Peripheral neuropathy

Reference-Harrison text book of internal medicine -20th edition

Slides by-Dr Jayasoorya P G,Junior resident,Department of General Medicine,Azeezia medical college,Kollam,Kerala

1. Peripheral Neuropathy Dr J ayasoorya P G Junior resident Department of General M edicine Azeezia medical college,kollam

2. Peripheral nerves are composed of sensory,motor and autonomic elements Disease can affect the cell body of neuron or its peripheral process (axon or the encancing mylin sheath) Most peripheral nerves are mixed Nerves can be 3 major groups 1)large myelinated 2)small myelinated 3)small unmyelinated Motor axons are –large myelinated fibers-conduct rapidly (50m/s)

3. Large diameter sensory fiber-conduct proprioception,vibratory sensation Small diameter myelinated and unmyelinated fibers-transmit pain and temperature Autonomic nerves are small in diameter PN can impair sensory,motor or autonomic function –either singly or in combination

4. Other classification Primarily affect cell body- neuronopathy,ganglionopathy Primarily affect myelin – myelinopathy Primarily affect axon- axonopathy

5. General approach Identify where the lesion Identify the cause Determine proper treatment

6. 7 KEY QUESTIONS ?

7. 1)WHAT SYSTEM ARE INVOLVED? To determine symptoms and signs are motor,sensory,autonomic,or mixed Only weaknes (without sensory and autonomic)- eg -motor neuropathy,NMJ abnormality,myopathy Some cases significant autonomic nervous system dysfunction Symptoms of autonomic involvement -fainting spells,orthostatic hypotension, light headedness,heat intolerance,bowel,bladder or sexual dysfunction Autonomic dysfunction in the absence of DM –possibility of amyloid polyneuropathy

8. 2)What is distribution of weakness? 1)weakness only distal/both proximal and distal? 2)is it focal and asymmetrical or symmetric ? Symmetric proximal and distal weakness-f/o acquired immune demyelinating polyneuropathy (both a/c form-GBS and c/c form-CIDP) ALS( amyotropic lateral sclerosis )-Prominent motor weakness-focal symmetrical weakness ALS- can produce neck extensor weakness(head drop),tongue and pharyngeal weakness ( dysarthria,dysphagia ),shortness of breath

9. 3)What is the nature of sensory involvement? Patient may have loss of sensation (numbness),altered sensation to touch ( hyperpathia or allodynia ) or un-comfortable spontaneous sensation (tingling ,burning or aching) Neuropathic pain can be- 1) burning,dull and poorly localized ( protopathic pain)-transmitted by polymodal C nociceptor fibers 2) sharp,lancinating ( epicritic pain)-by A delta fibers Pain, Temp-LOST, vibration,position sense-preserved , nl muscle strength,nl DTR,nl ncv -mostly small fibre neuronopathy -secondary to DM/glucose intolerence

10. Proprioceptive loss (imbalance in dark),loss of proprioception and vibration,normal strength-sensory neuronopathy / ganglionopathy If this loss asymmetric or affect arm more than leg-non length dependent process-seen in neuronopathy

11. 4)Is there evidence of UMN involvement? Patient has symmetric distal sensory symptoms+signs of a distal sensory neuropathy+evidence of symmetric UMN involvement=so consider combined system degeneration with neuropathy Causes- V it B12 deficiency (m c) other-Cu deficiency,HIV infection,severe hepatic disease,adrenomyeloneuropathy (AMN),hereditary spastic paraplegia+neuropathy

12. 5)What is temporal evolution ? Determine onset,duration,evolution of symptoms and signs Acute-days to 4 week Sub a/c-4-8 week c/c->8 wk Course- monophasic,progressive or relapsing Most neuropathies-insidious and slowly progressive Neuropathy with a/c and sub a/c presentation- GBS,vasculitis,radiculopathies related to DM or lymes disease Relapsing course- CIDP,Porphyria

13. 6)Is there any evidence of hereditary neuronopathy ? Slowly progressive distal weakness over many years with few sensory symptoms(significant sensory loss on examination)- hereditary neuronopathy Eg -Charcot-Marie-Tooth disease (CMT) Feet---High or flat arches,hammer toe,scoliosis Suspected cases-neurological and electrophysiology of family members also done

14. 7)Any other medical condition? Medical condition- SLE,DM Infection- diorheal illness preceding GBS Surgeries-gastric bypass and nutritional neuropathy Medication-toxic neuronopathy Over the counter vitamin use – VIT B6 Alcohol,dietary habit Use of denture-fixative contain Zn and lead to Cu deficiency

15. Pattern recognition approach to neuropathic disorders

16. Electrodiagnostic studies Consist of NCS,Needle EMG Can confirm whether it is mononeuropathy,multiple mononeuropathy ( mononeuropathy multiplexa ), radiculopathy,plexopathy,or generalized polyneuropathy Can identify whether involve sensory fiber,motor fiber,autonomic fiber or combination of these Can differentiate-1) axonopathies from myelinopathies 2)axonal degeneration secondary to ganglionopathies from more common length dependent axonopathies

17. NCS-Nerve Conduction study Classify neuronopathy as due to axonal degeneration or segmental demyelination Axonal neuropathy -low amplitude potential with relatively preserved distal latencies,conduction studies,late potential,fibrillation on needle EMG PRIMARY DEMYELINATING NEUROPATHY -slow conduction velocity,prolonged distal latency,late potentials,relatively preserved amplitudes,absence of fibrillation on needle EMG Non uniform slowing of conduction velocity,conduction block,temporal dispersion-s/o acquired demyelinating neuropathy (GBS,CIDP)

18. Autonomic studies used to acess small myelinated (A-delta) and unmyelinated (C) nerve fiber involvement Such testing include-Heart Rate response to deep breathing, HR,BP response to both valsalva and tilt table testing Sudomotor axon reflex testing These studies are usefull in pure small fiber neuropathy or autonomic neuropathy in which routinue NCS are normal

19. Other lab test CBC,ELECTROLYTE,LFT,RFT,FBS,HBA1C,URE,TFT,B12,FOLATE,ESR,RA FACTOR,ANA,SERUM PROTIEN ELECTROPHORESIS,IMMUNO ELECTROPHORESIS,IMMUNE FIXATION,URINE BJP Immuno fixation-detect monoclonal gammopathy -done if amyloidosis is suspected Skeltal survey-in acquired demyelinating neuropathy-M spike to look for osteosclerotic or lytic lesions Consider Bone marrow biopsy -patient with monoclonal neuropathy Oral glucose tolerance test-done in painfull sensory neuropathy-even if fbs,hba1c are normal

20. Patient with mononeuropathy multiplexa-vasculitis workup- ANCA,Cryoglobulin,hepatitis serology,western blot for lymes disease,HIV,cytomegalo virus titer Autoantibody panel test Heavy metal screen Severe painfull sensory motor and autonomic neuropathy and alopecia-thallium Severe painfull sensorymotor neuropathy with or without GI disturbance and Mees line- arsenic Wrist or finger extensor weakness,anemia,basophilic stippling- Lead

21. In suspected GBS,CIDP LP done-look for elevated protein Idiopathic GBS,CIDP- pleocytosis are absent in CSF If cells present- HIV,Lymes disese,sarcoidosis,lymphomatous or leuckemic infiltration of nerve roots Some GBS,CIDP –has elevated LFT In elevated LFT –also look for H ep B,Hep C ,HIV,CMV,EBV In patient with axonal GBS or patient with suspicious coinciding history(unexplained abdominal illness,psy illness,significant autonomic dysfunction)-screen for Porphyria

22. Patient with Severe S ensory A taxia Sensory neuronopathy or ganglionopathy should be considered Mcc of sensory G anglionopathy- sjogrens syndrome,paraneoplastic neuropathy So look for dry eye,dry mouth,sicca symptoms So patient with sensory ataxia should test for –antibody to SS-A/R0,SS-B/ La,ANA IN PARANEOPLASTIC SENSORY GANGLINOPATHY- ANTI NEURONAL NUCLEAR ANTIBODY (anti-Hu antibody) These patients are seen in small cell ca of lung (mc), ca breast,ovary,lymphoma

23. Nerve biopsy Rarely performed in evaluation of neuropathy Primary indication-Amyloid neuropathy or vasculitis Biopsy done when NCS are abnormal Sural nerve mc biopsied-it’s a pure sensory nerve In suspected vasculitis -combination biosy of superficial peroneal nerve (pure sensory)+ underlyng Peroneus brevis muscle –increases diagnostic yield

24. Skin biopsy Used to diagnose small fiber neuronopathy Punch biopsy of skin in distal lower extremity-immunological staining

25. SPECIFIC DISORDERS HEREDITORY NEUROPATHY

26. HEREDITORY NEUROPATHY MC type – CMT(Charcot Marie Tooth disease) CMT are classified according to NCV,predominant pathology,inheritance pattern,specific mutated genes

27. CMT 1 Most Common hereditary neuropathy Present with distal leg weakness( foot drop ),patient may remain asymptomatic even late in life o/e Asymptomatic,reduced sensation to all modalities,muscle stretch reflex are reduced,atrophy of muscle below knee(anterior compartment)-leading to so called inverted champagne bottle legs Biopsy are usually not done,if done- onion bulbs present CMT1A is most common sub type-70% cases CMT1B-20%-mutation in myelin protein zero (MPZ)

28. CMT-2 Appear later in life Symptomatic-second decade Difficult to distinguish from CMT 1-NCS helps in this Velocities are normal or slightly slowed here Cause-mutation of M itofusin 2 (MFN2) MFN2-located on outer mitochondrial membrane-where it regulate mitochondrial fusion

29. CMT-DI-dominant intermediate CMT NCV are faster than usually seen in CMT1 (>38 m/s),but slower than in CMT2

30. CMT3 Hereditory demyelinating sensory motor polyneuropathy presenting in infancy or early child hood Affected childrens are severely weak NCV- markedly slowed (< 5-10) Cause by point mutation in PMP -22,MPZ ,ERG 2

31. CMT4 Rare Severe childhood onset sensory motor polyneuropathy Autosomal Recessive NCV-demyelinating or axonal features

32. CMT1X X linked dominant c/f similar to CMT1,CMT2 Exception --- m>f Atrophy and weakness of distal arms and legs,areflexia,pes cavus,hammer toes NCV-f/o both demyelination and axonal degeneration Mutation in connexin 32 genes Connexin -gap junction structural protein –important in cell to cell communication

33. Other hereditary neuropathy Fabriys disease Adrenoleukodystrophy Tangiers disease Porphyria Refsum disease Familial amyloid polyneuropathy

34. FABRYS DISEASE Aka angiokeratoma corporis diffusum Xlinked dominant,M >F Mutation in Alpha G alactosidase gene,accumulation of Ceramide trihexocide in nerves and vessels Glycolipid granules may be appreciated in ganglion cells of peripheral and sympathetic nerves system and in perineurial cells Angiokeratoma -reddish ,purple maculopapular lesions –found around umbilicus, scrotum, inguinal region, perineum Burning or lancinating pain in the hands and feet often develops in males in late childhood or early adult life

35. Premature atherosclerosis occur-lead to HTN,Renal failure,cad,cva CVS-Dilated cardiomyopathy Rx Enzyme replacement therapy with Alpha G alactosidase B -improve neuropathy ,if patient treated early

36. Adrenoleukodystrophy / A drenomyelo neuropathy X linked dominant Mutation in ABC gene Present with mild to moderate peripheral neuropathy with progressive spastic paraplegia Rare case-adult onset S pinocerebellar A taxia,or only with adrenal insufficiency Edx -Primary A xonopathy with secondary demyelination Nerve biopsy-Loss of myelinated and unmyelinated nerve fiber with lamellar inclusion in cytoplasm of schwann cells Diagnosis confirmed-genetic testing

37. Rx Adrenal insufficiency –by replacement therapy Neurological problem-no proven effective therapy

38. Refsum disease Tetrad of Peripheral neuropathy,Retinitis pigmentosa,Cerebellar atxia and elevated CSF protein concentration Mutation in PAHX gene Serum P hytanic acid levels are elevated Progressive distal sensory loss and weakness in legs leading to foot drop Proximal arm and leg muscle may became weak Also had sensory neural hearing loss, cardiac conduction abnormality, icthyosis,anosmia Rx -removal of P hytanic acid precursor from food

39. Tangiers disease AR disorder Present as asymmetric multiple mononeuropathy,slowly progressive symmetric polyneuropathy predominantly affecting legs,pseudo-syringomyelia pattern with dissociated sensory loss(abnormal- pain,temp preserved-position /vibration in arms) Tonsils swollen,yellowish orange in colour Spleenomegaly,lymphadenopathy present Mutation in ABC1 gene Markedly reduced level of LDL,TAG level increase Nerve biopsy-axonal degeneration with demyelination and remyelination

40. Electron microscopy-Abnormal accumulation of lipid in schwann cells There is no specific treatment

41. Porphyria Perepheral neuropathy is present in a/c intermittent porphyria (AIP),hereditary coproporphyria (HCP),variegate porphyria (VP) AIP-PORPHOBILINOGEN DEAMINASE DEFFICIENCY HCP COPROPORPHYRIN OXIDASE DEFECT VP PROTOPORPHYRINIGEN OXIDASE DEFICIENCY Acute neurological manifestations are similar in each,Except photosensitive rashes seen in HCP and VP but not in AIP Attack of porphyria are precipitated by certain drugs,hormonal changes,dietary restriction

42. Weakness can occur-mimic GBS Weakness of arms and legs and can be asymmetric , proximal or distal in distribution , as well as affecting face and bulbar musculature Dysautonomia and signs of sympathetic over activity are common Edx -marked reduction in compound motor action potential (CMAP)amplitude and signs of active axonal degeneration on needle EMG

43. RX With glucose and hematin reduce accumulation of H eme precursor

44. Acquire neuropathy Primary or AL A myloidosis Diabetic neuropathy Hypothyroidism Sjogrens syndrome RA SLE Systemic sclerosis MTCD S arcoidosis

45. Hyper eosnophilic syndrome Celiac disease Inflammatory bowel disease Uremic neuropathy Chronic liver disease Critical illness poly neuropathy Leprosy ( H ansons disease) Lyme disease Dyphtheric neuropathy HIV,HSV,CMV,EBV,Hepatitis viruses

46. PRIMARY or AL AMYLOIDOSIS ABNORMAL PROTIEN DEPOSITION-IMMUNOGLOBULIN LIGHT CHAIN AL Amyloidosis occur in setting of MM,waldenstrom macroglobinemia , lymphoma,other plasmacytoma or lymphoproliferative disorder 30% patients-polyneuropathy- painfull dysesthesia and burning sensation of feet Trunk can be involved.Some presented with mononeuropathy multiplexa pattern CTS occur in 25% patients

47. Neuropathy is slowly progressive ,and eventually weakness develop along with large fiber sensory loss Most patients have autonomic involvement with postural hypotension, syncope, bowel and bladder incontinence, constipation, impotence, impaired sweating Lambda is more common than kappa (>2:1) CSF protein increased with normal cell count-So neuropathy may mistaken for CIDP NERVE BIOPSY-Axonal degeneration and amyloid deposition Death –congestive heart failure or renal failure

48. Rx Chemotherapy with M elphalan , P rednisone,colchicine -to reduce concentration of monoclonal protein Autologous stem cell transplantation-prolong survival Neuropathy improvement is controversial

49. Diabetic neuropathy Diabetic distal symmetric sensory and sensory motor polyneuropathy (DSPN) Diabetic autonomic neuropathy Diabetic radiculoplexus neuropathy (Diabetic amyotrophy or bruns garland-Syndrome) Diabetic Mononeuropathies or multiple mononeuropathies

50. DM is the most common cause of peripheral neuropathy in developed countries Risk factors for development of neuropathy include long standing ,poorly controlled DM and the presence of retinopathy and nephropathy

51. DSPN MC form of D iabetic neuropathy Manifestation-sensory loss beginning in the toes that gradually progresses over time up the legs and fingers and arms When severe patient may develop sensory loss in the trunk(chest and abdomen) NCV-reduced amplitude, mild to moderate slowing of conduction velocity Nerve biopsy-reveals axonal degeneration, endothelial hyperplasia, occasionally perivascular inflammation Tight glucose –improve Rx- A ntiepileptics , A ntidepressant, sodium channel blocker, analgesics

52. Diabetic Autonomic neuropathy Seen in combination with DSPN Manifest as-abnormal sweating, dysfunctional thermoregulation, dry eyes and dry mouth, pupillary abnormality, cardiac arrhythemia , postural hypotension, GI abnormality( gastroparesis , post prandial bloating, c/c diorhea , constipation),genitourinary dysfunction (impotence, retrograde ejaculation, incontinence) Test-sympathetic skin response test, quantitative sudomotor axon reflex testing

53. Diabetic R adiculoplexus N europathy (Diabetic A myotrophy or B runs G arland S yndrome ) Presenting manifestation of DM in 1/3 of patients Severe pain in low back,hip,and thigh in one leg Rarely diabetic polyradiculoneuropathy begin in both legs at the same time Atrophy and weakness of proximal and distal muscle in the affected leg become apparent within a few days or week Some times associated weight loss present Weakness continue to progress for 18 months or more Slow recovery but many are left with residual weakness, sensory loss and pain Some develop thoracic radiculopathy and some have cervical polyradiculopathy

54. CSF-protein elevated, cells-normal ESR-elevated NCV-active denervation in affected proximal and distal muscle in affected limbs and paraspinal muscle Nerve biopsy-axonal degeneration with perivascular inflammation Rx In severe pain-glucocorticoids

55. Diabetic mononeuropathies or multiple mononeuropathies MC M ononeuropathy -median neuropathy at wrist and ulnar neuropathy and elbow Cranial mononeuropathy - Most common is 7 th nerve palsy(non diabetic cause mainly) Most common in DM-3 rd nerve palsy Others in DM -2 nd -6 th nerve, less frequently 4 th nerve Diabetic 3 rd nerve palsies are characterized by pupil sparing

56. Neuropathy in HIV HIV related distal symmetrical polyneuropathy HIV related inflammatory demyelinating polyradiculoneuropathy HIV realted progressive polyradiculopathy HIV related multiple mononeuropathy HIV related sensory neuropathy/ ganglionopathy

57. Neuropathy associated with malignancy Paraneoplastic sensory neuronopathy / ganglionopathy Neuropathy secondary to tumour infiltration Neuropathy as a complication of marrow transplantation Lymphoma MM Neuropathy associated with MGUS Toxic neuropathy secondary to chemotherapy

58. Other toxic neuropathy Chloroquine,Hydroxy chloroquine Amiodarone Colchicine Thalidomide Pyridoxine toxicity Isoniazid Antiretroviral agents Hexa carbon/glue sniffers neuropathy

59. Lead Mercury Thallium arsenic

60. Nutritional neuropathy Cobalamin (V B12) Thiamine deficiency Vit e deficiency Vit b6 deficiency Pellagra Copper deficiency

61. Neuropathy associated with gastric surgery Polyneuropathy occur following gastric surgery for ulcer,cancer,weight reduction Rx Parenteral vitamin supplementation(thiamine)

62. Mononeuropathies / plexopathies /radiculopathies Median neuronopathy Ulnar neuronopathy at elbow- cubital tunnel syndrome Radial neuropathy Lateral femoral cutaneous neuropathy ( meralgia paresthetica ) Femoral neuropathy Sciatic neuropathy

63. Median neuropathy CTS is a compression of median nerve in the carpal tunnel of wrist Symptoms- numbness,paresthesias variably in thumb,index,middle and half of ring finger CTS is often misdiagnosed as thoracic outlet syndrome Sign of CTS-decreased sensation in median nerve distribution,reproduction of the sensation of tingling When a hammer tape over wrist- Tinels sign When Wrist is flexed for 30-60 s- Phalen sign

64. Treatment Avoid precipitating factors Control of underlying systemic associated conditions Nsaids Neutral position wrist splint Glucocorticoid injection into carpal tunnel Surgical decompression by transverse ligament

65. Ulnar neuropathy at elbow- cubital tunnel syndrome UN pass through the condylar groove between the medial epicondyle and the olecranon Symptoms- paresthesia,tingling,numbness in the medial hand and half of the fourth and entire fifth finger,pain at elbow or forearm and weakness Fromet sign-thumb adductor weaknessconsist of flexion of thumb at IP Joint when attempting to oppose the thumb against lateral boarder of second digit Rx-avoid aggravating factors,surgery

66. Radial neuropathy Radial nerve winds around proximal humerous in the spiral groove and proceeds down the lateral arm and enters the forearm,dividing into posterior interosseous nerve and superficial nerve Wrist drop,finger extension weakness,sensory loss in the dorsal web between thumb and index finger Triceps,brachioradialis power- normal,triceps reflex-intact Most will recover within 6-8 wks Rx-cock up wrist and finger splint

67. Meralgia paresthetica Lateral femoral ciutanious nerve arises from the upper lumbar plexus (spinal nerve L2/L3),crosses through the inguinal ligament near its attachment to iliac bone and supplies sensation to anterior lateral thigh Paresthesia,numbness,occasionally pain the lateral thigh Symptoms are increased by standing or walking and are relieved by sitting Normal power and knee reflex intact Symptoms resolve spontaniously over weeks or months,but patient may be left with permanent numbness Rx-weight loss,avoid tight belt

68. Femoral neuropathy Arises as complication of retroperitoneal hematoma,lithotomy position,hip arthroplastynor dislocation,iliac artery occlusion etc Difficulty in extending their knees and flexing the hip Quadriceps reflex(patellar) diminished

69. Peroneal neuropathy Sciatic nerve divide at the distal femur into tibial and peroneal nerve CPN around fibular head and divide into Superficial PN and Deep PN SPN-supply ankle evertor muscle, sensation over anterolateral distal leg and dorsum of foot DPN-Supply ankle dorsiflexors and toe extensor muscle,small area of sensation dorsally in the area of first and second toes Foot drop(ankle dorsiflexion,toe extension,and ankle eversion weakness),variable sensory loss Rx rapid weight loss,avoid leg crossing

70. Radiculopathy Mostly due to compression from degenerative joint disease and herniated disk

71. Plexopathy Brachial plexus Lumbosacral plexus Recurrent neoplastic disease or radiation induced plexopathy

72. Brachial plexus Has 3 trunk (upper, middle, lower),2 division (anterior and posterior) Trunks divided into 3 cords( medial, lateral and posterior).From these arises the multiple terminal nerves innervating the arms Anterior primary rami of C5,C6 fuse to form upper trunk Anterior primary rami of C7 continue as middle trunk Anterior primary rami of C8 ,T1 fuse to form the lower trunk

73. Brachial plexopathy Immune mediated brachial plexus neuropathy Brachial plexopathy associated with neoplasm Perioperative plexopathy ( median sternotomy )

74. Immune mediated brachial plexus neuropathy Aka acute brachial plexitis , neuralgic amyotrophy , parsonage –turner syndrome Present with acute onset severe pain in the shoulder region Mc pattern-involve upper trunk or a single or multiple mononeuropathies primarily involving the suprascapular , long thoracic,or axillary nerve Edx is help in localize lesion Emperical R x with glucocorticoids

75. Brachial plexopathy associated with neoplasm Primary nerve tumours ( schwanomas,neurinomas,neurofibromas ),local cancers expanding into the plexus( pancoast tumour , lymphoma),metastatic tumours Secondary tumours affecting Brachial Plexopathy are more common and are always malignant Pancoast tumour -compress lower trunk, cause insidious onset of pain in upper arm, sensory disturbance in the medial aspect of forearm and hand,and weakness and atrophy of intrinsic hand muscles along with an ipsilateral horners syndrome Metastatic –spread of breast cancer into axillary LN

76. Perioperative plexopathy (median sternotomy ) Secondary to median sternotomies Eg -open heart surgery,thoracotomies 5% of patients following median sternotomy develop Brachial Plexopathy Sensory defect affect medial aspect of forearm and hand along with weakness of intrinsic hand muscle Recover within few months

77. Lumbosacral plexus Lumbar plexus arise from the ventral primary rami of the first to fourth lumbar spinal nerves These nerves pass downward and laterally from the vertebral coloum within the psoas major muscle Femoral nerve-dorsal branch of L2-L4 lumbar ventral rami Obturator nerve-ventral branch of L2-L4 lumbar ventral rami Lumbar plexus communicate with sacral plexus by lumbosacral trunk Sacral plexus is part of lumbosacral plexus-formed by union of lumbosacral trunk with ventral rami of the S1-S4 sacral nerves

78. Evaluation and treatment of plexopathy MRI,Edx Severe pain may respond to short course of glucocorticoids

79. THANK YOU