NEUROMUSNEUROMUSCCULULOO

SKELETALSKELETAL

Dr. Dr. Jumraini Tammasse, Jumraini Tammasse, SpSSpS. .

NEUROPATNEUROPATHYHY

NEUROPATNEUROPATHYHYDefiniDefinitiontion (WHO, 1980) (WHO, 1980) Permanent dysfunction Permanent dysfunction ((more than more than

several hours)several hours) Spinal neurons, cranial neuronsSpinal neurons, cranial neurons MotoriMotoricc, sensori, sensoric,c, or autonomicor autonomic Confirmed by clinical evidence and/or Confirmed by clinical evidence and/or

electroneurographic or morphplogic electroneurographic or morphplogic (P(Pathologic Anatomy) evidenceathologic Anatomy) evidence

ClassificationClassification1.1. Dominant clinical featuresDominant clinical features

MotoMotoricric SensoriSensoricc AutonomicAutonomic CompoundCompound

2.2. Anatomical DistributionAnatomical Distribution Symmetrical distal Symmetrical distal (polineuropat (polineuropathyhy)) Multiplex mMultiplex mononeuropatononeuropathy hy RadiRadicculopaulopathythy LLocalized nocalized neeuropathyuropathy

3. 3. Onset Onset andand course of diseasecourse of disease AAccututee Sub aSub acutecute CChronihronicc RecurrentRecurrent

4. 4. Prominent pathological featuresProminent pathological features AAxxonopatonopathyhy MMyyelinopatelinopathyhy Other featuresOther features

AXONAL AXONAL NEUROPATNEUROPATHYHY Axons are disturbed with secondary Axons are disturbed with secondary

effect to myelin effect to myelin Large axons Large axons attacked first attacked first IsIschaemia causes vasculopathychaemia causes vasculopathy

DEMDEMYYELINAELINATING NEUROPATHYTING NEUROPATHY Attacks Attacks schwann schwann cells of cells of mmyyelin elin sheaths, sheaths,

causes causes demdemyyelinaelinating of peripheral ting of peripheral axonsaxons, , segmental distributionsegmental distribution ( (between between nodes ofnodes of Ranv Ranviier)er)

COMPOUND TYPE COMPOUND TYPE Most neuropathiesMost neuropathies are compound type, are compound type,

wherewhere myelin myelin are attacked more than are attacked more than axons, or axons are atacked more than axons, or axons are atacked more than myelinmyelin

This compound type can be divided asThis compound type can be divided as : : Primary axonal degeneration with secondary Primary axonal degeneration with secondary

segmental demyelination , e.g. uremic segmental demyelination , e.g. uremic polineuropatpolineuropathy.hy.

Primary myelin degeneration followed by Primary myelin degeneration followed by axonal degeneration, e.g. axonal degeneration, e.g. polineuropatpolineuropathy hy caused by caused by ddiphteria infectioniphteria infection..

Commonly, it’s difficult to differentiate the Commonly, it’s difficult to differentiate the process: primary or secondary process: primary or secondary

ETIOLOGETIOLOGYY

I.I. DANG THERAPISTDANG THERAPIST D iabetiD iabeticc A lA lccoholohol N utriN utrittionalional G uillain-Barre syndromeG uillain-Barre syndrome

T raumaT rauma H ereditH ereditaarryy E ntrapmentE ntrapment R enal/radiationR enal/radiation A IDS/amiloidA IDS/amiloid P araprotein/poriaP araprotein/poria I nfeI nfectionction (lepros (leprosyy)) S S yystemistemicc/sar/sarkkoidoid T oT oxxin in

II. II. Based on course of disease, Based on course of disease, distribution, and EMG examinationdistribution, and EMG examination

A.A. AAcutecute, general, general1.1. Axonal, degeneration :Axonal, degeneration :

a.a. Infections : Lyme, HIV, EBV, hepatitis, CMV.Infections : Lyme, HIV, EBV, hepatitis, CMV.

b.b. Miscellaneous : Porphyria, axonal Guillain-Barre Miscellaneous : Porphyria, axonal Guillain-Barre syndrome, ICU neuropathy.syndrome, ICU neuropathy.

22. Demyelin. Demyelinaation : Guillain-Barre syndrome, arsenic, tion : Guillain-Barre syndrome, arsenic, infections, e.g. infections, e.g.

HIV and diphtheria.HIV and diphtheria.

B. Chronic, generalized :B. Chronic, generalized :1.1. Axonal degeneration :Axonal degeneration :

Nutritional : Alcohol, folate, vitamin BNutritional : Alcohol, folate, vitamin B6, B, B1212, or , or E.E.

Toxic : Phenytoin, vineristine, heavy metals, Toxic : Phenytoin, vineristine, heavy metals, acrylamide, etc.acrylamide, etc.

Endocrine : DM, hypothyroidismEndocrine : DM, hypothyroidism InfeInfecctiotionn : HIV, Lyme : HIV, Lyme Genetic : Charcot-Marie-Tooth (CMT) type II, Genetic : Charcot-Marie-Tooth (CMT) type II,

Familial amyloidosis, Friedreich’s ataxia, etc.Familial amyloidosis, Friedreich’s ataxia, etc. Lipid Problems : Fabry’s dLipid Problems : Fabry’s diseaseisease, Tangier , Tangier

ddiseaseisease, Bassen-Kornzweing d, Bassen-Kornzweing diseaseisease Other : Uremia, Vasculitis.Other : Uremia, Vasculitis.

2. Demyelination :2. Demyelination :a.a. Uniform Slowing on EMG : CMT types 1A, 1B, Uniform Slowing on EMG : CMT types 1A, 1B,

and X; myelin dysmetabolisme, e. and X; myelin dysmetabolisme, e. g. g. Metachromatic leukodystrophy, Refsum Metachromatic leukodystrophy, Refsum ddiseaseisease, Krabbe d, Krabbe diseaseisease..

b.b. Nonuniform SlowingNonuniform Slowing Infectious or inflammator : HIV, CIDP, Infectious or inflammator : HIV, CIDP,

multifocal neuropathy with conduction multifocal neuropathy with conduction block.block.

Paraprotein : Lymphoma, myeloma, POEMS Paraprotein : Lymphoma, myeloma, POEMS syndrome (polyneuropathy with syndrome (polyneuropathy with organomegaly, endocrinopathy, m-protein, organomegaly, endocrinopathy, m-protein, and skin changes), Waldenstrom’s and skin changes), Waldenstrom’s macroglobu-linemia, MGUS (monoclonal macroglobu-linemia, MGUS (monoclonal gammopathy of uncertain significance), gammopathy of uncertain significance), cryglobulinemia.cryglobulinemia.

B. Mononeuropathy multiplex B. Mononeuropathy multiplex (multifocal or (multifocal or asymmetric) asymmetric)

1.1. Axonal :Axonal :

a. Vascular : DM, Vasculitis (polyarteritis a. Vascular : DM, Vasculitis (polyarteritis nodosa, Wegener’s, nodosa, Wegener’s, giant cell arteritis, giant cell arteritis, hypersensitivity), connective tissue dz, hypersensitivity), connective tissue dz, subacute bacterial endocarditis.subacute bacterial endocarditis.

b. Infectious or inflammatory : HIV, Lyme, b. Infectious or inflammatory : HIV, Lyme, Leprosy, VZV, Leprosy, VZV, hepatitis A, sarcoid. hepatitis A, sarcoid.

c. Neoplastic : Neurofibromatosis, leukemia, c. Neoplastic : Neurofibromatosis, leukemia, direct local direct local invasion. invasion.

d. Miscellaneous : Genetic, e.g. Inherited d. Miscellaneous : Genetic, e.g. Inherited brachial plexus brachial plexus neuropathy; traumatic, neuropathy; traumatic, e.g. multiple compressionse.g. multiple compressions

2. Demyelinating :2. Demyelinating :a.a. Inflammatory : Guillain-Barre; multifocal Inflammatory : Guillain-Barre; multifocal

motor neuropathy with conduction block.motor neuropathy with conduction block.

b.b. Genetic : Hereditary neuropathy with Genetic : Hereditary neuropathy with liability to pressure palsies (HNPP)liability to pressure palsies (HNPP)

c.c. Multiple compressionsMultiple compressions

Generally, etiologies are divided Generally, etiologies are divided

as: as: 1.1. Metabolic diseaseMetabolic disease

2.2. DefiDeficiency (nutritional)ciency (nutritional)

3.3. AlergAlergyy

4.4. IntoIntoxxiiccaattiionon

5.5. InfeInfectctiionon

6.6. HereditHereditaarryy

7.7. IsIschaechaemimiaa

8.8. CCompresompressionsion

CLINICAL FEATURESCLINICAL FEATURES

Clinical features vary, based on: Clinical features vary, based on: etetiiologologyy onset onset and course of diseaseand course of disease pathological featurespathological features lolocationcation/distribu/distributiontion type of neurons which are attacked type of neurons which are attacked

most most

TTHHERAPERAPYY

TThheraperapyy based on etiologybased on etiology

((discussed in each type of discussed in each type of neuropathy)neuropathy)

TTHANK HANK YOUYOU

DIABETDIABETIIC NEUROPATHYC NEUROPATHY CLASSIFICATIONCLASSIFICATION (Green, AM.J.Med, (Green, AM.J.Med,

1999)1999)A.A. Diffuse neuropathyDiffuse neuropathy

1.1. Distal symmetric sensorimotor polyneuropathy.Distal symmetric sensorimotor polyneuropathy.2.2. Autonomic neuropathyAutonomic neuropathy

a. Sudomotor na. Sudomotor neeuropathyuropathyb. Cardiovascular autonomic neuropathyb. Cardiovascular autonomic neuropathyc. Gastrointestinal neuropathyc. Gastrointestinal neuropathyd. Genitourinary neuropathyd. Genitourinary neuropathy

3. Symmetric proximal lower limb motor 3. Symmetric proximal lower limb motor neuropathy neuropathy (amyotrophy). (amyotrophy).

B.B. Focal neuropthyFocal neuropthy

1. Cranial neuropathy1. Cranial neuropathy

2. Radiculopathy / plexopathy2. Radiculopathy / plexopathy

3. Entrapment neuropathy3. Entrapment neuropathy

4. Asymmetric lower limb motor 4. Asymmetric lower limb motor neuropathy neuropathy (amyotrophy). (amyotrophy).

I. DIFFUSE NEUROPATHYI. DIFFUSE NEUROPATHY a. a. DISTAL SYMMETRICDISTAL SYMMETRIC SENSORIMOTORSENSORIMOTOR POLINEUROPATHYPOLINEUROPATHY

- Most common type of diabetic - Most common type of diabetic neuropathyneuropathy- - ParestParesthhesiaesia/h/hipestipesthhesia, esia, numbnessnumbness- - PainPain- Initially in the distal part of distal extremity - Initially in the distal part of distal extremity (fingers) (fingers) upward upward- Stocking and glove pattern of sensory - Stocking and glove pattern of sensory disturbancedisturbance

Large neural fibers:Large neural fibers:- Disturbance of sensation of Disturbance of sensation of

vibration, joint potitionvibration, joint potition- Negative physiological reflexesNegative physiological reflexes- Ataxia Ataxia DIABETIC TABES DIABETIC TABES

Motoric DisturbanceMotoric Disturbance

- Motoric dysfunction - Motoric dysfunction atrophy atrophy

Neuropathic Pain :Neuropathic Pain :

Patients with uncontrolled blood Patients with uncontrolled blood glucose level):glucose level):- Burning pain, pricky, electric Burning pain, pricky, electric

sharp pain sharp pain - Allodynia, hyperalgesia, Allodynia, hyperalgesia,

hyperpatia (stimulus evoked pain).hyperpatia (stimulus evoked pain).- Onset: immediately or slow.Onset: immediately or slow.

Trias of PolineuropathyTrias of Polineuropathy

Stocking and glove pattern of Stocking and glove pattern of sensory disturbancesensory disturbance

Paresthesia, especially on the distal Paresthesia, especially on the distal part of extremities part of extremities

Hyporeflex. Hyporeflex.

b. AUTONOMIC NEUROPATHYb. AUTONOMIC NEUROPATHY Can exist itself or with symmetric Can exist itself or with symmetric

polineuropathypolineuropathy

Sudomotor Dysfunction of Bone and Sudomotor Dysfunction of Bone and JointJoint Hyperhydrosis in the half upper part of bodyHyperhydrosis in the half upper part of body Anhydrosis in the half lower part of body Anhydrosis in the half lower part of body

dry skin and easy to develop fissuredry skin and easy to develop fissure Sweating in the night Sweating in the night Joint, especially genu/foot Joint, especially genu/foot swelling but swelling but

not painful (not painful (charcot’s jointcharcot’s joint)) Bone hyperostosis Bone hyperostosis

CardiovascularCardiovascular Postural hypotensionPostural hypotension

Change of heart rate response in Change of heart rate response in

valsava manuevrevalsava manuevre

Digestion System Digestion System Decreased gustatory Decreased gustatory Weak instestine peristaltic: Weak instestine peristaltic:

dysphasia, vomiting, epigastric dysphasia, vomiting, epigastric burn, delayed gaster emptying burn, delayed gaster emptying (gastroparesis)(gastroparesis)

Intermittent diarrheaIntermittent diarrhea

Urogenital System:Urogenital System:Impotent:Impotent: Common (35 – 75%)Common (35 – 75%) Increase with aging process, Increase with aging process,

vascular complication (retinopatthy vascular complication (retinopatthy and diabetic neuropathy) and diabetic neuropathy) (neurogenic, vascular and (neurogenic, vascular and psychogenic factors)psychogenic factors)

Urogenital System:Urogenital System:Cystopathy :Cystopathy : Develop in advanced stageDevelop in advanced stage Paient couldn’t feel that his baldder Paient couldn’t feel that his baldder

was full (atonic bladder)was full (atonic bladder) Residual urine after mictie Residual urine after mictie risk risk

factor / can be recurrent. factor / can be recurrent.

c. SYMMETRIC PROXIMAL c. SYMMETRIC PROXIMAL LOWER LOWER MOTOR NEUROPATHY MOTOR NEUROPATHY Also called as femoral diabetic amiotrophy or Also called as femoral diabetic amiotrophy or

flexopitflexopit Specifically attacks man with DM type 2, Specifically attacks man with DM type 2,

decade 5 – 6decade 5 – 6 Associated with significant weight loss and bad Associated with significant weight loss and bad

blood glucose control blood glucose control Initially, sharp pain in upper extremities, Initially, sharp pain in upper extremities,

symmetric or asymmetricsymmetric or asymmetric Muscular atrophy Muscular atrophy Recover gradually if blood glucose was well Recover gradually if blood glucose was well

controlledcontrolled

II. FOCAL NEUROPATHY II. FOCAL NEUROPATHY

a.a. Cranial Nerves Neuropathy Cranial Nerves Neuropathy - Most common n.oculomotorius- Most common n.oculomotorius- Also can attack n.trokhlearis and - Also can attack n.trokhlearis and abducensabducens- Acute onset (frontal or periorbital - Acute onset (frontal or periorbital pain) pain) ptosis, diplopia.ptosis, diplopia.- Cause: nerve venous occlusion- Cause: nerve venous occlusion- Well controlled blood glucose- Well controlled blood glucose recover recover in 3 in 3 months months

b. Radiculopathy b. Radiculopathy

- Seldom- Seldom

- thoracoabdominal radicular pain - thoracoabdominal radicular pain

- commonly in elderly- commonly in elderly

- can attack motoric - can attack motoric abdominal abdominal herniation herniation

c. Entrapment Neuropathyc. Entrapment Neuropathy

- Carpal Tunnel Syndrome (n. - Carpal Tunnel Syndrome (n. medianus)medianus)

- Tarsal Tunnel Syndrome (n.tibialis - Tarsal Tunnel Syndrome (n.tibialis post)post)

- Elbow Tunnel Syndrome (n. - Elbow Tunnel Syndrome (n. ulnaris)ulnaris)

EtiopathogenesisEtiopathogenesis

Not yet clearNot yet clear Every components of neuron can be Every components of neuron can be

disturbed disturbed Pathology examination : any Pathology examination : any

disturbance of neuron, axon, or disturbance of neuron, axon, or myelinmyelin

Several theories:Several theories:

1. Metabolic Theory/ 1. Metabolic Theory/ hyperglicemiahyperglicemia

ComplicatedComplicated Hypergcemia Hypergcemia metabolism of metabolism of

poliol, formation of advanced poliol, formation of advanced glycation end product (AGE), glycation end product (AGE), oxidative stress, deficiency of oxidative stress, deficiency of essential amino acid such as gamma essential amino acid such as gamma linolenic acid (GLA).linolenic acid (GLA).

2. Vascular Theory2. Vascular Theory Decrease of blood flow in endo and Decrease of blood flow in endo and

epineuralepineural Increase of vascular resistanceIncrease of vascular resistance Decrease of PO2Decrease of PO2 Change in membran permeabilityChange in membran permeability

Thickening of vascular endotel basal Thickening of vascular endotel basal membran vascular, endo and epineural.membran vascular, endo and epineural. ischaemia of neural tissueischaemia of neural tissue a lot of a lot of reactive oxygen (anaerob metabolism)reactive oxygen (anaerob metabolism)

Others: hyperviscosity, atherosclerosis, Others: hyperviscosity, atherosclerosis, formation intraluminal fibrin.formation intraluminal fibrin. hypoxia and thrombocyte aggregationhypoxia and thrombocyte aggregation

3. Immunologic 3. Immunologic MechanismMechanism

Antibody of anti-Gm1-Antibody of anti-Gm1-gangliotide and anti fosfolipid gangliotide and anti fosfolipid antibody (anti-PLA)antibody (anti-PLA)

incerase the tendency of incerase the tendency of vascular thrombosis formingvascular thrombosis forming

4. Neurotrophyn Deficiency4. Neurotrophyn Deficiency

Nerve growth factor (NGF) : has role in Nerve growth factor (NGF) : has role in sustaining and regenerating ganglion, sustaining and regenerating ganglion, dorsal root, and symphatetic neuron, dorsal root, and symphatetic neuron, decrease of AGF.decrease of AGF.

NT3 : has role in conduction of large NT3 : has role in conduction of large fibers, motorneuron and sympathetic fibers, motorneuron and sympathetic fibers, decerase of AGF.fibers, decerase of AGF.

Insulin Growth Factor (IGF) : IGF and its Insulin Growth Factor (IGF) : IGF and its receptors found in in whole central dan receptors found in in whole central dan peripheral neuronal system. Role peripheral neuronal system. Role not not clear yet. clear yet.

Diagnosis Diagnosis

1. Diagnosis of DM1. Diagnosis of DM

Clinical features : poliuria, Clinical features : poliuria, polidipsya, poliphagia, decrease of polidipsya, poliphagia, decrease of body weight with unclear causebody weight with unclear cause

Result of laboratory examination: Result of laboratory examination:

- venous fasting blood glucose > 126 - venous fasting blood glucose > 126 mg/dlmg/dl

- random blood glucose > 200 mg/dl- random blood glucose > 200 mg/dl

2. Neuropathy2. Neuropathy- There were clinical signs of neuropathy- There were clinical signs of neuropathy- Abnormality of nerve conduction- Abnormality of nerve conduction- Abnormality in kwantitative sensory - Abnormality in kwantitative sensory test and test and sensory autonomic sensory autonomic function: dysfunction of function: dysfunction of

hot-cold sensation, vibration, hot-cold sensation, vibration, positional, positional,

glove-and-stocking type sensory glove-and-stocking type sensory deficitdeficit- Can be abnormal in motoric - Can be abnormal in motoric examination and examination and decrease of achilles decrease of achilles reflexreflex

3. Autonomic 3. Autonomic ExaminationExamination

Dry skin of the foot, there is fissure Dry skin of the foot, there is fissure (sudimotor dysfunction) (sudimotor dysfunction)

Charcot jointCharcot joint Heart rate response to valsavaHeart rate response to valsava Orthestatic hypotensionOrthestatic hypotension EKG: prolonged QR intervalEKG: prolonged QR interval

4. EMG4. EMG Nerve Conduction Velocity (NCV)Nerve Conduction Velocity (NCV) AmplitudoAmplitudo Motoric and Sensoric Distal Latency Motoric and Sensoric Distal Latency Demyelinating :Demyelinating :

Decreased NCVKHS menurunDecreased NCVKHS menurun Prolonged Motoric Distal Latency (MDL)Prolonged Motoric Distal Latency (MDL) Temporal Depression Temporal Depression

Axonal DegenerationAxonal Degeneration Decreased amplitudoDecreased amplitudo NCV and MLD normal or decrease slightlyNCV and MLD normal or decrease slightly Potential denervation / fibrilation and Potential denervation / fibrilation and

positive to wavespositive to waves

4. Skin Biopsy4. Skin Biopsy

Management :Management :

Management approach based on Management approach based on pathogenesis :pathogenesis :

1. Aldose Reductase Inhibitor (ARI)1. Aldose Reductase Inhibitor (ARI)

- Inhibit the mechanism of ARI - Inhibit the mechanism of ARI enzymeenzyme * Sorbitol and fructose not storaged * Sorbitol and fructose not storaged

* mencegah penurunan potensial * mencegah penurunan potensial redoksi redoksi

2. Asam linoleik2. Asam linoleik

3. Aminoguaidin3. Aminoguaidin

Penghambat produk akhir AGEPenghambat produk akhir AGE

4. Pemberian diet tinggi miyo-inositol4. Pemberian diet tinggi miyo-inositol

5. Human Intravenous Imunoglobulin5. Human Intravenous Imunoglobulin

Recombinan human NGFRecombinan human NGF

Pemberian methylcobalamin 2 kali Pemberian methylcobalamin 2 kali seminggu selama 12 minggu.seminggu selama 12 minggu.

Nyeri neuropatik diberi antidepresan Nyeri neuropatik diberi antidepresan trisiklik dan anti epilepsitrisiklik dan anti epilepsi

Gastroparesis makan dan minum sedikit-Gastroparesis makan dan minum sedikit-sedikit dan frekuen, metoclopramide 3 sedikit dan frekuen, metoclopramide 3 kali 10 mg.kali 10 mg.

Hipotonik kandung kemih diberi Hipotonik kandung kemih diberi bethanecol 3 kali 10-30 mg atau bethanecol 3 kali 10-30 mg atau kateterisasi intermiten.kateterisasi intermiten.

Inpotensi dgn sildenetil peroral 25-100 Inpotensi dgn sildenetil peroral 25-100 mgmg

Hipotensi ortostatik diberi fludrocortison Hipotensi ortostatik diberi fludrocortison

Rehabilitasi medik / fisioterapi Rehabilitasi medik / fisioterapi

akupuntur, modulasi termal, trans akupuntur, modulasi termal, trans cutaneus electris nerve stimulation cutaneus electris nerve stimulation (TENS) mengaktivasi proses (TENS) mengaktivasi proses nosiseptif endogen (endorfis) nosiseptif endogen (endorfis) berefek menghilangkan rasa sakit.berefek menghilangkan rasa sakit.