensorimotor ) neuropathy in chronic liver disease: a clinical and electrophysiologic study. Hepatology . 1999;29(6):1698-1703.

19. Pathophysiology Cirrhosis-associated PN ,cirrhosis itself, not the specific cause of cirrhosis. A 2003 study by Kharbanda et al failed to show statistically significant difference in neuropathy incidence between patients with alcohol and non-alcohol cirrhosis. Pathogenesis unknown PN is associated with noninfectious liver disease. Kharbanda PS, Prabhakar S, Chawla YK, et al. Peripheral neuropathy in liver cirrhosis.  J Gastroenterol Hepatol .  2003; 18: 922-926.

20. Liver Disease Chronic hepatitis: the majority are subclinical, with a distal symmetric pattern, sensory > motor, large-fiber ( paresthesia , numbness) axonal PN. Infectious hepatic: mononeuritis multiplex pattern is most common. Donofrio , Peter D. Textbook of Perhipheral Neuropathies . New York (NY): Demos Medical; 2012.

21. Hepatitis B and C cause vasculitic PN, immune complex deposition into vasculature, activating monocytes to release proinflammatory cytokines. attracts neutrophils , which release free radicals that ultimately cause nerve damage. Increased messenger ribonucleic acid expression in hepatitis C suggests involvement of cytotoxic T-cells. Donofrio , Peter D. Textbook of Perhipheral Neuropathies . New York (NY): Demos Medical; 2012

22. Thyroid disease Hypothyroidism: Highly variable between studies. About 50% incidence. Hyperthyroidism: about 25% of severe thyrotoxicotics . Most PN in hypothyroidism is subclinical with electromygraphic findings only. Dyck PJ, Lambert EH. Polyneuropathy associated with hypothyroidism. J Neuropathol Exp Neurol . 1970;29(4):631-658.

23. Hypothyroidism Commonly associated with proximal myopathy, but some patients typically develop Carpel Tunnel Syndrome Generalised neuropathy characterised by painful paresthesias and numbness in legs and hands can occur

24. Thyroid Hypothyroid-associated PN presents similarly to diabetic polyneuropathy as a distal symmetric, large fiber sensory polyneuropathy . It is often asymptomatic. Woltman sign is a delayed relaxation phase on muscle stretch reflexes (MSRs) seen with clinically overt hypothyroidism and has a 72% positive predictive value. Hyperthyroid- associated neuropathy commonly presents clinically as a distal symmetric sensory axonal PN. Sözay S, Gökçe-Kutsal Y, Celiker R, Erbas T, Başgöze O. Neuroelectrophysiological evaluation of untreated hyperthyroid patients. Thyroidology . 1994;6(2):55-59.

25. Hypothyroidism increased compartmental pressure from mucinous infiltration of the perineurium and endoneurium leading to focal demyelination and compression disruption of microtubule assembly axonal degeneration, and secondary demyelination . Pollard JD, McLeod JG, Honnibal TG, Verheijden MA. Hypothyroid polyneuropathy . Clinical, electrophysiological and nerve biopsy findings in two cases. J Neurol Sci . 1982;53(3):461-471.

26. Diabetic neuropathy is the most common systemic disease with peripheral neuropathy. In a large prospective study done by Pirart , the prevalence rose from 7.5% at the time of diagnosis to 50% after 25 years.  

27. Diabetic Neuropathy Distal symmetric sensory and sensorimotor polynneuropathy Autonomic neuropathy Diabetic neuropathic cachexia Polyradiculoneuropathies Cranial neuropathies Other mononeuropathies

28. Diabetic Distal Symmetric Sensory and Sensorimotor Polyneuropathy (DSPN) Begins in toes, gradually progress over time upto legs and into arms and legs When severe, sensory loss also occurs on trunk, initially over midline anteriorly and then laterally Tingling, burning, deep aching pains occur

29. Diabetic Autonomic Neuropathy Abnormal sweating, dysfunctional thermoregulation, dry eyes and mouth, pupillary abnormal i ties , cardiac arrythmias, postural hypotension, GI abnormalities (gastroparesis, post prandial bloating, chronic diarrhoea or constipation) and genitourinary disturbances (impotence, retrograde ejaculation, incontience ) Tests for autonomic dysfunction are abnormal – sympathetic skin responses and quantitative sudomotor axon reflex testing

30. Diabetic Radiculoplexus Neuropathy (Diabetic Amyotrophy or Bruns- Garland Syndrome) Severe pain in lower back, hip and thigh in one leg Atrophy and weakness of proximal and distal muscles , appa r ent within a few days to weeks Severe weight loss Recovery is slow and partial with residual weakness, sensory loss, and pain ESR, CSF protein are elevated Presentation may be like the typical lumbosacral radiculoplexus neuropathy , thoracic radiculopathy or even an uncommon cervical polyradiculoneuropathy

31. Diabetic Mononeuropathies Median neuropathy at wrist Ulnar neuropathy at elbow Peroneal neuropathy at fibular head Cranial Neuropathies Seventh cranial nerve Third cranial nerve palsy (typically pupil sparing)

32. Critical illness 70% of patients in intesive care unit for ≤2 weeks. Seen with severe inflammatory response syndrome (SIRS), sepsis, multiorgan failure Associated with increased mortality and length of weaning from the ventilator. Latronico N, Peli E, Botteri M. Critical illness myopathy and neuropathy. Curr Opin Crit Care . 2005;11(2):126-132.

33. Critical Illness Neurosurgical, multitrauma , burns, and after major vascular repair (aortic abdominal aneurysm, coronary artery bypass graft). Suspicion should be raised in a patient with limb weakness, loss of MSRs, or unable weaning off ventilation post-SIRS. Latronico N, Peli E, Botteri M. Critical illness myopathy and neuropathy. Curr Opin Crit Care . 2005;11(2):126-132.

34. Critical Illness Polneuropathy Acute generalised weakness leading to admission in ICU are GBS M yasthenia gravis

35. Critical illness PN (CIP) Multiple pathways ( metabolic, inflammatory, bioenergetic alterations ). Microvascular changes in peripheral nervous system (PNS) (increased E- selectin expression), altered lipid serum profile, damage or inhibition of complex I of the respiratory chain causing muscle adenosine triphosphate depletion, bioenergetic failure. Latronico N, Peli E, Botteri M. Critical illness myopathy and neuropathy. Curr Opin Crit Care . 2005;11(2):126-132.

36. Cranial nerve (CN) involvement suggests Guillain-Barre Syndrome (GBS)or critical illness myopathy . Difficulty evaluating sensation is common from encephalopathy or sedation. In the setting of absent nail bed pressure response, supraorbital pressure grimace suggests intact pain sensation Latronico N, Peli E, Botteri M. Critical illness myopathy and neuropathy. Curr Opin Crit Care . 2005;11(2):126-132.

37. Amyloidosis About 15%-30% of patients. Presenting feature in 10%-20%. Symptoms usually present 1 year prior to diagnosis. Dyck , Peter J, Thomas PK. Peripheral Neuropathy . Philadelphia (PA): Saunders; 2005.

38. Primary or AL Amyloidosis Multiple myeloma, Waldenstrom macroglobulinemia, lymphoma or plasmacytomas 30 % patients with neuropathy – painful dysesthesias and burning sensation of feet. Sometimes mononeuritis multiplex can occur Slowly progressive eventually with large fibre sensory loss Autonomic dysfunction with postural hypotension, syncope, bowel and bladder disturbances, constipation, impotence and impaired sweating

39. Amyloid PN insoluble beta- fibrillar protein deposition in nerve sheaths, perineuronal tissues, and neural vasculature. Ischemic, infiltrative, inflammatory, and toxic metabolic factors ,causing axon and neural capillary compression loss of myelin fibers and axonal degeneration. Loss of unmyelinated fibers is also observed. Coelho T, Maia LF, Martins da Silva A, et al. Tafamidis for transthyretin familial amyloid polyneuropathy .  Neurology.  2012; 79: 785-792.

40. Amyloidosis Slowly progressive, distal symmetric mixed-fiber, sensorimotor PN with or without autonomic involvement (orthostatic hypotension, diarrhea, bladder dysfunction, impotence). Carpal tunnel syndrome (CTS) present in 25% from wrist flexor retinaculum amyloid deposition. Small-fiber findings (pain, temperature) and CTS mandate amyloidosis workup. Constitutional symptoms (weight loss, organ involvement) should raise suspicion of primary amyloidosis . Coelho T, Maia LF, Martins da Silva A, et al. Tafamidis for transthyretin familial amyloid polyneuropathy .  Neurology.  2012; 79: 785-792

41. Monoclonal protein may be composed of IgG, IgA, IgM, or only free light chain. Lambda is more common than kappa light chain CSF protein is often increased (with normal cell count) mimicking neuropathy Nerve Biopsy – axonal degeneration and amyloid deposition Chemotherapy reduces the concentration of monoclonal proteins, and autologous stem cell transplantation may prolong survival, but improvement of neuropathy is controversial

42. A Mayo Clinic study demonstrated a median survival of 13.2 months following diagnosis, with 7% surviving after 5 years. Systemic symptoms at presentation is a poor prognosticator. Median survival if congestive heart failure is seen at presentation is 4 months. Coelho T, Maia LF, Martins da Silva A, et al. Tafamidis for transthyretin familial amyloid polyneuropathy .  Neurology.  2012; 79: 785-792

43. Vasculitic Neuropathy Most Common childhood cause PAN (Polyarteritis Nodosa ); occuring in half the cases clinically and in 100% cases on post mortem examination Churg strauss syndrome Multifocal (asymmetric) motor-sensory neuropathy (mononeuropathy multiplex) due to ischemic lesions of nerve trunks and roots

44. Suspected when mononeuropathy multiplex occurs in conjugation with constitutional symptoms (fever, anorexia, weight loss, malaise) Diagnosis by combined nerve and muscle biopsy Connective Tissue Disorders Rheumatoid Arthritis Cryoglobulinemia Wegener’s SLE Systemic Sclerosis

45. Connective tissue disorder Prevalence: 1-64 in 100,000. Onset mostly around 20-29 years of age, usually before 40 years old. Scandinavian and Japanese women with second peak incidence when >50 years old. Prevalance African-American >> Caucasians. 5% with both peripheral nervous system and central nervous system involvement. Children rare but cases reported Dyck , Peter J, Thomas PK. Peripheral Neuropathy . Philadelphia (PA): Saunders; 2005.

46. Connective tissue disorder cell-mediated immune response,nerve granulomas and multinucleated giant cell (MNGC) formation. Memory T-cells recruit and activate macrophages, fuse into MNGCs gain secretory capabilities and release proteolytic enzymes damaging neighboring cells. granuloma -related necrotizing vasculitis , endoneurium inflammation,ischemic nerve lesions ,axonal degeneration. Tavee JO, Karwa K, Ahmed Z, et al. Sarcoidosis -associated small fiber neuropathy in a large cohort: clinical aspects and response to IVIG and anti-TNF alpha treatment.  Respiratory Medicine . 2017; 126: 135-138.

47. Systemic Lupus Erythmatosus (SLE) 2 to 27% patients develop neuropathy Slowly progressive sensory loss beginning in feet Burning pain and paresthesias with normal reflex (small fibers) NCS – pure small-fiber neuropathy Immunosuppressive therapy is beneficial in SLE with vasculitis

48. Sa r c oido s is Cranial nerve – VII – affected bilaterally Radiculopathy or polyradiculopathy If generalised root involvement is present, then it mimics GBS Multiple mononeuropathies or a generalised, slowly progressive, sensory greater than motor polyneuropathy can occur EDx – Axonal Neuropathy

49. Sarcoidosis Predominantly involves cranial nerves: multiple fluctuating and remitting CN palsies, CNs successively and randomly involved over weeks or months. Up to 50% with facial nerve palsy. Ocular involvement in about 25%. Hearing loss, vertigo, and tinnitus also reported. Kollmer J, Bendszus M, Pham M. MR neurography : diagnostic imaging in the PNS.  Clin Neuroradiol . 2015; 25(2):283-289 .

50. Outside of the CN, PN with granulomas is extremely uncommon Focal and multifocal sensorimotor neuropathy, GBS, multifocal subacute or chronic sensorimotor neuropathy, chronic symmetric sensory PN, subacute multifocal sensorimotor neuropathy with conduction block). However, small fiber neuropathy is fairly common.

51. Sjog r en’s Syndrome Complex of sicca complex of xerophthalmia, xerostomia, dryness of mucus membranes, can be complicated by neuropathy Length-dependent axonal sensorimotor neuropathy of small fibre or cranial neuronopathy, particularly of trigeminal nerve Progressive tingling and numbness of trunk and limbs, or face (with sometimes face > limbs)

52. Patients with sensory ganglionopathies develop progressive numbness and tingling of the limbs, trunk, and face in a non-length- dependent manner; so that face or arms are affected more than legs ANAs, SS-A/Ro and SS-B/La antibodies in the serum NCVs & nerve biopsy – axonal degeneration Vasculitis is suspected, immunosuppressive agents can be beneficial

53. Rheumatoid Arthritis Seen in 50% of patients Vasculitis Mononeuropathy multiplex, generalised pattern or combination of both Also be due to drugs used to treat RA (tumor necrosis blockers, leflunomide) Responsive to immunomodulating therapies

54. Celiac disease 6%-12% prevalance . Celiac disease prevalence about 1% in American and Europeans. Considerable number of undiagnosed patients possible. Dyck , Peter J, Thomas PK. Peripheral Neuropathy . Philadelphia (PA): Saunders; 2005.

55. Celiac Disease (Gluten-induced enteropathy or nontropical sprue) Ataxia and peripheral neuropathy occurs in 10% of patients with celiac disease Generalised sensorimotor polyneuropathy, pure motor neuropathy, multiple mononeuropathies, autonomic neuropathy, small-fiber neuropathy, and neuromyotonia Nerve biopsy – loss of large myelinated fiber – (Secondary to malabsorption of Vitamin B12 and E)

56. Celiac PN Progressive course correlates with disease severity and duration. Can present as a non-length-dependent neuropathy ( ganglionopathy ) or exclusively small-fiber neuropathy. Donofrio , Peter D. Textbook of Perhipheral Neuropathies . New York (NY): Demos Medical; 2012.

57. Celiac disease Malabsorption vs other immunologic mechanisms Malabsorption includes vitamins B12, B6, and E and metals, especially copper. Similarity between antigens targeted by the immune system and proteins expressed in the PNS (molecular mimicry)possibility. Donofrio , Peter D. Textbook of Perhipheral Neuropathies . New York (NY): Demos Medical; 2012.

58. Uremic polyneuropathy Second most common neuropathy is that associated with uremia, with studies showing ranges of peripheral neuropathy prevalence of 10-80%. Uremic neuropathy is more frequent in males than in females. Dyck PJ, Lambert EH. Polyneuropathy associated with uremia. J Neuropathol Exp Neurol . 1970;29(4):631-658.

59. Uremic polyneuropathy Subacute , sensorimotor , distal, and more prominent in the lower extremities. Muscle cramps and the restless leg syndrome. The earliest finding in uremic neuropathy-loss of ankle jerks or elevation of the vibratory sensation threshold. Most common mononeuropathy in CKD is CTS, but mononeuropathies of ulnar or femoral nerves may be caused by compression by fistulas or dialysis catheters. Multiple cranial nerve neuropathies also have been reported in uremia.

60. Uremic Neuropathy 60 % of patients with renal failure develops polyneuropathy – length dependent numbness, tingling, allodynia and mild distal weakness Rapidly progressive weakness and sensory loss, very similar to GBS, can occur which improves by increasing the intensity of dialysis or with transplantation

61. Uremic polyneuropathy Conduction velocity slowing Inhibition of axolemma -bound NA + /K +  -ATP ase by uremic toxins, Leading to intracellular sodium accumulation Altered resting membrane potentials Axonal degeneration with secondary segmental demyelination .

62. PORPHYRIA Only hepatic porphyrias are associated with neurologic disease Neural energy failure from heme deficiency. Neurotoxicity from porphyrin precursors . Acute intermittent porphyria may be associated with attacks of acute motor neuropathy with mild sensory symptoms very similar to Guillain-Barré syndrome

63. HIV HIV- related distal symmetric polyneuropathy HIV – related inflammatory demyelinating polyneuropathy HIV – related progressive radiculopathy HIV – related multiple mononeuropathies HIV – related neuronpathy / ganglionopathy

64. HIV – Related Distal Symmetric Polyneuropathy (DSP) DSP most common neuropathy in HIV-AIDS Characterised by numbness and painful paresthesias in distal extremities Immune mediated – cytokines from surrounding inflammation Antiretroviral drugs – Dideoxycytidine, stavudine causes painful sensory neuropathy

65. HIV – Related Inflammatory Demyelinating Polyneuropathy AIDP and CIDP occurs in HIV AIDP during the time of sero-conversion, while CIDP can occur at any stage in the disease Elevated protein levels, lymphocytic pleocytosis is evident on CSF; which helps to distinguish it from idiopathic AIDP/CIDP

66. HIV – related progressive polyradiculopathy Acute progressive lumbosacral polyradiculopathy occurs secondary to CMV infection Severe radicular pain, numbness and weakness in legs – usually asymmetric

67. HIV – related multiple mononeuropathies Weakness, numbness, paresthesias, and pain occur in distribution of affected nerves Axonal degeneration with necrotizing vasculitis or perivascular inflammation occurs

68. HIV – related sensory neuronopathy / ganglionopathy Dorsal root gangli o nitis occurs and neuronopathy is the presenting feature Sensory ataxia

69. Leprosy (Hansen’s Disease) Most common cause of peripheral neuropathy in Southeast Asia, Africa and South America Superficial cutaneous nerves of the ears and distal limbs are commonly affected Mononeuropathies , multiple mononeuropathy occurs Slowly progressive distal symmetric sensorimotor polyneuropathy Childhood leprosy ,important marker of the status of the ongoing leprosy control programme , indicator of active disease transmission in the community.

70. Sensory NCVs usually absent in lower limbs and reduced in amplitude in arms Motor NCS reduced amplitude in affected nerves and also shows delayed latent conduction velocities

71. Lyme Disease Neurological complications occurs in second and third stages of infection Facial neuropathy is most common and is bilateral Other nerves are symmetrically affected It is a primary axonopathy

72. Diphtheritic Neuropathy 20 – 70 % patients develop peripheral neuropathy by a toxin released by bacteria In third to forth week of illness, decreased sensation in throat, dysphagia, dysarthria , hoarseness , blurred vision ( impaired accomodation occurs ) More generalised neuropathy 2 to 3 months later, characterised by numbness, paresthesias, weakness of arms and legs , respiratory failure

73. CSF protein can be elevated with or without pleocytosis EDx – diffuse axonal sensorimotor polyneuropathy Antitoxin and antibiotics should be given within 48 hours of symptom onset; however, it does not alter the natural history of associated peripheral neuropathy

74. Herpes Varicella-Zoster Virus 2/3 rd adults there is dermal zoster with pain and paresthesias in dermatomal region followed within a week or two by vesicular rash in same distribution Weakness in muscles innervated by roots corresponding to dermatological distribution of skin lesions occurs in 5 – 30% patients About 25 % patients have continued pain (post herpetic neuralgia – PHN)

75. Cytomegalovirus Acute lumbosacral polyradiculopathy and multiple mononeuropathies in patients with HIV and other immune deficiency disorders

76. Epstein-Barr Virus Associated with GBS, cranial neuropathies, mononeuropathy multiplex, brachial plexopathy, lumbosacral radiculoplexopathy, and sensory neuronopathies

77. Nutritional Neuropathies Cobalamin (Vitamin B12) deficiency Numb hands typically appear before lower extremity parasthesias Large fibre sensory loss affecting proprioception & vibration with sparing of small fibre modalities, sensory ataxia H yp e reflexia and absent Achilles reflex Sometimes – optic atrophy with behavioral changes may be visible

78. Thiamine Deficiency Consequence of malnutrition Mild sensory loss to burning dysesthesias in toes and feet and aching and cramping in lower legs followed by distal sensory loss

79. Copper Deficiency Myeloneuropathy Lower limb paresthesias, weakness, spasticity and gait difficulties Most commonly large fibres sensory function is affected sometimes ; small fibres are affected too

80. Acute Inflammatory Demyelinating Polyneuropathies Clinical Features Areflexic motor paralysis with or without sensory disturbances Ascending paralysis with dysesthesias in the extremities Facial diparesis in 50 % of patients Lower cranial nerves also be involved Pain in neck, shoulder, back or over spine in 50 % patients Autonomic dysfunction (fluctuation in BP, arrythmias) Bladder dysfunction not a prominent feature, but if present suggests some alternative diagnosis (spinal cord)

81. Subtypes of GBS SUBTYPE FEATURES ELECTRODIAGNOSIS Acute inflammatory demyelinating polyneuropathy (AIDP) Adults more than children; anti-GM1 antibodies Demyelinating Acute motor axonal neuropathy (AMAN) Children and yourng adults, maybe seasonal; anti-GD1a antibodies Axonal Acute motor sensory sxonal neuropathy (AMSAN) Mostly adults, recovery slow and often incomplete Axonal Miller Fisher Syndrome (MFS) Adults and children; ophthalmoplegia, ataxia and areflexia; anti-GQ1B antibodies Axonal or demyelinating

82. Antecedent Events 70% GBS occurs 1 – 3 weeks after acute infectious process, usually respiratory or gastrointestinal 20 – 30 % cases in western world after C. jejuni infection Others include – HHV, CMV, EBV, M. peumoniae Older type of rabies vaccine, prepared in nervous system, is implicated as a trigger for GBS in developing countries. GBS also occurs in lymphona . HIV-se r opositive patients, SLE

83. Immu n op a tho g enes i s of GBS

84. Chronic Inflammatory Demyelinating Polyneuropathy Onset gradual over a few months or longer Weakness of limbs is symmetric but can be asymmetric in multifocal aquired demyelinating sensory and motor (MADSAM) neuropathy variant Some have chronic progressive course, while others have replasing and remitting course Some have only motor findings, while some have pure sensory ataxia Tremors in 10 % patients

85. Pathogenesis Biopsy reveals – inflammation and onion-bulb appearance (from recurernt remyelination and demyelinatin ) CIDP responds to glucocorticoids Some patients have antibodies against P0, myelin P2, PMP22 or neurofuscin 25% patients have monoclonal gammopathy and antibodies against myelin-associated glycoprotein (MAG)

86. Fabry’s disease Angiokeratoderma corporis diffusum; X-linked dominant disorder. Angiokeratomas – umbilicus, scrotum, inguinal region andperineum Burning pain in hands and feet occur, but disease presents with other system complications like HTN, Renal disease, cardiac disease and stroke, dialted cardiomyopathy Mutation in a-galactosidase gene, acumulation of ceramide trihexoside in nerves and blood vessels

87. Refsum’s Disease Infancy to early childhood with tetrad of: Peripheral Neuropathy Retinitis Pigmentosa Cerebellar ataxia Elevated CSF protein levels Progressive distal sensory loss and weakness, leading to foot drop in their 20s

88. Tangier Disease Autosomal recessive disorder with reduced amount of HDL cholestrol Asymmetric multiple mononeuropathies Slowly progressive symmetric polyneuropathy predominantly in legs Pseudo-syringomyelia pattern with dissociated sensory loss

89. Inflammatory Bowel Disease UC & Crohn may be complicated by GBS, CIDP, generalised axonal sensory or sensorimotor polyneuropathy, small fibre neuropathy or mononeuropathy

90. Neuropathies Associated With Malignancy Acute   neuropathy  is reported in 20–60% of  children  with acute lymphoblastic leukaemia and up to 85% of  children  with lymphoma and nonCNS solid  tumours Mechanism of neuropathy Direct effect of cancer by invasion or compression of the nerves Remote or paraneoplastic effect Toxic effect of treatment Consequence of immune compromise by immunosuppressive medications

91. Other malignancies Lymphoma Neuroblastoma As a complication of bone marrow transplantation Even as a complication of chemotherapy

92. Multiple Myeloma Polyneuropathy occurs in 5% of the patients of MM who exhibit either lytic or diffuse osteroporotic bone lesions Sensorimotor, mild and slowly progressive and do not reverse with supression of myeloma Rare in children

93. Specific Characteristics of osterosclerotic MM Demyelinating in nature and resembles CIDP Respond to radiation therapy or removal of primary lesion Assocciated with lambda light chain. Lytic lesions are associated with kappa light chain Refractory to typical treatment of CIDP Associated with other systemic findings: Organomegaly Endocrinopathy Skin Changes These features with polyneuropathy and Monoclonal Gammopathy forms POEMS Syndrome

94. Metachromatic Leukodystrophy (MLD) MLD is a rare autosomal recessive lysosomal storage disease that causes progressive demyelination of CNS and PNS Disease diagnosed in childhood Result of consangious marriage Arylsulfatase A deficiency Children in 1 to 2 years of age presents with progresive weakness, hypotonia and diminished reflexes

95. Krabbe disease Globoid cell leukodystrophy which is a fatal degenerative disorder that affects the myelin sheath of nervous system

96. Adrenoleukodystrophy Disorder of peroxisomal fatty acid beta oxidation which results in accumulation of very long chain fatty acids in tissues throughout the body Affects myelin in CNS, adrenal cortex and Leydig cells of testis

97. Friedreich’s Ataxia Autosomal recessive ataxia resulting from mutation in gene locus 9 (leading to GAA triplet repeats; reduced frataxin) Causes progressive damage to the nervous system. Clinical Features: Muscle weakness in arms and legs Loss of coordination Vision and hearing defects Slurred speech Diabetes & heart disorders High-arched palate

98. Pathology Scle r osi s and de g ene r a ti on o f d o r sa l r oot ganglion, spinocerebellar tracks, lateral corticospinal tracks and posterior column Loss of myelin in large myelinated fibres

99. MITOCHONDRIAL Related to point mutations of mitochondrial DNA Particularly in 3 genes: polymerase gamma 1 ( POLG1 ), mitofusin 2 ( MFN2 ), and ganglioside -induced differentiation-associated protein 1 ( GDAP1 ) Most patients have sensory-motor neuropathy, sometimes associated with ophthalmoplegia , ataxia, seizures, parkinsonism, myopathy , or visceral disorders Eg.Leigh disease,NARP (neuropathy, ataxia and retinitis pigmentosa )

100. ESSENTIALS OF ASSESSMENT History Obtaining history of distribution and onset of symptoms associated medical conditions, family history helps guide making the diagnosis

101. Physical examination PNASD generally presents as a distal symmetric sensory neuropathy. Depending on etiology, symptoms may be indicative of dysfunction of small fibers (pain, temperature, light touch), large fibers (vibration, proprioception , light touch), or both. Motor involvement occurs in late disease leading to atrophy and weakness of intrinsic foot and hand muscles.

102. Laboratory studies Blood glucose, glucose tolerance test and glycosylated hemoglobin levels, vitamin B-12, folate , vitamin E, cryoglobulins , hepatitis profile, and antibodies to antinuclear antigen (ANA), extractable nuclear antigen (ENA), and sulfatide Creatinine Thyroid function tests Liver function tests Serum protein electrophoresis or serum immunofixation , anti-MAG antibodies

103. Suggested studies for disorders of carbohydrate metabolism (when metabolic myopathy is being ruled out) Ischemic forearm exercise test Serum lactate, ammonia, and pyruvate Urine myoglobin Muscle histochemistry Enzyme assays of muscle, blood, and fibroblast Leukocyte glycogen levels to detect acid maltase deficiency Leukocyte, DNA analyses ( McArdle disease)

104. Suggested investigations for mitochondrial disorders Resting lactate and pyruvate level Muscle histochemistry and electron microscopy Serum mitochondrial DNA deletion and mutation Enzyme assays of muscle, platelets, liver, and fibroblasts Muscle cytochrome oxidase analysis

105. Other suggested studies Biotinidase levels Aminolevulinic acid synthase in urine ( porphyria ) Arylsulfatase A and B ( leukodystrophies ) Hexosaminidases Urine oxalate levels to rule out primary hyperoxaluria , which in patients who are undergoing hemodialysis may present with peripheral neuropathy (direct deposition of oxalate crystals on Schwann cells)

106. Imaging Studies Magnetic resonance neuronography and ultrasound - demonstrate extrinsic compressive lesions, focal neural lesions such as neural edema and swelling, focal neural scarring (posttraumatic neuroma in continuity) and intraneural ganglia. Ultrasound -intrinsic lesions in small peripheral nerves because of the superior spatial resolution of ultrasound in assessing superficial structures. Plain radiography (and sometimes computed tomography scanning) -bone changes and should be the initial imaging modality

107. Acute or subacute denervation -increased signal in skeletal muscle on short tau inversion-recovery and fat-suppressed T2-weighted images. Chronic denervation produces fatty atrophy of skeletal muscles, resulting in increased muscle signal on T1-weighted images.   Phosphorus magnetic resonance spectroscopy of muscle -carbohydrate metabolism ( McArdle disease, phosphofructokinase deficiency) and mitochondrial disorders. MRI of the brain - leukodystrophies .

108. Magnetic Resonance Neurography (MRN) provides a direct and non-invasive look at peripheral nerve injuries. Direct imaging of nerves in the body by optimizing selectivity for unique MRI water properties of nerves. Yields a detailed image of a nerve from the resonance signal that arises from in the nerve itself rather than from surrounding tissues or from fat in the nerve lining. Because of the intraneural source of the image signal, the image provides a medically useful set of information about the internal state of the nerve such as the presence of irritation, nerve swelling edema, compression, pinch or injury.   Kollmer J, Bendszus M, Pham M. MR neurography : diagnostic imaging in the PNS.  Clin Neuroradiol . 2015; 25(2):283-289.

109. There are limited studies on the use of MRN to detect PNASDs, Studies in patients with transthyretin familial amyloid polyneuropathy , Able to detect early nerve lesions in asymptomatic TTR gene carriers. Kollmer J, Bendszus M, Pham M. MR neurography : diagnostic imaging in the PNS.  Clin Neuroradiol . 2015; 25(2):283-289.

110. Nerve conduction studies (NCS) and electromyography (EMG) - severity of any neuropathy NCS abnormalities in axonal sensory or sensory motor polyneuropathies -action potentials and compound motor action potentials, distal and F-wave latencies, conduction velocities, and conduction block. EMG abnormalities are more common in axonal neuropathies -(fibrillations and positive sharp waves and reduced recruitment patterns) and reinnervation (large-amplitude, broad-duration polyphasic motor unit potentials).

111. Quantitative sensory testing (QST): -small nerve fibers. ,technique to assess perceptual thresholds to pain, temperature, or vibration. Quantitative sudomotor axonal reflex testing (Q-SART ) - autonomic involvement and prognosis. Measurement of nerve excitability by threshold tracking -activity of a variety of ion channels, energy-dependent pumps, and ion exchange processes activated during the process of impulse conduction. .  

112. Sural nerve biopsy in diabetic neuropathy may reveal a histologic pattern suggestive of nerve ischemia (selective fascicular involvement, diffuse loss of myelinated fibers). Sural nerve biopsy - vasculitic , demyelinating , hereditary, or infectious origin for the neuropathy. Muscle biopsy should be done with nerve biopsy to increase the diagnostic yield for vasculitic and amyloid neuropathies.

113. Punch skin biopsy and immunohistochemical staining Peripheral nerve axons Advances in immunohistochemical techniques, specifically the development of antibodies to human protein gene product 9.5 Fiber density -excellent correlation between reductions in intradermal nerve fiber density and severity of symptoms in a wide range of neuropathies.

114. Histologic Findings Loss of myelinated fibers, epineurial periarteriolar lymphocytic infiltrates, and selective involvement of fascicles can be observed in diabetic radiculoplexopathy or other vasculitic neuropathies. Amyloid birefringent deposits (under polarized light) within the endoneurium are revealed in amyloid neuropathy.

115. TREATMENT

116. COORDINATION OF CARE NEUROLOGIST, ENDOCRINOLOGISTS, RHEUMATOLOGISTS, GASTROENTEROLOGISTS, PHYSICAL THERAPIST, DIETICIAN, PODIATRIST, ORTHOTIST

117. Only symptomatic treatments exist for pain and other conditions such as gastroparesis . Insulin pump Aldose reductase inhibitors Neurotrophic factors Gangliosides Linoleic acid Advanced glycosylation end products (AGE) Human intravenous immunoglobulin

118. Gastroparesis : Metoclopramide,cisapride , Jejunostomy Enteropathy : Ampicillin or Tetracycline,metronidazole , Anticholinergics,gluten -free Diet Cystopathy : Manual Downward Pressure,Bethanecho l

119. Treatment of painful neuropathy Tricyclic antidepressants( amitryptylline,nortryp ) Selective antidepressent ( paroxetine,duloxetine ) Lidocaine Mexiletine Phenytoin Carbamazepine

120. Gabapentin Lamotrigine N  -methyl-D- aspartate (NMDA) antagonists( aspartate,ketamine ) Opioids Levodopa (inhibit noxious stimulus spinal cord) Capsaicin(depletes subs p) Miscellaneous: ( coenzyme Q10, menadione , vitamin E, ascorbic acid,  N  - acetylcysteine , riboflavin, succinate , L- carnitine , and dichloroacetate )

121. Surgical Care Surgical release of entrapment neuropathy (CTS, ulnar neuropathy at the elbow, TTS) Specialized surgical care of diabetic foot and foot ulcers, including vascular and plastic surgery evaluation Jejunostomy for severe gastroparesis

122. Pancreatic islet transplants have been reported to improve diabetic neuropathy and pancreas-kidney transplantation in patients with diabetes and renal failure Liver transplantation (may improve familial amyloid neuropathy) Renal transplantation (may improve uremic neuropathy)

123. Two randomized clinical trials showed rituximab was superior to placebo and conventional treatments including steroids, plasmapheresis and cyclophosphamide in treating hepatitis C neuropathy.  However, a 2014 Cochrane Review found there was insufficient evidence to guide HCV neuropathy treatment decisions with the use of rituximab , antiviral treatment or interferon alfa . Ferro JM, Viana P, Santos P. Management of neurologic manifestations in patients with liver disease.  Curr Treat Options Neurol . 2016; 18: 37.

124. In familial amyloid PN with transthyretin mutation, liver transplantation has shown to benefit. Jonsen et al showed 10 of 12 patients reported an improved quality of life following transplant. Adams et al showed that motor nerve involvement stabilized in 7 of 11 patients with mild sensory motor neuropathy and in 2 of 8 with severe sensory motor neuropathy. Tafamadis (80mg/day) may delay progression of peripheral neuropathy impairments in patients with familial amyloid PN. Coelho T, Maia LF, Martins da Silva A, et al. Tafamidis for transthyretin familial amyloid polyneuropathy .  Neurology.  2012; 79: 785-792.

125. Prednisone, initially at 1 mg/kg/d, is used to treat neurosarcoidosis . In resistant cases, immunosuppressive treatment with methotrexate , cyclosporine, and azathioprine has been used. PN improves with treatment in most cases.  Small fiber neuropathy symptoms may improve with intravenous immune globulin or anti-tumor necrosis factor α. Tavee JO, Karwa K, Ahmed Z, et al. Sarcoidosis -associated small fiber neuropathy in a large cohort: clinical aspects and response to IVIG and anti-TNF alpha treatment.  Respiratory Medicine . 2017; 126: 135-138.

126. In celiac disease, a gluten-free diet must be started whether or not PN is associated with the disease. It is unclear if a gluten-free diet has an effect on PN. In 2006, Hadjivassiliou et al performed a systematic, controlled study of the effect of a gluten-free diet on 35 patients with celiac disease-associated neuropathy, with close serologic monitoring of adherence to the gluten-free diet. They found significant improvement in the treated group compared with the control group after 1 year on the diet. Dyck , Peter J, Thomas PK. Peripheral Neuropathy . Philadelphia (PA): Saund ers; 2005

127. Vitamin and mineral supplementation may have some benefit. The use of immunomodulatory treatments, immunoglobulin infusions, or immunosuppressants for celiac disease-associated neuropathy remains controversial. Dyck , Peter J, Thomas PK. Peripheral Neuropathy . Philadelphia (PA): Saunders; 2005

128. Patient & family education Education on careful skin care of feet is important. Fall prevention strategies (stretching exercise,gait balancing ).

129. Practice Pearls Treatment for neuropathies associated with systemic diseases is usually treatment of the underlying disease. Care should be exercised when treating neuropathic pain in patients with liver disease. Reduced hepatic metabolism results in increased adverse effects. Frequent weight shifting is mandatory for patients in the intensive care unit to prevent decubitus ulcers.

130. References Bradley’s neurology clinical practice,7 th edition Oxford Textbook of Neuromuscular Disorders Neuromuscular disorder Anton & Russel ,2 nd edition Uptodate.com

131. THANK YOU