APPROACH TO A PATIENT WITH PERIPHERAL

NEUROPATHY

BY:Dr. Tikal Kansara

R2 Medicine D Unit

GLOBAL BURDEN• Overall prevalence – 2 to 4 %– But increases to 8 % in patients over 55 years of age

(Does not include traumatic neuropathies)• In developed world, Diabetes Mellitus is the

most common cause (Dutch study of 362,693 patients – mononeuropathy (4.3/1000/year), carpel tunnel syndrome (2.3/1000/year), diabetic neuropathy (0.72/1000/year), post herpetic neuralgia (0.42/1000/year)

• In developing countries, leprosy is the most common cause

• In India, with rise in incidence of diabetes, diabetic neuropathy is also likely to increase

• Over 100 causes of neuropathy• Among several sudies, around 20 to 50 %

patients remain undiagnosed

BASIC ANATOMY

Components of a Peripheral Nerve

• Peripheral Nerves including the cranial nerves (except the Ist and IInd)

• Spinal Nerve Roots• Dorsal Root Ganglia• Peripheral Nerve trunk with its terminal

branches• Peripheral Autonomic Nervous System

Components of a Peripheral Nerve

Components of a Peripheral NerveInflammation of interstitium

Necrotising panarteritis

Endoneural amyloid deposition

Vasculitis, ischemic infarctions

Pathogenic Mechanism of Peripheral Nerve Damage

• Several changes are identified but are not disease specific:– Segmental Degeneration– Wallerian Degeneration– Axonal Degeneration

• Myelin sheath is the most suseptible to damage. It can break down as a parimary process afecting Schwann Cells, myelin itself, or secondarily to the diseases affecting axon.

• Focal degeneration of myelin sheath with sparing of the axon is called segmental Degeneration.

• The characteristic change is the disappearance of sheath over segments of variable length, bounded on each end by a preserved segment of myelin.

Segmental Degeneration (Demyelinating)

Wallerian Degeneration

• It is the reaction of both axons and myelin distal to the site of disruption of an axon.

• Described as “dying-forward” phenomenon

Axonal Degeneration

• A “dying-back” phenomenon which typically occurs in a generalised metabolically determined polyneuropathy

• Axon affected progressively from distal-most site to the proximal, with dissolution of myelin parallel with axon. Certain toxic and metabolic processes affect axons uniformly along their length or impair anterograde axonal trasnport to the periphery; functional impairment is proportioanl to the size and length of axon blocked.

• Destruction of proximal spinal root – gradual destruction of distal motor nerve and its myelin sheath. (Wallerian degeneration)

• Neuronal motor cell body undergoes characteristic morphological change but does not die.

• Destruction of dorsal spinal root produces secondary Wallerian Degneration of posterior columns of spinal cord, but not of the peripheral sensory nerve.

Types of Nerves and their function

Topography

• Mononeuropathy– Single peripheral nerve involvemment• Trauma, compression or entrapement– Carpel Tunnel Syndrome, Ulnar nerve entrapement,

peroneal nerve entrapement• Related to pregnancy, thyroid disease or

occupation• Or due to hereditary disorder liable to pressure

palsy

• Mononeuropathy multiplex– Multiple, separate, noncontiguous peripheral

nerves either simultaneously or sequentially• Leprosy, Vasculitis (PAN, Churg-Strauss Syndrome, RA,

Sjogren’s Syndrome) and requires urgent diagnosis• Superficial peroneal or sural nerve palsy often helpful

(Vasculitis)

• Polyneuropathy– A general degeneration of nerves that spread

typically towards the center of body

• Ganglionopathy / Neuronopathy– Sensory neuronopathies (SN) are specific group diseases

characherised by primary degeneration of dorsal root ganglia and their projections

– Multifocal sensory symptoms are often associated with ataxia• Localised

– Herpes Zoster• Immune

– Sjogren’s syndrome– Autoimmune Heptitis– Celiac Disease

• Idiopathic– Pan-sensory– CANVAS (Cerebellar Ataxia, Neuronopathy, Vestibular Areflexia Syndrome)

• Hereditary

Vital Questions to ask for

• What systems are involved?• What is the duration of weakness?• What is the nature of sensory involvement?• Is there evidence of Upper Motor Involvement?• What is the temporal evolution?• Is there evidence of hereditary neuropathy?• Does the patient have any other medical

conditions?

Symptomatology of peripheral neuropathy

• Symptoms comprises the following types:– Motor Symptoms– Sensory Symptoms– Autonomic Symptoms– Trophic Symptoms

Sensory Symptoms

Loss of function“- symptoms”

Disordered function“+ symptoms”

Sensory “Large Fiber”

↓ Vibration↓ ProprioceptionHyporeflexiaSensory ataxia

Paresthesias

Sensory “Small Fiber”

↓ Pain↓ Temperature

DysesthesiasAllodynia

Motor SymptomsLoss of function“- symptoms”

Disturbed function“+ symptoms”

Motor nervesLarge fibre

WastingHypotoniaWeaknessHyporeflexiaOrthopedic deformity

Fasciculation Cramps

•Initially distal motor weakness is common – difficulty in turning keys of lock, unfasten buttons and opening lids of bottles and jars•Proximal Motor Weakness – Difficulty in keeping and bringing down bags in upper parts of closets, hanging shirts, climbing stairs

Autonomic Symptoms

Loss of function“- symptoms”

Disturbed function“+ symptoms”

Autonomic nerves

↓ SweatingHypotensionUrinary retentionImpotenceVascular color changesGI Complaints

↑ Sweating Hypertension

What is the distribution of weakness?

• Distal, proximal or both• Focal and asymmetric or symmetric

• Symmetric distal and proximal weakness – Immune demyelinating polyneuropathy (Acute & Chronic)

• Asymmetric acute or subacute sensory and motor symptoms and signs – radiculopathies, compressive mononeuropathies, mononeuritis multiplex must be coinsidered

Is there evidence of upper motor neuron involvement?

• If symmetric distal sensory symptoms and signs (distal sensory neuropathy), but additional symmetric upper motor neuron involvement – Combined Degeneration– Vitamin B12 Deficinecy– Copper Deficiency– HIV Infection– Severe Hepatic Disease

What is the Temporal Evolution?• Acute (days to 4 weeks)

– Vasculitis – hyperacute mononeuropathies 24 – 72 hours– AIDP

• Subacute (4 to 8 weeks)– CIDP

• Chronic (>8 weeks)– Diabetes– Hereditary

• Monophasic, progressive or relapsing– Monophasic – GBS– Progressive – Diabetes, CIDP– Relapsing – Recurrent GBS

Is there evidence of Hereditary Neuropathy?

• Very slowly progressive weakness over many years – with minimal sensory symptoms but significant sensory signs – Hereditary Neuropathy

• Eg. CMT Disease – arch and toe abnormalities (High or flat arched, hammer toes, etc.)

• Evidence from remote history like funny feet, unevenly worn shoes, childhood onset clumsiness especially in sports and tasks that require fine coordination

Does the patient have any other medical condition?

• Associated medical conditions– Diabetes– Systemic Lupus Erythemstosus– Anaemia

• Preceding or concurrent infections– Diarrhoea in GBS

• Surgeries– Gastric bypass and nutritional neuropathies

• Medications– Toxic Neuropathy

• Alcohol• Dietary Habits• Dental Fixatures (zinc leading to copper deficinecy)

Past History

• Concurrent illness, particularly organ failure, endocrine disorders, and connective tissue disease

• Diabetes, and latent diabetes, should always be sought.

Family History

• Detailed family history is often crucial, and if negative– Examination of relatives; atleast tapping the ankle

jerk– Recording a lower limb motor conduction velocity

• Worthwhile to ask for family history of porphyria, if present

Drugs causing neuropathies• Axonal– Vincrisitne, Paclitaxel, Nitrous oxide, Colchicine,

Isoniazid, Hydralazine, Metronidazole, Pyridoxine, Chloroquine

• Demyelinating– Amiodarone, chloroquine, gold

• Neuronopathy– Thalidominde, cisplatin, pyridoxine

• Sensory Neuropathy– Cisplatin, Paclitaxel, etoposide, colchicine,

thalidomide, disulfiram, pyrodixine, INH, lithium, gold

• Motor Neuropathy– Dapsone, lead

• Sensory – Motor Neuropathy– Vincristine, vinblastine, cytarabine, metronidazole,

amiodarone, thallium

General Examination• Purpura, Livodereticularis – Vasculitis, Cryoglobulinemia• Fabry’s disease – Angiokeratomas• Skin pigmentation – Leprosy, POEMS, adrenoleukodystrophy• Icthyosis – Refsum’s Disease• Mees’ line – Arsenic / Thallium Intoxication• Alopecia – Thallium Poisoning, Hypothyroidism, SLE• Maculoanaesthetic patches with thickened nerves - Leprosy• Orange Tonsils – Tangier’s disease• Pes cavus, high-arched feet and mutilation – Hereditary

neuropathy• Macroglossia – Amyloidosis• Chelosis/Glossitis – Multivitamin deficiency

Livedo reticularis

Purpura

Angiokeratomas

Skin Pigmentation

Icthyosis

Mee’s lines

High Arched Foot

Thickenend Nerves in Neuropathy

• Leprosy• Neurofibromatosis• Roussy Levy Syndrome• Refsum’s disease• Amyloidosis

SYSTEMIC EXAMINATION

• CENTRAL NERVOUS SYSTEM EXAMINATION– Higher Functions

Altered in – Porphyria, HIV, Lead and other toxins, alcohol– 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

• 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• Foot deformities: CMT, HMSN, HSAN

– Trophic Changes:• Diabetes, Leprosy, Hereditary Neuropathies

• 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

• RESPIRATORY SYSTEM EXAMINATION– Asthma – Churg-Strauss Syndrome– Sarcoidosis– Tuberculosis – HIV– Carcinoma Lung– Connective Tissue Disorder

• CARDIOVASCULAR SYSTEM– Cardiomyopathy: Diptheria, Alcohol, Amyloidosis– Pericarditis: Connective Tissue disorder

• 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

Differencial Diagnosis of Peripheral Neuropathy / Pitfalls in diagnosis @ nerve level

• In patients with neuropathic symptoms, spinal cord is the most common differential

• Spinal Canal Stenosis – intermittent claudiacation symptoms, but in advanced stages, may present with persistent symptoms simulating peripheral neuropathy

• In elderly, co existance of cervical spondylitic meylopathy with late onset predominantly sensory axonal neuropathy

• In the same way, spondylotic radiculopathies may co-occur with upper limb entrapement neuropathies

• As stated before, coexistance with CNS disease is common, Vitamin B12 deficiency, neuroacanthocytosis, spinocerebellar syndromes

• Lacunar stroke may rarely present with sensory loss in the region of median or ulnar nerve distribution

Various classifications of neuropathies

Neuropathies by pattern of involvement

• Focal– Entrapement

• Myxoedema• Rheumatiod arthritis• Amyloidosis• Acromegalyt

– Compressive neuropathies– Trauma– Ischemic lesions

• Diabetes mellitus• Vaculitis

– Leprosy– Sarcoidosis– Neoplastic infiltration or compression

• Multifocal– Diabetes mellitus– Vaculitis• Polyarteritis nodosa• Systemic lupus erythematosus• Sjogren’s syndrome

– Sarcoidosis– Leprosy– HIV/AIDS– Multifocal variant of CIDP– Hereditary predisposition to pressure palsies

Neuropathies with less common patterns of involvement

Neuropathies with cranial nerve involvement– Diabetes mellitus– Guillian-Barre Syndrome– HIV/AIDS– Lyme disease– Sarcoidosis– Neoplastic invasion of skull base or meninges– Diptheria– Friedrich’s ataxia

Neuropathies predominant in upper limbs– Porphyria– Lead neuropathy

Neuropathies with rapid/abrupt onset

• Ischemic neuropathies• Polyarteritis nodosa• Rheumatoid arthritis• Diabetes mellitus– Cranial neuropathies– Diabetes amyotrophy

• Nerve compression– Hemorrhage– Swelling within a restricted anatomic compartment– Direct external compression

• Penetrating wounds

Neuropathies by clinical course• Acute – Guillian-Barre Syndrome– Acute intermittent porphyria– Critical illness polyneuropathy– Diptheric neuropathy– Thallium toxicity

• Subacute – Maintained exposure to toxic agents/medications– Persisting nutritional deficiency– Abnormal metabolic state– Paraneoplastic syndrome– CIDP

• Chronic – Hereditary motor sensory neuropathies– Dominantly inherited sensory neuropathies– CIDP

• Relapsing/remitting course– Guillian-Barre Syndrome– CIDP– HIV/AIDS– Toxic– Porphyria

Laboratory Tests

• First line screening tests– Blood counts, ESR– Blood sugar– Liver and renal function tests– Serum Vitamin B12 levels– Paraprotein levels– Thyroid funtion tests– Vasculitis Profile

NERVE CONDUCTION STUDIES (NCS)

• NCS is a medical diagnostic test commonly used to evaluate the function, especially the ability of electrical conduction, of the motor and sensory nerves

• Three important conclusions are– Confirm that the disease process is due to

neuropathy– Find out subclinical neuropathies– Prognosticate the condition

Evoked Potentials

•Electrical signals passes recording and reference electrodes and is shown on oscilloscope•Time to onset and amplitude of the electrical signal is measured

Amplitude

Reduced in axonal blockade

Latency

Prolonged in demyeliating lesions

Nerve Conduction Velocity

AXONAL DEGENERATION

SEGMENTAL SEGMENTATION

Motor Nerve Conduction StudiesCMAP amplitude Decreased Normal

Distal Latency Normal Prolonged

Conduction Velocity Normal Slow

F wave Normal or absent Prolonged or absent

H reflex Normal or absent Prolonged or absent

Sensory Nerve Conduction Studies

SNAP amplitude Decreased Normal or decreased

Distal latency Normal Prolonged

Conduction velocity Normal Slow

• If Hx, examination, EDx and the above mentioned Ix does not reveal a diagnosis,then– Revise family history or examine the relatives

• Nerve Biopsy – Vasculitis restricted to nerves or neuropathy of recent origin, amyloid, CIDP

• Anti-Hu antibodies• CSF– AIDP, CIDP and other chronic immune-medicated

axonal neuropathies– Significant pleocytosis shoud raise the suspicion of

Borrelia, Sarcoidosis, HIV

• Genetic Testing– E.g. PMP22 duplication test and others in CMT– Due to high mutation rate, genetic disorder can also

be considered without a family history• Anti-ganglioside antibodies elevated in patients

with multifocal motor neuropathy with conduction block (MMN-CB) in 50% patients

• Anti-GQ1b IgG – Miller-Fisher Syndrome• Motor Axonal Variant of GBS – Anti-GM1 and

anti-GDI antibodies

• Nerve Biopsy– Places where electron microscope, teased fibre

technique and immunohistochemistry are available– Indications: Suspicion of vasculitis , amyloid

deposition, leprosy, sarcoidosis or immune neuropathies (eg CIDP)

– Location: superficial sensory nerves are generally used. Superficial peroneal nerve in legs & superficial radial nerve or branch of ulnar nerve

• Combined nerve and muscle biopsy may sometimes be required

Specific Neuropathies

Hereditary Neuropathies

• Charcot-Marie-Tooth disease• Hereditary Neuropathy with liability to pressure palsies

(HNPP)• Hereditary Neuralgic Amotrophy (HMA)• Hereditary Sensory and Autonomic Neuropathy (HSAN)• Fabry’s disease• Refsum’s disease• Tangier’s disease• Porphyria• Familial Amyloid polyneuropathy

RARE HEREDITARY NEUROPATHIES

HEREDITARY DISORDERS OF LIPID METABOLISM

Metachromatic leukodystrophy

Krabbe’s disease (globoid cell leukodystrophy)

Fabry’s disease

Adrenoleukodystrophy / adrenomyeloneuropathy

Refsum’s disease

Tangier disease

HEREDITARY ATAXIAS WITH NEUROPATHY

Friedreich’s ataxia

Vitamin E deficiency

Spinocerebellar ataxia

Abetalipoproteinemia (Bassen-Kornzweig disease)

RARE HEREDITARY NEUROPATHIESDISORDERS OF DEFECTIVE DNA REPAIR

Ataxia-Telangictesia

Cockayne’s Syndrome

GIANT AXONAL NEUROPATHYPORPHYRIA

Acute Intermittent Porphyria (AIP)

Hereditary coprophyria (HCP)

Varigate porphyria (VP)

FAMILIAL AMYLOID POLYNEUROPATHY (FAP)

Transthyretin-related

Gelsolin-related

Apolipoprotein A1-related

Aquired Neuropathies• Primary or AL Amyloidosis• Diabetic Neuropathy• Hypothryiodism• Sjogren Syndrome• Rheumatiod Arthritis• Systemic Lupus Erythematosus • Systemic Sclerosis (Scleroderma)• Mixed Connective Tissue Disorder (MCTD)• Sarcoidosis• Hypereosinophilic Syndrome• Celiac Disease (Gluten – induced Enteropathy)• Uremic Nephropathy• Chronic Liver Disease• Critical Illness Polyneuropathy• Leprosy• Lyme Disease• Diphtherritic Neuropathy• HIV

Diabetic Neuropathy

• Distal symmetric sensory and sensorimotor polynneuropathy

• Autonomic neuropathy• Diabetic neuropathic cachexia• Polyradiculoneuropathies• Cranial neuropathies• Other mononeuropathies

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

Diabetic Autonomic Neuropathy

• Abnormal sweating, dysfunctional thermoregulation, dry eyes and mouth, pupillary abnormailties, 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

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 in

the affected leg becomes appatent 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 maybe like the typical lumbosacral

radiculoplexus neuropathy, thoracic radiculopathy or even an uncommon cervical polyradiculoneuropathy

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)

HIV

• HIV- related distal symmetric polyneuropathy• HIV – related inflammatory demyelinating

polyneuropathy• HIV – related progressive radiculopathy• HIV – related multiple mononeuropathies• HIV – related neuronpathy / ganglionopathy

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

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

HIV – related progressive polyradiculopathy

• Acute progressive lumbosacral polyradiculopathy occurs secondary to CMV infection

• Severe radicular pain, numbness and weakness in legs – usually asymmetric

HIV – related multiple mononeuropathies

• Weakness, numbness, paresthesias, and pain occur in distribution of affected nerves

• Axonal degeneration with necrotizing vasculitis or perivascular inflammation occurs

HIV – related sensory neuronopathy / ganglionopathy

• Dorsal root ganglianitis occurs and neuronopathy is the presenting feature

• Sensory ataxia

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

– Diffuse hyporeflexia and absent Achilles reflex– Sometimes – optic atrophy with behavioral

changes may be visible

Thiamine Deficiency

• Consequence of chronic alcohol abuse, recurrent vomitting, total parentral nutrition and bariatric surgery

• Mild sensory loss to burning dysesthesias in toes and feet and aching and cramping in lower legs followed by distal sensory loss

Copper Deficiency

• Myeloneuropathy• Lower limb paresthesias, weakness, spasticity

and gait difficulties• Most commonly large fibres sensory function

is affected, but sometimes; small fibres are affected too

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

• 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

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)

Subtypes of GBSSUBTYPE FEATURES ELECTRODIAGNOSIS

Acute inflammatory demyelinating

polyneuropathy (AIDP)

Adults more than children; anti-GM1

antibodiesDemyelinating

Acute motor axonal neuropathy (AMAN)

Children and yourng adults, maybe seasonal;

anti-GD1a antibodiesAxonal

Acute motor sensory sxonal neuropathy

(AMSAN)

Mostly adults, recovery slow and often

incompleteAxonal

Miller Fisher Syndrome (MFS)

Adults and children; ophthalmoplegia, ataxia and areflexia; anti-GQ1B

antibodiesAxonal or demyelinating

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-seopositive patients, SLE

Immunopathogenesis of GBS

Laboratory Features• CSF – elevated protein levels without accompanying pleocytosis• CSF normal if symptoms <= 48 hours

• In AIDP, the earliest features are prolonged F-wave latencies, prolonged distal latencies, and reduced amplitude of compound muscle action potentials (CMAP)

• Late findings, slowing of conduction velocity, conduction blocks, temporal dispersion may be appreciated

• In primary axonal pathology, Edx shows reduced amplitude of CMAPs without conduction slowing or prolongation of distal latencies

DiagnosisBrighton Criteria for GBS• Level 1 of diagnostic certainity

– Motor (B/l and flaccid)– Reflexes– Antecedent illness– Edx– CSF– Absence of any alternative diagnosis

• Level 2 of diagnostic certainty– Above except as in– CSF / Edx

• Level 3 of diagnostic certainty – Motor– Reflexes– Antecedent illness– Alternative diagnosis

Treatment

• Plasmapheresis• IVIg

Chronic Inflammatory Demyelinating Polyneuropathy

• Onset gradual over a few months or longer• Acute onset form of CIDP when GBS deteriorates > 9 weeks

after onset or relapse three times

• 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

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)

Diagnosis• Clinical, CSF and Edx• CSF

– Albuminocytological dissociation

• Edx– Variable degrees of conduction slowing, prolonged distal latencies, distal

and temporal dispersion of CMAPs, and conduction block– Presence of conduction block is hallmark of aquired demyelinating

process– Axonal loss, secondary to demyelination, is present in 50% patients

• Serum protein electrophoresis and immunofixation – Monoclonal gammopathy

• CIDP – exclude vasculitis, collagen vascular disease (especially SLE), chronic hepatitis, HIV, amyloidosis, and diabetes

Treatment

• Treatment initialted when progression is rapid or walking is compromised

• High dose IVIg, PE and glucocorticoids all more effective than placebo

• Patients who fail this therapy, should be given a trial of– Azathioprine, methotrexate, cyclosporine, and

cyclophosphamide– Anti-CD20 (Rituximab) is also promsing

• Fails to respond to treatment, think of POEMS (monoclonal gammopathy)

Charcot-Marie-Tooth Disease

• Most common type of hereditary neuropathy• Classified on the basis of nerve conduction

velocities, predominant pathology and inheritance pattern– Type I – Demyelinating

• Nerve Conduction Velocity < 38 m/s– Type II – Axonal

• Nerve Conduction Velocity > 38 m/s

• CMT 1, 2 & 3 – Autosomal Dominant; CMT 4 – Autosomal Recessive

• CMT Type 1– (anterior compartment) – inverted champagne

bottle legs– First to third decade of life with distal weakness

(e.g. footdrop); but many remain asymmtomatic – Reduced sensations to all modalities on

examination

Three copies of peripheral myelin protein – 22 (PMP-22)

• CMT Type 2– Usually becomes symptomatic in second decade

of life; – Clinically indistinguishable from CMT1; but NCVs

show a slightly higher velocity• CMTDI – dominant Intermediate, NCVs faster

than in CMT1, but slower than CMT2• CMT3– Hereditary demyelinating sensorimotor

polyneuropathy in infancy or childhood• NCVs usually in 5 – 10 m/s

• CMT4– Severe, childhood-onset sensorimotor

polyneuropathy inherited as autosomal recessive pattern

– EDx & histology shows demyelinating and axonal features

• CMT1X– X-linked dominant disorder; with clinical features

similar to CMT1 and CMT2, but more severe in men than in women

– 10 – 15 % of CMT overall– First two decades of life with atrophy and

weakness of distal arms and legs, pes cavus, and hammertoes

– NCVs in between 15 – 35 m/s; (among which majority in 25 – 35 m/s – intermediate slowing)

– Mutation in connexin 32

Hereditary Neuralgic Amotrophy (HMA)

• Autosomal dominant; mutation in Septin 9 (SEPT 9)• Recurrent attacks of pain, weakness and sensory loss in

the distribution of brachial plexus, which begins in childhood; with recovery in weeks or months (sensorimotor)

• Confused with brachial plexitis• Occurs in postpartum state, stress or following surgery• Clincal:

– Slighly dysmorphic features including hypotelorism, epicantal folds, cleft palate, syndactyly, micrognathia, and facial asymmetry occurs

• NCV – Axonal neuropathy

• Clinical patterns– Classic (severe pain followed by paresis and

symptom-free interval in between)– Chronic (interictal persistance of pain and paresis)

• Treatment:– NSAIDS in combination with opoids and/or TCAs

like amitryptylline or BZDs– Supportive physical therapy including

transcutaneous electrical neurostimulation (TENS)

Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)

• Second or third decade of life; due to a single copy of PMP-22; autosomal dominant

• Painless numbness and weakness in the distribution of a single peripheral nerve, although multiple mononeuropathies can occur; which takes weeks or months to resolve

• Precipitated by trivial compression of nerves – wearing a backpack, leaning on elbows, crossed legs

Hereditary Sensory and Autonomic Neuropathy (HSAN)

• Sensory and Autonomic dysfunction predominated over muscle weakness

• HSAN 1 in adults – second to forth decade of life, autosomal dominant

• Degeneration of small myelinated and unmyelinated nerve fibres– Severe loss of pain and temperature sensations, gross foot

and hand deformities, bone loss, recurrent osteomyelitis, amputed digits – self mutilating behaviour

– Sometimes, bladder dysfunction, reduced sweating in feet can occur

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

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

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

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

• 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

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

• Rx – Correction of hypothyroidism

Sjorgen’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)

• 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

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

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

Systemic Sclerosis (Scleroderma)

• Distal symmetric, mainly sensory, polyneuropathy complicated 5 – 67% of scleroderma cases

• Cranial mononeuropathies, commonly trigeminal, produces numbness and dysesthesias in the face

• Muliple mononuropathies also occur

• EDx & Biopsy – axonal sensory >> motor polyneuropathy

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

• Mononeuropathies (eg CTS can occur)

Sarcoidosis

• 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

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)

Inflammatory Bowel Disease

• UC & Crohn may be complicated by GBS, CIDP, generalised axonal sensory or sensorimotor polyneuropathy, small fibre neuropathy or mononeuropathy

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• Rx - Antibiotics

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 and blurred vision due to impaired accomodation occurs

• More generalised neuropathy occurs 2 to 3 months later, characterised by numbness, paresthesias, weakness of arms and legs and respiratory failure

• 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

Herpes Varicella-Zoster Virus

• 2/3rd 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)

Cytomegalovirus

• Acute lumbosacral polyradiculopathy and multiple mononeuropathies in patients with HIV and other immune deficiency disorders

Epstein-Barr Virus

• Associated with GBS, cranial neuropathies, mononeuropathy multiplex, brachial plexopathy, lumbosacral radiculoplexopathy, and sensory neuronopathies

Chronic Liver Disease

• Generalised senorimotor neuropathy – numbness, tingling, and minor weakness in the distal aspects of lower limbs

• EDx – sensory >> motor axonal neuropathy

Critical Illness Polneuropathy

• Acute generalised weakness leading to admission in ICU are GBS and myasthenia gravis

• However, weakness developing in critically ill patients while in ICU is caused by critical illness poluneuropathy (CIP) or critical illness myopathy (CIM)

• Complication of sepsis or multiple organ failure– Leads to inability to wean patient off the ventilator

• Exact mechanism is not known; but circulating toxins and metabolic abnormalities are associated with sepsis and multiorgan failure impair axonal transport or mitochondrial function, leading to axonal degeneration

Neuropathies Associated With Malignancy

• 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

• Most common is lung cancer.

Paraneoplastic Sensory Neuronopathy/ Ganglionopathy

• Paraneoplastic encephalomyelitis/sensory neuronopathy (PEM/SN) – Small – Cell Carcinoma

• Polyclonal antineuronal antibodies (IgG) – anti-Hu antigen

• Numbness or parasthesias in distal extremities, sensory ataxia, motor neuronopathy (pseudoathetosis, inability to walk, stand or even sit without support)

• Neurological symptoms precede on an average of 6 months before identification of SCLC

• Even though, most of subacute sensory neuropathies are idiopathic, more than half the cases have underlying lung cancer– So in selected cases, it is necessaryto screen for

paraneoplastic antibody, or even PET Scan for early diagnosis of the tumor

Other malignancies

• Lymphoma• Multiple myeloma• As a complication of bone marrow

transplantation• Associated with monoclonal gammopathy of

uncertain significance

• Even as a complication of chemotherapy

Toxic Neuropathies

• Chloroquine and Hydroxychloroquine– Neuromyopathy

• Pyridoxime (Vitamin B6) Toxicity– Severe sensory neuropathy with dysesthesias

• Lead– Most common presentation is encephalopathy– But primary motor neuropathy can also occur• Weakness – usually beginning in arms, involving wrist

and finger extensors.

• Thallium– Burning parasthesias of the feet, abdominal pain and

vomitting– First week – Pigmentation of hairs, acne-like rash in

malar area of face, hyperreflexia– Second & third week – autonomic instability with labile

heart rate and BO– Third to forth week – hyporeflexia and alopeciA

• Arsenic– Mimics GBS– Abrupt onset abdominal pain, nanusea, vomitting, pain

and diarrhoea follwed several days later by burning sensation in feets and hands

Cryptogenic (Idiopathic) Sensory and Sensorimotor Polyneuropathy

• SCPN – diagnosis of exclusion• 6ht or 7th decade of life• Distal numbness, tingling, often burning pain

that begins in feet and eventually involves the fingers and hands

• Both small and large fibre loss on neurological exam and EDx

Common Mononeuropathies

• Median neuropathy• Ulnar neuropathy at elbow – “Cubital Tunnel

Syndrome”• Radial neuropathy• Lateral femoral cutaneous neuropathy (Meralgia

paresthetica)• Femoral neuropathy• Sciatic neuropathy• Peroneal neuropathy

Plexopathies

• Brachial Plexus– Immune-medicated brachial neuropathy– Brachial plexopathies associated with neoplasms– Perioperative Plexopathies

• Lumbosacral Plexopathies• Recurrent Neoplastic disease or radiation

induced plexopathy

Multifocal Motor Neuropathy

• Uncommon neuropathy presents as slowly progressive motor weakness and atrophy developing over years in distribution of selected nerve trunks

• Sensory fibres are spared; >75 % males• < 50% patients presents with high titres of polyclonal

IgM antibody to ganglioside GM1• Demyelinating and mild inflammatory changes at the

sites of conduction block• Treatment – IVIg; sometimes rituximab or

cyclophosphamide

Neuropathies with Monoclonal Gammopathy

• Multiple Myeloma• Monoclonal gammopathy of undetermined

signifance

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

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

Monoclonal Gammopathy of Undetermined Significance

• Immunoglobulin types IgG, IgA and IgM• Sensorimotor neuropathy• Generally males, >50 years• Do not respond to immunotherapies desgined

to reduce monoclonal proteins• Indistinguishable from CIDP

• Demyelination and remyelination occurs

Vasculitic Neuropathy

• Common in PAN (Polyarteritis Nodosa); ooccuring in half the cases clinically and in 100% cases on post mortem examination

• Multifocal (asymmetric) motor-sensory neuropathy (mononeuropathy multiplex) due to ischemic lesions of nerve trunks and roots

• 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

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

Krabbe disease• Globoid celll leukodystrophy which is a fatal

degenerative disorder that affects the myelin sheath of nervous system

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

• A variant of ALD; adrenimyeloneuropathy has age of onset 21 – 37 and presents with progressive neuropathy, paraparsis and cerebral involvement

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

• Pathology– Sclerosis and degeneratino of dorsal root

ganglion, spinocerebellar tracks, lateral corticospinal tracks and posterior column

– Loss of myelin in large myelinated fibres

Treatment of Neuropathy in general

• Treat the underlying cause– Eg. Plasmapheresis, IVIg in AIDP– Steroids in CIDP

• Symptomatic– For Sensory Neuropathy

• TCAs, Gabapentin, pregabalin• Carbamazepine, Phenytion, Vanlafaxine• Mexiletine

– For Motor Neuropathy• Rehabilitation and Physiotherapy