Approach to peripheral

neuropathyDr. Anoop.K.R

Dept of General Medicine

Generalized term including disorders of any cause affecting PNS

May involve sensory nerves, motor nerves, or both

May affect one nerve (mononeuropathy), several nerves together (polyneuropathy) or several nerves not contiguous (Mononeuropathy multiplex)

2

Definitions

Further classified into those that primarily affect the cell body (e.g., neuronopathy or ganglionopathy), myelin (myelinopathy), and the axon (axonopathy)

Most common causes

Disease Diabetes1 2

Paraproteinaemia2 3

Alcohol misuse1

Renal failure1

Vitamin B-12 deficiency1

HIV infection1

Chronic idiopathic axonal neuropathy4

Prevalence 11-41% (depending on

duration, type,and control) 9-10% 7% 4% 3.6%

16% (depending on the population studied, usually much lower)

10-40% of different hospital series

BMJ 2010:341:c6100

Loss of function“- symptoms”

Disordered function“+ symptoms”

Sensory “Large Fiber”

↓ Vibration↓ ProprioceptionHyporeflexiaSensory ataxia

Paresthesias

Sensory “Small Fiber”

↓ Pain↓ Temperature

DysesthesiasAllodynia

The clinical response to sensory nerve injury

Loss of function“- symptoms”

Disturbed function“+ symptoms”

Motor nervesLarge fibre

WastingHypotoniaWeaknessHyporeflexiaOrthopedic deformity

Fasciculation Cramps

The clinical response to motor nerve injury

Loss of function“- symptoms”

Disturbed function“+ symptoms”

Autonomic nerves ↓ SweatingHypotensionUrinary retentionImpotenceVascular color changes

↑ Sweating Hypertension

The clinical response to autonomic nerve injury

Axonopathies

By far the majority of the toxic, metabolic and endocrine causes

NCVs: CMAPs ↓ 80% lower limit of normal w/o or min velocity or distal motor latency change.

Legs>> arms. EMG: Signs of denervation (acute, chronic) and

reinnervation

Myelinopathies

Unusual by comparison with axonopathies Clues: hypertrophic nerves on exam

global arreflexiaweakness without wastingmotor >> sensory deficitsNCS can discriminate inherited from

acquired NCS: Distal motor latency prolonged (>125% ULN)

Conduction velocities slowed (<80% LLN)May have conduction blockEMG: Reduced recruitment w/o much denervation

Causes of large fibre/ataxic NP SJOGREN’S SYNDROME VIT B12 NEUROPATHY CISPLATIN PYRIDOXINE NEUROTOXICITY FRIEDEREICH’S ATAXIA

SMALL FIBRE NEUROPATHY

PAIN-burning,shock like,stabbing,prickling,shooting,lancinatingAllodynia

Decreased pinprick sensation

Tight band like pressureInsensitive to heat and cold

Diminished temperature sensation

Causes of small fibre neuropathy(painful NP&dissociated sensory loss)

Heriditary sensory neuropathy Lepromatous leprosy Diabetes mellitus Amyloidosis(early familial&primary) Tangier disease Fabry’s disease-pain predomonates Dysautonomia-riley-day syndrome HIV & antiretroviral therapy neuropathy

SMALL & LARGE FIBRE NEUROPATHY Global sensory loss Carcinomatous sensory neuropathy Hereditary sensory neuropathy Diabetic sensory neuropathy Vacor intoxication Xanthomatous neuropathy of primary biliary

cirrhosis

Motor predominant neuropathy Immune neuropathies Heriditary motor sensory neuropathies Acute intermittent porphyria Diphtheritic neuropathy Lead neuropathy Brachial neuritis Diabetic lumbosacralplexus neuropathy

Autonomic Acute-pandysautonomia -botulism -porphyria -GBS -Amiodarone -vincristine Chronic-amyloid,diabetes,sjogren’s,HSN

1&3,chagas,paraneoplastic

Distribution of neuropathy ?

MONONEUROPATHY

Focal involvement of a single nerve

Weakness & sensory loss in the territory of a single peripheral nerve

Pain along the pathway of the nerve

Direct trauma

compression

entrapment Vascular lesions

neoplasms

?MONONEUROPATHY MULTIPEX Random pattern of nerve involvement In distribution of separate nerves,asymmetric May/may not be painful Not length dependent Isolated reflex loss CAUSES—inflammatory-leprosy,sarcoid Vascular-Diabetes Pressure,Trauma,Infiltration Vasculitis-

PAN,SLE,RA,scleroderma Immune-vaccination

?POLYNEUROPATHY MC type –Distal symmetric polyneurpathy Burning sensation,tingling,numbness Length dependent pattern Starts in feet,distal stocking glove pattern Fairly symmetric Symmetrically decreased reflexes Sensory>motor

CAUSES Diabetes mellitus Alcohol Vit B12 deficiency HIV Although more than one nerve involved one will be prominant

DDs of distal symmetricNP Lumbosacral polyradiculopathy/stenosis Myelopathy-structural -nonstructural Vascular insufficiency-exercise related

cramps,aching pain>numbness Orthopedics –stress #,plantar fascitis

?POLYRADICULOPATHY Disease of multiple peripheral nerve roots Asymmetric with erratic distribution-proximal in

one,distal in another Pain is a common feature ?MONORADICULOPATHY Root disease by disease of spinal column Changes in distribution of spinal nerve root

?SENSORY NEURONOPATHY Ganglion cells predominantly affected Both proximal & distal involvement Sensory ataxia is common No weakness But awkward movement d/t sensory disturbances ?MOTOR NEURONOPATHY Disorder of ant horn cells Weakness,fasciculation,atrophy Not properly a process of peripheral NP

?PLEXOPATHY Asymmetric Painful onset Multiple nerves in a single limb Rapid onset of weakness,atrophy Isolated reflex loss

?polyneuritis cranialis

a/c idiopathic polyneuritis Peripheral nerve+cranial nerve involvement Self limiting painful ophthalmoplegia CAUSES-TB meningitis osteomyelitis skull otitis media syphilitic meningitis sarcoidosis carcinomatous meningitis

COURSE OF DISEASE1.syndrome of a/c ascending motor paralysis a.acute idiopathic polyneuritis b.IMN with polyneuritis c.diphtheria d.hepatitis with polyneuritis e.porphyria f.TOCP poisoning g.paraneoplastic h.post vaccinial

2.syndome of subacute sensorymotor NPA.Deficiency=alcoholic beriberi pellagra vit B12B.Toxins=arsenic,lead,Hg,PbC.Drugs=nitrofurantoin,INH dapsone,disulfiram clioquinolD.UremicE.DM,PAN,sarcoidosisA,B,C,D====SYMMETRIC

3.C/C sensorimotor polyneuropathy syndrome

GENETIC ACQUIREDPeronealmuscle atrophy/CMT leprosy

Dejerine sottas disease Diabetes mellitusHereditary sensory NP uremiaPortugeseamyloidosis/andrade’s disease

carcinoma

Refsum’s disease myelomaA beta lipoproteinemia paraproteinemiaTangier’s disease amyloidosisMetachromaticleucodystrophy

RECURRENT POLYNEUROPATHY Relapsing CIDP Porphyria Refsum’s disease HNPP GBS Beriberi Toxic neuropathy

SENSORY ATAXIC NEUROPATHY Sensory NP(polyganglionopathy) Paraneoplastic sensory NP=sjogren’s =idiopathic Toxic=cisplatin =vit B6 excess Demyelinating polyradiculopathy=MGUS =Millerfisher

Clues for diagnosis

Constitutional symptoms

DM hypothyroidism chronic renal failure liver disease intestinal

malabsorption malignancy connective tissue

diseases

[HIV] drug use Vitamin B6 toxicity alcohol and dietary

habits

•Weight loss, malaise, and anorexia.

Conditions Associated withPainful Peripheral Neuropathy Diabetes and Pre-Diabetes Alcohol neuropathy Chemotherapy

◦ Platinum-based Paraproteinemia Vasculitis and Connective Tissue Diseases Heavy metals and other toxins HIV Amyloidosis Porphyria

Medications Causing Neuropathies Axonal

Vincristine Paclitaxel Nitrous oxide Colchicine Probenecid Isoniazid Hydralazine Metronidazole Pyridoxine Didanosine Lithium Alfa interferon Dapsone

Axonal - continued..Phenytoin Cimetidine Disulfiram Chloroquine Ethambutol Amitriptyline

Demyelinating Amiodarone Chloroquine Suramin Gold

Neuronopathy Thalidomide Cisplatin Pyridoxine

ETIOLOGICAL CLASSIFICATION 1.metabolic-DM,amyloidosis,porphyria 2.infections-leprosy,HIV,CMV,syphilis, diphtheria,lymedisease 3.immune- GBS,CIDN,MMN 4.hereditary-CMT 5.Toxic-drugs,alcohol,heavymetals 6.vasculitis-PAN,CSS,cryoglobulinemia 7.paraneoplastic-lung 8.nutritional- B1,B6,B12

Proximal Symmetric Motor Polyneuropathies

◦ Guillain-Barré syndrome◦ Chronic inflammatory demyelinating

polyradiculoneuropathy ◦ Diabetes mellitus ◦ Porphyria ◦ Osteosclerotic myeloma◦ Waldenstrom's macroglobulinemia ◦ Monoclonal gammopathy of undetermined significance◦ Acute arsenic polyneuropathy ◦ Lymphoma ◦ Diphtheria ◦ HIV/AIDS ◦ Lyme disease◦ Hypothyroidism◦ Vincristine (Oncovin, Vincosar PFS) toxicity

History The temporal course of a neuropathy varies,

based on the etiology.

◦ With trauma or ischemic infarction, the onset will be acute, with the most severe symptoms at onset.

◦ Inflammatory and some metabolic neuropathies have a subacute course extending over days to weeks.

◦ A chronic course over weeks to months is the hallmark of most toxic and metabolic neuropathies.

History A chronic, slowly progressive neuropathy

over many years occurs with most hereditary neuropathies or with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

Neuropathies with a relapsing and remitting course include CIDP, acute porphyria, Refsum's disease, hereditary neuropathy with liability to pressure palsies (HNPP), familial brachial plexus neuropathy, and repeated episodes of toxin exposure.

Ischemic neuropathies often have pain as a prominent feature.

Small-fiber neuropathies often present with burning pain, lightning-like or lancinating pain, aching, or uncomfortable paresthesias (dysesthesias).

History

Dying-back (distal symmetric axonal) neuropathies initially involve the tips of the toes and progress proximally in a stocking-glove distribution.

History

Peripheral neuropathy can present as restless leg syndrome.

Proximal involvement may result in difficulty climbing stairs, getting out of a chair, lifting and bulbar involvement can also be seen

History

The clinical assessment should include:◦ careful past medical history, looking for systemic

diseases that can be associated with neuropathy, such as diabetes or hypothyroidism.

History

All patients should be questioned regarding ◦ HIV risk factors◦ diet (nutrition)◦ vitamin use (especially B6) ◦ possibility of a tick bite (Lyme disease) ◦ Constitutional symtoms (malignancy)

History

Differential Diagnosis of Neuropathies by Clinical Course Acute onset (within days)

Subacute onset (weeks to months)

Chronic course/ insidious onset

Relapsing/ remitting course

Guillain-Barré syndrome

Maintained exposure to toxic agents/medications

Hereditary motor sensory neuropathies

Guillain-Barré syndrome

Acute intermittent porphyria

Persisting nutritional deficiency

Dominantly inherited sensory neuropathy

CIDP

Critical illness polyneuropathy

Abnormal metabolic state

CIDP HIV/AIDS

Diphtheric neuropathy

Paraneoplastic syndrome

Toxic

Thallium toxicity CIDP Porphyria

Physical Examination A cranial nerve examination can provide

evidence of mononeuropathies.

Funduscopic examination may show abnormalities such as optic pallor, which can be present in leukodystrophies and vitamin B12 deficiency.

Thickened nerves

Physical examination

Assessing Autonomic Nervous System

Cardiovagal◦ Heart rate variability

Adrenergic◦ Valsalva maneuver

Induces BP changes and monitors pulse reaction

Postganglionic sudomotor function◦ QSART

Recommendations for lab testing: Screening laboratory tests may be

considered for all patients with DSP (Level C).

Tests with the highest yield of abnormality:1. blood glucose (fasting)2. serum B12 with metabolites (methylmalonic acid, homocysteine)3. SPEP(serum protein electrophoresis)

(Level C).

Other laboratory studies ANA, RF, Anti-dsDNA, Anti-Ro, Anti-La, ANCA

screen, cryoglobulins Urine for heavy metals, porphyrins IFE/urine IFE/ plasma light chain analysis

INVESTIGATIONS BLOOD TC,DC,ESR Urea,electrolytes,LFT RBS,HbA1C Serum protein electrophoresis Auto Ab=ANA,Antiganglioside,Antineuronal Vit B 12 level DNA analysis=chr 17 duplication-HMSN1&1A =chr 17 deletion -HLPP

URINE BJ protein Porphyria Heavy metals CSF ANALYSIS NERVE CONDUCTION STUDY Variation in axonal,demyelinating neuropathy Conduction block-CIDP,GBS,MMN EMG-muscle denervation changes Sensory threshold Thermal & vibration threshold

Neuropathies + Serum AutoantibodiesAntibodies against Gangliosides GM1 : Multifocal motor neuropathy GM1, GD1a : Guillain-Barré syndrome GQ1b : Miller Fisher variant

Antibodies against Glycoproteins Myelin-associated glycoprotein : MGUS

Antibodies against RNA-binding proteins Anti-Hu, antineuronal nuclear antibody 1: Malignant

inflammatory polyganglionopathy

Electrodiagnostic studies

(1) Confirming the presence of neuropathy,

(2) Locating focal nerve lesions,

(3) Nature of the underlying nerve pathology

Distal motor latency prolonged

Nerve conduction velocity slow

Reduced action potential

The limitations of EMG/NCS should be taken into account when interpreting the findings. ◦ There is no reliable means of studying proximal

sensory nerves. ◦ NCS results can be normal in patients with small-

fiber neuropathies◦ Lower extremity sensory responses can be

absent in normal elderly patients.

EMG/NCS are not substitutes for a good clinical examination.

Laboratory Evaluation

IMAGES CXR-sarcoidosis,malignancy Skeletal survey-multiple myeloma Screening for malignancy

AUTONOMIC FUNCTION TESTS

Diagnostic tests imp in Asymmetric,motor

predominant,rapid onset,demyelinating neuropathy

NERVE BIOPSY-indicationssural,sup peroneal&sup radialNVASCULITIS GIANT AXONAL NPthy

AMYLOIDOSIS Infantile neuroaxonal dystrophy

SARCOIDOSIS CMT 1&3

LEPROSY CIDPolyradiculoneuropathy

KRABBE’S Paraprotein neuropathy

METACHROMATIC LEUKODYSTROPY

Nerve biopsy In vasculitis, amyloid neuropathy, leprosy,

CIDP, Inherited disorders of myelin, and rare axonopathies

The Sural nerve is selected most commonly The superficial peroneal nerve – alternative;

:advantage of allowing simultaneous biopsy of the peroneus brevis muscle through the same incision.

This combined nerve and muscle biopsy procedure increases the yield of identifying suspected vasculitis

Skin biopsy “For symptomatic patients with suspected

polyneuropathy, skin biopsy may be considered to diagnose the presence of a polyneuropathy, particularly SFSN.”

Slow progression◦ Treat causative factors if possible◦ If rapidly progressing

IVIG Immunomodulating agents

Symptom Management

Treatment

Tricyclic antidepressants◦ Amitryptilin, nortryptilin

Calcium channel alpha-2-delta ligands◦ Gabapentin, pregabalin

SNRI’s◦ Duloxetine, venlafaxine

Topical Agents◦ Lidocaine, Capsaicin

Symptom Management

Antiepileptic Drugs◦ Carbamazepine, phenytoin, lacosamide

SSRI’s Opioid analgesics Tramadol Miscellaneous

◦ Botulinum toxin◦ Mexiletine◦ Alpha lipoic acid

Symptom Management

Physical Therapy ◦ Gait and balance training

Assistive devices Safe environment Footwear at all times Foot hygiene

Thanks