how to write a case history of presenting complaints [with also ruling out other diagnosis from history of presenting complaints] and clinical examination [with also ruling out other diagnosis from clinical examination] of a patient with symptoms of peripheral neuropathy

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Here is a detailed, clinically structured guide to writing a case history of peripheral neuropathy, with systematic differential diagnosis reasoning at each step.

Writing a Case History of Peripheral Neuropathy

Core principle (Harrison's, 22nd Ed.): The clinician has three goals when approaching a patient with suspected neuropathy: (1) localise the lesion, (2) identify the cause, (3) determine treatment. History and examination answer where the lesion is; investigations confirm why.

Diagnostic flowchart for peripheral neuropathy - Harrison's 22e

PART 1 - HISTORY OF PRESENTING COMPLAINTS (HPC)

A. Opening Statement

Begin with a structured opening line that captures the key demographics and chief complaint:

"Mr/Ms [X], a [age]-year-old [occupation], presented with a [duration]-history of [numbness/tingling/weakness/burning pain] in the [hands/feet/limbs]."

B. The Seven Key Questions - Ask These Systematically

Harrison's 22e frames the entire HPC around seven pivotal questions:

1. What Systems Are Involved?

Ask the patient to describe what bothers them most:

Sensory symptoms: Numbness, tingling (paraesthesiae), burning pain, electric-shock sensations, hypersensitivity to touch (allodynia), loss of balance
Motor symptoms: Weakness of hands/feet, difficulty gripping, foot drop, difficulty climbing stairs, wasting of muscles
Autonomic symptoms: Fainting/light-headedness on standing (orthostatic hypotension), heat intolerance, excessive or absent sweating, erectile dysfunction, bladder urgency/retention, constipation/diarrhoea

Ruling out from the HPC:

Symptom Pattern	Diagnosis Favoured	Diagnoses Ruled Out
Purely sensory, no weakness	Sensory polyneuropathy, small-fiber neuropathy	Motor neuron disease (ALS), myopathy
Purely motor, no sensory loss	Motor neuropathy, multifocal motor neuropathy	Sensory neuropathy, radiculopathy with pure sensory features
Autonomic + sensory, minimal motor	Amyloid neuropathy, diabetic autonomic neuropathy	CMT, GBS (which typically has motor predominance)
Sensory + motor combined	Most polyneuropathies (diabetic, CIDP, toxic)	Isolated CNS lesion (no peripheral nerve involved)

2. Distribution of Weakness (If Present)

Ask: "Where exactly is the weakness? Is it the hands, the feet, or all over? Is both sides affected equally?"

Symmetric distal weakness (worse in feet than hands) = polyneuropathy (length-dependent)
Symmetric proximal + distal weakness = hallmark of GBS or CIDP - do not miss
Asymmetric or focal weakness = mononeuropathy, mononeuropathy multiplex, plexopathy, or radiculopathy

Ruling out from distribution history:

Distribution in History	Rules In	Rules Out
Symmetric distal ("stocking-glove")	Diabetic poly-neuropathy, toxic, CIDP, cryptogenic	Mononeuropathy, radiculopathy, plexopathy
One limb or one nerve territory	Mononeuropathy (carpal tunnel, ulnar, peroneal)	Generalised polyneuropathy
Multiple non-contiguous nerves	Mononeuropathy multiplex (vasculitis, leprosy, DM)	Pure length-dependent polyneuropathy
Proximal + distal	GBS, CIDP, Charcot-Marie-Tooth if chronic	Distal-only metabolic neuropathy

3. Nature of Sensory Symptoms

Ask: "Is it a burning/stabbing pain or is it more like numbness and loss of balance?"

Burning, stabbing, or dysaesthetic pain + preserved reflexes + normal NCS = small-fiber neuropathy (diabetes or glucose intolerance most common; also amyloid, idiopathic)
Vibration loss + proprioceptive loss + ataxia = large-fiber neuropathy (B12 deficiency, CIDP, paraneoplastic, sensory neuronopathy)
Neuropathic pain types: Protopathic (dull, burning, C-fiber mediated) vs. epicritic (sharp, lancinating, A-delta mediated)

Ruling out from sensory character:

Sensory History	Rules In	Rules Out
Pain + temperature loss, vibration preserved	Small-fiber neuropathy, amyloid, diabetic	Large-fiber neuropathy, posterior column disease
Vibration + proprioception loss, balance problems	Large-fiber neuropathy, B12 deficiency, sensory neuronopathy	Small-fiber only neuropathy
Asymmetric proprioceptive loss in arms > legs	Sensory neuronopathy/ganglionopathy (paraneoplastic, Sjögren's, CANVAS)	Length-dependent polyneuropathy

4. Evidence of Upper Motor Neuron (UMN) Involvement

Ask: "Any stiffness, spasticity, or symptoms above the neck/trunk?"

Peripheral neuropathy = LMN signs only (flaccid weakness, wasting, absent reflexes)
If patient reports both sensory loss AND UMN features (spasticity, extensor plantar response), consider combined system degeneration: vitamin B12 deficiency, copper deficiency, HIV myelopathy, adrenomyeloneuropathy, hereditary spastic paraplegia plus neuropathy

Rules out pure peripheral neuropathy if UMN features are prominent without another explanation.

5. Temporal Evolution - Onset and Course

Ask: "When did it start? Did it come on suddenly, over weeks, or gradually over years? Is it getting worse, same, or better?"

Acute (days to 4 weeks): GBS, vasculitis, porphyria, toxic (thallium), ischaemia, diphtheria, acute nerve compression
Subacute (4-8 weeks): Most toxins, nutritional deficiencies, diabetic plexopathy, neoplasm-related, uraemia
Chronic (months to years): CIDP, diabetic polyneuropathy, hereditary neuropathies (CMT), alcohol
Relapsing course: CIDP, porphyria, Refsum disease, HIV, GBS (rare relapse)
Monophasic and improving: GBS, acute toxic exposure

Temporal ruling out:

Onset	Rules In	Rules Out
Acute (days)	GBS, vasculitis, porphyria	CIDP, CMT, diabetic polyneuropathy
Progressive over years, childhood onset	CMT, hereditary neuropathy	GBS, toxic, drug-induced
Relapsing and remitting	CIDP, porphyria	Purely axonal toxic neuropathy

6. Evidence of a Hereditary Neuropathy

Ask: "Anyone else in the family with similar problems? Any foot deformities since childhood?"

Positive family history + high-arched feet (pes cavus) + hammer toes + scoliosis + slow progression over years + significant signs but few symptoms = Charcot-Marie-Tooth (CMT) or other hereditary neuropathy
Key clue: Lack of sensory symptoms despite significant sensory signs on examination (patients adapt over time and do not notice what they never had)

Rules out: Acquired neuropathies (diabetic, toxic, inflammatory) when there is clear multigenerational family history with childhood onset.

7. Associated Medical Conditions - Systematic Enquiry

This is the most critical aetiological screen. Ask directly about:

System	Specific Questions	Neuropathy Implicated
Metabolic	Diabetes, glucose intolerance, hypothyroidism, uraemia, liver disease	Diabetic poly-neuropathy, uraemic neuropathy
Nutritional	Alcohol use, gastric bypass, dietary habits, B12/folate intake	Alcoholic neuropathy, B12 deficiency neuropathy
Medications/toxins	Chemotherapy (cisplatin, vincristine, paclitaxel), isoniazid, metronidazole, nitrofurantoin, over-the-counter B6, statins, thalidomide, heavy metals	Drug-induced neuropathy
Malignancy	Weight loss, night sweats, haematological symptoms	Paraneoplastic sensory neuronopathy, paraproteinaemic neuropathy
Infection	HIV risk factors, Lyme disease tick exposure, leprosy exposure, recent GI illness (GBS)	HIV neuropathy, Lyme, leprous neuropathy, GBS
Autoimmune/connective tissue	Rheumatoid arthritis, SLE, Sjögren's (dry eyes/mouth), sarcoidosis	Vasculitic neuropathy, Sjögren's sensory neuronopathy
Family history	As above (Question 6)	Hereditary neuropathies
Preceding events	Recent infection, vaccination, surgery (for GBS); denture fixatives (zinc toxicity causing copper deficiency)	GBS, toxic neuropathy

C. Past Medical and Drug History

List all medications with doses and duration
Note specifically: chemotherapy agents, antibiotics (metronidazole, nitrofurantoin), anti-TB drugs (isoniazid), antiretrovirals
Alcohol consumption in units/week over how many years

D. Social and Occupational History

Occupation (toxic exposures: lead, arsenic, acrylamide, organic solvents)
Dietary habits, vegetarianism (B12 risk)
Travel history (leprosy endemic area, Lyme-endemic region)

E. Family History

Any family member with neuropathy, foot deformities, walking problems, or undiagnosed neurological disease

PART 2 - CLINICAL EXAMINATION

The neurological examination of peripheral neuropathy is structured around the same seven questions - you are now looking for the objective correlates of what the patient described.

A. General Inspection Before Formal Examination

Look for clues at a glance:

Observation	Suggests
High-arched feet (pes cavus), hammer toes	Hereditary neuropathy (CMT)
Wasting of intrinsic hand/foot muscles	Chronic motor neuropathy
Foot drop gait (steppage gait)	Peroneal neuropathy or distal motor polyneuropathy
Skin changes: thickened, hypopigmented patches	Leprosy
Enlarged superficial nerves (e.g., great auricular nerve, ulnar at elbow)	Leprosy, CMT, CIDP, amyloid
Skin trophic changes, ulcers, Charcot joints	Severe sensory loss (diabetic, amyloid, hereditary sensory neuropathy)
Cushingoid features, signs of systemic disease	Secondary neuropathy (DM, amyloid, paraneoplastic)
Postural tremor of hands	CMT (Roussy-Levy variant)

B. Motor Examination

Tone: Typically reduced (hypotonia) in peripheral neuropathy; spasticity rules in a central cause or combined central + peripheral lesion
Power (MRC grading, 0-5):
- Test distally first: toe extensors/flexors, ankle dorsiflexion/plantarflexion, hand intrinsics, wrist extensors/flexors
- Then proximally: hip flexion/extension, knee flexion/extension, shoulder abduction
- Distal > proximal weakness = typical polyneuropathy
- Proximal = distal weakness = GBS or CIDP
Wasting: Assess thenar/hypothenar eminences, dorsal interossei, peroneal compartment, tibialis anterior

Motor examination ruling out:

Motor Finding	Suggests	Rules Out
Distal weakness + wasting, normal proximal power	Length-dependent polyneuropathy	GBS, CIDP, myopathy
Proximal + distal weakness equally	GBS, CIDP	Distal toxic/metabolic neuropathy
Focal weakness (one nerve territory)	Mononeuropathy (e.g., foot drop = peroneal nerve palsy)	Generalised polyneuropathy
Normal power throughout	Small-fiber neuropathy, early polyneuropathy	Motor neuropathy, ALS

C. Sensory Examination

Test all modalities carefully and document the boundary of deficit:

Light touch (cotton wool) - tests large myelinated fibres
Pin-prick (sharp vs. blunt) - tests small myelinated (A-delta) fibres; loss in small-fiber neuropathy
Temperature (warm vs. cold tuning fork or test tubes) - tests small unmyelinated fibres (C fibres)
Vibration (128 Hz tuning fork) - tests large myelinated fibres; start distally (great toe) and move proximally
Proprioception (joint position sense) - tests large myelinated fibres; test great toe first, then ankles, knees
Romberg's test: Stand with feet together, eyes open then closed; positive (fall with eyes closed) = proprioceptive loss

Pattern of sensory loss:

Sensory Examination Finding	Suggests	Rules Out
Pin-prick + temperature loss, vibration preserved, normal reflexes	Small-fiber neuropathy (DM, amyloid, idiopathic)	Large-fiber neuropathy, central lesion
Vibration + proprioception loss, positive Romberg	Large-fiber neuropathy; also posterior column disease	Small-fiber neuropathy alone
Stocking-glove pattern (distal-symmetric)	Polyneuropathy (length-dependent: DM, toxic, alcohol, B12)	Mononeuropathy, radiculopathy, CNS lesion
Dermatomal pattern (one/two nerve roots)	Radiculopathy	Generalised polyneuropathy
Single nerve territory (e.g., median nerve distribution)	Mononeuropathy (carpal tunnel)	Polyneuropathy
Asymmetric, patchy, non-dermatomal	Mononeuropathy multiplex (vasculitis, leprosy, DM)	Symmetric polyneuropathy

D. Reflexes

Peripheral neuropathy typically reduces or abolishes deep tendon reflexes (DTRs) in affected areas:

Ankle jerks lost first in distal length-dependent polyneuropathy
All DTRs lost or very reduced in GBS or CIDP
Brisk reflexes rule against pure peripheral neuropathy and suggest UMN pathology or concurrent CNS disease (e.g., subacute combined degeneration of the cord from B12 deficiency where cord + peripheral nerve are both affected)
Plantar response: Should be flexor (downgoing) in pure peripheral neuropathy; extensor (upgoing Babinski) indicates UMN involvement

Reflex examination ruling out:

Reflex Finding	Suggests	Rules Out
Absent ankle jerks, reduced knee jerks	Distal polyneuropathy	CNS-only lesion (would have normal or brisk ankle jerks)
Globally absent reflexes	GBS (especially with acute onset), CIDP	Focal mononeuropathy
Brisk reflexes + sensory loss	Combined system degeneration (B12, copper deficiency), early GBS (may have preserved reflexes), syringomyelia	Pure peripheral neuropathy
Normal reflexes throughout	Early or small-fiber neuropathy	Advanced polyneuropathy

E. Autonomic Examination

Lying and standing blood pressure: Orthostatic hypotension (fall >20/10 mmHg) without compensatory tachycardia = autonomic neuropathy; particularly in DM, amyloid
Skin: Anhidrosis or hyperhidrosis of distal extremities
Trophic changes: Dry skin, hair loss on legs, trophic ulcers

F. Special Examination Points for Differential Diagnosis

Examination Finding	Specific Diagnosis to Confirm
Palpably thickened peripheral nerves	Leprosy, CMT, CIDP, neurofibromatosis
Pes cavus + hammer toes + distal wasting	CMT (hereditary neuropathy)
Loss of pain + temperature in saddle distribution	Cauda equina lesion - not a peripheral neuropathy
Asymmetric proprioceptive loss, arms affected	Sensory neuronopathy (ganglionopathy) - paraneoplastic, Sjögren's
Bilateral facial weakness	GBS (facial diplegia), CIDP, sarcoid
Cranial nerve involvement + distal neuropathy	GBS, CMV radiculitis, sarcoid, vasculitis
Skin: hypopigmented anaesthetic patches + nerve thickening	Leprosy
Postural tremor with polyneuropathy	CMT Roussy-Levy type, IgM paraprotein neuropathy
Hepatosplenomegaly + neuropathy	Amyloidosis, vasculitis, lymphoma, sarcoidosis

Summary: Pattern Recognition Table (Harrison's 22e - Table 457-2)

Pattern	Key Features	Primary Differential
1	Symmetric proximal + distal weakness + sensory loss	GBS (acute), CIDP (chronic)
2	Symmetric distal sensory loss ± distal weakness	Diabetic, toxic, cryptogenic (CSPN), B12 deficiency
3	Asymmetric distal weakness + sensory loss (multiple nerves)	Vasculitis, cryoglobulinaemia, amyloid, leprosy, Lyme, HNPP
4	Asymmetric proximal + distal weakness + sensory loss	Diabetic polyradiculopathy, meningeal carcinomatosis, sarcoid
5	Asymmetric distal weakness, no sensory loss	Motor neuron disease, multifocal motor neuropathy
6	Symmetric sensory loss + distal areflexia + UMN signs	B12/copper deficiency combined system degeneration, HIV
7	Symmetric weakness without sensory loss	Spinal muscular atrophy (SMA), CMT variants
9	Asymmetric proprioceptive loss, no weakness	Sensory neuronopathy (paraneoplastic, Sjögren's, CANVAS, cisplatin)
10	Prominent autonomic features	Amyloidosis, DM, hereditary sensory-autonomic neuropathy, GBS

Quick Template for Writing the Case History

PRESENTING COMPLAINTS
1. [e.g., Tingling and numbness in both feet x 6 months]
2. [e.g., Burning pain in feet, worse at night x 4 months]
3. [e.g., Weakness of both feet, difficulty walking x 2 months]

HISTORY OF PRESENTING COMPLAINTS
- Onset, duration, progression
- Distribution (symmetric/asymmetric, distal/proximal)
- Sensory character (burning = small fiber; vibration/balance = large fiber)
- Motor involvement (distal vs. proximal)
- Autonomic features (postural dizziness, sweating, bladder, bowel)
- Temporal course (acute/subacute/chronic/relapsing)
- Aggravating/relieving factors

DIFFERENTIAL DIAGNOSIS SCREEN (from history):
[Document which diagnoses are supported and which are excluded at each step]

PAST MEDICAL HISTORY
DRUG AND TOXIN HISTORY
ALCOHOL AND NUTRITIONAL HISTORY
FAMILY HISTORY (neuropathy, foot deformities)
SOCIAL/OCCUPATIONAL HISTORY (toxic exposures)

CLINICAL EXAMINATION
General: gait, foot deformity, skin, enlarged nerves
Motor: tone, power (MRC), wasting
Sensory: all modalities + pattern mapping
Reflexes: DTRs + plantars
Autonomic: lying/standing BP, skin changes
Cranial nerves if applicable

DIFFERENTIAL DIAGNOSIS AFTER EXAMINATION:
[Update and refine the differential based on examination findings]

Sources:

Harrison's Principles of Internal Medicine, 22nd Edition, Chapter 457 (Approach to Peripheral Neuropathy) - "Seven Key Questions" framework, Tables 457-1 and 457-2, Figure 457-1
Textbook of Family Medicine, 9th Edition, Chapter 41 - classification and laboratory evaluation of peripheral neuropathy

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Peripheral Neuropathy DDx

Presentation · PPTX

What's Inside (19 Slides)

The presentation uses a navy / teal / gold colour scheme with colour-coded "Rule In" (green) and "Rule Out" (red) panels throughout.

Slide	Content
1	Title slide
2	The Clinical Framework - 3 Goals + 7 Key History Questions
3	Section divider - Pattern Recognition
4	Patterns 1 & 2 - Symmetric polyneuropathy (GBS/CIDP vs. metabolic)
5	Patterns 3 & 4 - Asymmetric (mononeuropathy multiplex, plexopathy)
6	Patterns 5, 6 & 7 - Motor-predominant & combined system degeneration
7	Patterns 9 & 10 - Sensory neuronopathy & autonomic neuropathy
8	Section divider - Specific Diagnoses
9	GBS - Rule In / Rule Out / Key Tests (3-column dark layout)
10	CIDP - same 3-column format
11	Diabetic Peripheral Neuropathy
12	Vasculitic Neuropathy (Mononeuropathy Multiplex)
13	Charcot-Marie-Tooth Disease (Hereditary)
14	Vitamin B12 Deficiency / Combined System Degeneration
15	Master Differential Comparison Table (all diagnoses side-by-side)
16	Small-Fiber vs Large-Fiber Neuropathy - critical distinction
17	Temporal Evolution as a Diagnostic Filter (table: acute / subacute / chronic / relapsing)
18	Investigation Strategy - Tier 1, 2, and 3 tests
19	Take-Home Summary - 7 clinical pearls

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Peripheral Neuropathy: Differential Diagnosis Patterns & How to Rule Out Each Diagnosis

Based on Harrison's Principles of Internal Medicine, 22nd Ed.

THE CLINICAL FRAMEWORK

Three Goals when approaching a patient with suspected neuropathy:

Localise the lesion
Identify the cause
Determine treatment

Seven Key History Questions:

Q1: What systems are involved? (Motor / Sensory / Autonomic)
Q2: What is the distribution of weakness?
Q3: What is the nature of sensory involvement?
Q4: Is there upper motor neuron (UMN) involvement?
Q5: What is the temporal evolution? (Acute / Subacute / Chronic)
Q6: Is there evidence of a hereditary neuropathy?
Q7: Are there associated medical conditions?

PART A - PATTERN RECOGNITION

Pattern 1 - Symmetric Proximal + Distal Weakness + Sensory Loss

Clinical picture: Weakness affects both proximal and distal muscles equally. Areflexia. Ascending paralysis (GBS). Chronic relapsing form (CIDP). Sensory loss variable.

Rules In:

Symmetric proximal + distal weakness
Onset days to weeks (GBS) or months (CIDP)
Cytoalbuminous dissociation in CSF
Demyelinating NCS: slow velocity, prolonged latency
Preceding GI or respiratory illness (GBS)

Rules Out:

Asymmetric or distal-only weakness - NOT GBS/CIDP
Length-dependent distribution - NOT GBS/CIDP
Normal NCS - NOT demyelinating
Genetic or childhood onset - NOT acquired CIDP

Pattern 2 - Symmetric Distal Sensory Loss ± Distal Weakness

Clinical picture: Classic stocking-glove pattern. Distal > proximal. Feet affected before hands (length-dependent). Insidious onset.

Rules In:

Stocking-glove sensory loss
Ankle jerks lost first
Slow, progressive course
Diabetes or glucose intolerance on history
Alcohol, B12 deficiency, toxic exposure
Axonal NCS: reduced amplitude, preserved velocity

Rules Out:

Asymmetric distribution - NOT metabolic polyneuropathy
Proximal > distal weakness - NOT length-dependent
Acute onset - NOT diabetic or toxic (consider GBS)
UMN signs present - NOT pure peripheral neuropathy

Pattern 3 - Asymmetric Distal Weakness + Sensory Loss (Multiple Nerves)

Clinical picture: Multiple nerves individually affected (mononeuropathy multiplex). Involvement is patchy, asymmetric, non-contiguous. Often painful.

Rules In:

Non-contiguous, asymmetric nerve deficits
Constitutional symptoms (vasculitis, malignancy)
Elevated ESR, ANCA, cryoglobulins
Skin lesions: leprosy, vasculitis, sarcoid
Tick bite history: Lyme neuropathy
Hepatitis B or C serology positive

Rules Out:

Symmetric stocking-glove - NOT mononeuropathy multiplex
No systemic illness - vasculitis less likely
Slow hereditary pattern - NOT vasculitis
Single nerve territory only - mononeuropathy, not multiplex

Pattern 4 - Asymmetric Proximal + Distal Weakness + Sensory Loss

Clinical picture: Radiculopathy or plexopathy pattern. Painful, asymmetric. Common in diabetic amyotrophy (Bruns-Garland syndrome). Thigh pain and weakness.

Rules In:

Proximal limb pain and weakness asymmetrically
Diabetes mellitus on history
MRI showing plexopathy or leptomeningeal enhancement
CSF with elevated protein and cells: carcinomatosis
Sarcoidosis: serum ACE elevated

Rules Out:

Symmetric pattern - NOT plexopathy
No diabetes or malignancy - reconsider
Pure distal distribution - NOT plexopathy
Normal MRI and CSF - unlikely carcinomatosis

Pattern 5 - Asymmetric Distal Weakness WITHOUT Sensory Loss

Clinical picture: Focal or multifocal motor weakness, no sensory deficit. Differential includes motor neuron disease (ALS) vs. treatable multifocal motor neuropathy (MMN).

Rules In (Multifocal Motor Neuropathy):

Anti-GM1 antibodies positive
Conduction block on NCS
No UMN signs
Responds to IVIg

Rules Out ALS:

No conduction block found: consider ALS
UMN signs present: ALS, not MMN
Sensory loss present: NOT pure motor neuropathy

Pattern 6 - Symmetric Sensory Loss + Distal Areflexia + UMN Signs

Clinical picture: Combined central and peripheral disease. Spastic legs + sensory loss + absent ankle jerks. B12 deficiency is the most common cause.

Rules In:

Low serum B12 or elevated MMA + homocysteine
Low serum copper
HIV with myelopathy and neuropathy
Adrenomyeloneuropathy (VLCFA elevated)
MRI: T2 signal in posterior and lateral columns

Rules Out pure peripheral neuropathy:

UMN signs (hyperreflexia, Babinski): NOT pure peripheral neuropathy
Normal B12 and copper: consider HIV, adrenomyeloneuropathy

Pattern 7 - Symmetric Weakness WITHOUT Sensory Loss

Clinical picture: Pure motor weakness, symmetric, with no sensory symptoms. Suggests anterior horn cell disease (SMA) or hereditary motor neuropathy.

Rules In:

Positive family history
SMN1 gene deletion: SMA
Proximal + distal: SMA
Distal only: distal SMA or CMT variant
No sensory deficit on formal testing

Rules Out:

Any sensory loss: NOT pure motor neuropathy
UMN signs: motor neuron disease, NOT SMA

Pattern 9 - Asymmetric Proprioceptive Loss WITHOUT Weakness

Clinical picture: Sensory ataxia, pseudoathetosis. Proprioception and vibration severely impaired. Arms may be equally or more affected than legs (non-length-dependent). Positive Romberg.

Rules In (Sensory Neuronopathy / Ganglionopathy):

Arms affected as much as or more than legs
Anti-Hu antibodies: paraneoplastic (lung cancer)
Sjögren's: anti-Ro/La, dry eyes and mouth
Cisplatin chemotherapy history
CANVAS: cerebellar ataxia + vestibular loss
B6 toxicity (>200 mg/day)

Rules Out:

Symmetric stocking-glove: NOT ganglionopathy
Distal > proximal loss: length-dependent, NOT sensory neuronopathy
Normal anti-Hu, no cancer: paraneoplastic less likely
No Sjögren's features: reconsider cause

Pattern 10 - Prominent Autonomic Features

Clinical picture: Orthostatic hypotension, anhidrosis, erectile dysfunction, gastroparesis, bladder dysfunction, cardiac arrhythmia. Distal sensory loss may coexist.

Rules In:

Orthostatic hypotension WITHOUT compensatory tachycardia
Diabetes mellitus on history (most common)
Congo red staining on biopsy: amyloidosis
Porphyria: elevated urine porphyrins
Vincristine or chemotherapy history
Hereditary sensory and autonomic neuropathy (HSAN): childhood onset

Rules Out:

No diabetes and no amyloid: look for porphyria, GBS, vincristine
Only postural symptoms without sensory or motor features: consider primary dysautonomia, not neuropathy
Normal sweat tests and normal BP: NOT significant autonomic neuropathy

PART B - SPECIFIC DIAGNOSES

Guillain-Barré Syndrome (GBS)

Rule In:

Ascending flaccid paralysis, days to 4 weeks
Preceding GI or respiratory illness (1-4 weeks prior)
Areflexia - globally absent DTRs
Cytoalbuminous dissociation in CSF (protein up, cells normal)
Demyelinating NCS: prolonged latency, slow velocity
Bilateral facial weakness (facial diplegia)
Autonomic instability: tachycardia, BP lability

Rule Out:

Asymmetric or purely focal weakness
Gradual onset > 8 weeks: CIDP, not GBS
Persistent hyperreflexia: NOT GBS
Fever + CSF pleocytosis: meningitis or encephalitis
Bladder and bowel symptoms at onset: myelopathy first
Pure sensory without motor: NOT classic GBS

Key Tests:

CSF: albuminocytologic dissociation
NCS/EMG: demyelinating or axonal pattern
Anti-ganglioside antibodies (anti-GM1, anti-GQ1b)
Anti-GQ1b: Miller-Fisher variant
MRI spine to exclude cord compression
Respiratory function: FVC - ICU if <20 mL/kg

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

Rule In:

Symmetric proximal + distal weakness > 8 weeks
Sensory loss with reduced reflexes
Relapsing-remitting or chronic progressive course
Elevated CSF protein (no pleocytosis)
Markedly slow NCS: demyelinating features
Responds to IVIg, corticosteroids, or plasmapheresis

Rule Out:

Onset and peak < 4 weeks: GBS, not CIDP
Axonal NCS: NOT primary demyelinating
Strong family history + genetic test positive: CMT, not CIDP
No response to immunotherapy: reconsider diagnosis
Concurrent paraprotein: consider POEMS or anti-MAG neuropathy
Pure motor with no sensory: MMN, not CIDP

Key Tests:

NCS/EMG: prolonged distal latency, conduction block
CSF: raised protein, normal cell count
Serum protein electrophoresis (paraprotein screen)
Anti-MAG antibodies if IgM paraprotein
POEMS screen: VEGF, bone survey
Nerve biopsy: onion-bulb formation if uncertain
IVIg trial: response confirms diagnosis

Diabetic Peripheral Neuropathy

Rule In:

Known DM or impaired fasting glucose
Stocking-glove pattern, feet >> hands
Burning feet worse at night (small fiber)
Absent ankle jerks
Autonomic features: impotence, gastroparesis, orthostasis
Axonal NCS: low amplitude, normal velocity
Trophic changes: ulcers, Charcot joint
HbA1c consistently >7%

Rule Out:

Normal blood glucose and HbA1c: other aetiology
Asymmetric distribution: vasculitis or mononeuropathy multiplex
Acute or subacute onset: NOT typical diabetic neuropathy
Proximal > distal weakness: consider diabetic amyotrophy (Pattern 4)
Demyelinating NCS: CIDP, not diabetic
B12 or thyroid deficiency found: correct these first
Alcohol > 14 units/week: alcoholic neuropathy

Key Tests:

Fasting glucose + HbA1c
OGTT if fasting normal (glucose intolerance)
NCS/EMG: axonal sensorimotor
Serum B12, folate, TSH
Skin punch biopsy: reduced IENFD (small fiber)
Ankle-brachial index (peripheral arterial disease)

Vasculitic Neuropathy (Mononeuropathy Multiplex)

Rule In:

Asymmetric, painful, stepwise nerve deficits
Constitutional: fever, weight loss, malaise
Elevated ESR, CRP
ANCA positive (p-ANCA, c-ANCA)
Cryoglobulins + hepatitis C positive
Skin: purpura, livedo reticularis, ulcers
Nerve biopsy: perivascular inflammation + axonal loss

Rule Out:

Symmetric stocking-glove: NOT vasculitis
Normal ESR, CRP, ANCA: vasculitis less likely
No systemic illness: consider DM or leprosy
Demyelinating NCS: NOT vasculitic (vasculitis is axonal)
Single nerve territory only: compressive mononeuropathy
No constitutional symptoms: low probability

Key Tests:

ESR, CRP, CBC
ANCA (anti-PR3 + anti-MPO)
Cryoglobulins + hepatitis B/C serology
ANA, anti-dsDNA, rheumatoid factor
Nerve + muscle biopsy (gold standard)
NCS: multifocal axonal involvement
CT chest/abdomen (lymphoma, carcinoma)

Charcot-Marie-Tooth Disease (Hereditary Motor and Sensory Neuropathy)

Rule In:

Family history of neuropathy (multigenerational)
Childhood or adolescent onset
Pes cavus (high-arched feet), hammer toes, scoliosis
Distal > proximal wasting ("inverted champagne bottle" legs)
Significant sensory signs with few sensory symptoms (patients have adapted)
Demyelinating (CMT1) or axonal (CMT2) on NCS
PMP22 duplication (CMT1A) on genetic testing

Rule Out:

No family history: acquired neuropathy first
Acute or subacute onset: GBS, toxic
Age > 50 at first presentation: less likely CMT
Inflammatory markers elevated: vasculitis
Responds to IVIg: CIDP, not CMT
Relapsing course: CIDP, porphyria

Key Tests:

NCS/EMG: slowed velocity < 38 m/s (CMT1)
Genetic panel: PMP22, MFN2, GJB1, MPZ
Family neurological examination
Electrophysiology of parents and siblings
Nerve biopsy: onion-bulb formation (CMT1)
X-ray feet: pes cavus confirmation
Genetic counselling recommended

Vitamin B12 Deficiency - Combined System Degeneration

Rule In:

Symmetric distal sensory loss + absent ankle jerks
UMN signs: brisk knee jerks, Babinski positive
Subacute combined degeneration of cord on MRI
Macrocytic anaemia (MCV > 100)
Low serum B12 < 200 pg/mL
Elevated serum MMA + homocysteine
Veganism, pernicious anaemia, gastric bypass history
Glossitis, angular stomatitis

Rule Out:

Normal B12: consider copper deficiency, HIV, adrenomyeloneuropathy
Pure peripheral signs, no UMN: not combined system degeneration
Normal MMA + homocysteine: functional B12 sufficient
No macrocytic anaemia: B12 less likely (but not impossible)
Responds to glucose control alone: DM neuropathy, not B12

Key Tests:

Serum B12 (low sensitivity alone - use MMA + homocysteine)
Serum methylmalonic acid (MMA)
Serum total homocysteine
Serum copper + ceruloplasmin
MRI spine: T2 hyperintensity in posterior columns
NCS: axonal sensorimotor neuropathy
Anti-intrinsic factor antibodies (pernicious anaemia)
VLCFA if adrenomyeloneuropathy suspected

SMALL-FIBER vs LARGE-FIBER NEUROPATHY

This distinction is critical because NCS is normal in small-fiber neuropathy.

Small-Fiber Neuropathy

Fibres: C fibres (unmyelinated) + A-delta (small myelinated)
Symptoms: Burning, stabbing, dysaesthetic pain; allodynia; worse at night; loss of pain and temperature sensation
Examination: Normal strength, normal reflexes, normal vibration and proprioception, impaired pinprick and temperature
NCS: NORMAL - large-fiber tests only; NCS misses small-fiber disease entirely
Causes: Diabetes or glucose intolerance (most common), amyloidosis, Fabry disease, idiopathic (50%), HIV, sarcoidosis
Confirmatory test: Skin punch biopsy - reduced intra-epidermal nerve fiber density (IENFD); QSART for autonomic involvement

Large-Fiber Neuropathy

Fibres: A-alpha and A-beta (large myelinated)
Symptoms: Numbness, imbalance, gait ataxia, positive Romberg; less pain
Examination: Reduced vibration, impaired proprioception, absent ankle jerks, sensory ataxia, positive Romberg
NCS: ABNORMAL - reduced SNAP amplitudes; slowed velocity if demyelinating
Causes: B12 deficiency, CIDP, GBS, CMT, paraneoplastic sensory neuronopathy, advanced diabetes, toxic (cisplatin, taxanes)
Confirmatory test: NCS (SNAP + CMAP amplitude and velocity); nerve biopsy if needed

TEMPORAL EVOLUTION AS A DIAGNOSTIC FILTER

Timeframe	Duration	Diagnoses to Consider	Diagnoses Ruled Out
Acute	Days to 4 weeks	GBS, vasculitis, porphyria, diphtheria, ischaemia, thallium toxicity, acute compression	CIDP, CMT, diabetic polyneuropathy, alcoholic neuropathy
Subacute	4 to 8 weeks	Most toxins, drug-induced, nutritional deficiency, uraemia, diabetic plexopathy, neoplasm-related	GBS (too slow), CMT, pure metabolic polyneuropathy
Chronic	Months to years	CIDP, diabetic polyneuropathy, CMT, alcohol, hypothyroid, B12 deficiency, paraprotein neuropathy	GBS (unless very atypical), acute toxic, acute vasculitis
Relapsing	Episodic worsening	CIDP, porphyria, Refsum disease, HIV, GBS (rare relapse), HNPP	Simple metabolic or toxic neuropathy

MASTER DIFFERENTIAL COMPARISON

Diagnosis	Onset	Pattern	Key Feature to Rule In	Key Feature to Rule Out
GBS	Acute (days-4w)	Symmetric proximal+distal	Ascending paralysis + cytoalbuminous dissociation	Gradual >8w, asymmetric, normal CSF
CIDP	Chronic (>8w)	Symmetric proximal+distal	Demyelinating NCS + IVIg response	Family history, onset <4 weeks
Diabetic polyneuropathy	Gradual	Distal symmetric	Known DM, stocking-glove, HbA1c elevated	Asymmetric, acute, demyelinating NCS
Vasculitic	Subacute, stepwise	Asymmetric multiplex	Constitutional symptoms, elevated ESR/ANCA	Symmetric, no systemic illness
CMT (hereditary)	Childhood	Distal motor+sensory	Pes cavus, family history, signs > symptoms	Acute onset, no family history, responds to treatment
B12 deficiency	Subacute	Distal + UMN signs	Brisk knee jerks + absent ankle jerks + low B12/MMA	No UMN signs, normal MMA + homocysteine
Sensory neuronopathy	Variable	Asymmetric, non-length-dep	Arms >= legs, anti-Hu, Sjögren's features	Stocking-glove symmetric pattern
Leprous neuropathy	Chronic	Asymmetric + nerve thickening	Enlarged nerves, hypopigmented anaesthetic patches	Temperate climate, no skin lesions
Toxic or drug-induced	Subacute	Distal symmetric axonal	Chemotherapy / isoniazid / alcohol exposure	No toxic history, demyelinating features

INVESTIGATION STRATEGY - TIER-BASED APPROACH

Tier 1 - All Patients

Fasting glucose + HbA1c
Serum B12 + folate
TSH (thyroid function)
Full blood count + ESR/CRP
Serum urea, creatinine, electrolytes
Liver function tests
Serum protein electrophoresis
NCS and EMG (electrophysiology)

Tier 2 - If Tier 1 Negative

Methylmalonic acid + homocysteine
Serum copper + ceruloplasmin
OGTT (if fasting glucose normal)
ANA, ANCA, anti-dsDNA, rheumatoid factor
Cryoglobulins + hepatitis B/C serology
HIV serology
Anti-Hu, anti-Ro antibodies (paraneoplastic, Sjögren's)
VDRL / Lyme serology if exposure history

Tier 3 - Specialist Tests

Skin punch biopsy (IENFD - small-fiber neuropathy)
Nerve biopsy (vasculitis, amyloid, CMT)
Autonomic testing (QSART, tilt table test)
MRI spine and brain
CSF analysis (protein, cells, cytology)
Genetic panel (PMP22, MFN2, GJB1, MPZ)
Anti-GM1, anti-VGCC antibodies
Urine porphyrins (porphyria screen)

TAKE-HOME SUMMARY

Pattern first: Localise the lesion before investigating. Is it symmetric or asymmetric? Distal or proximal? Motor, sensory, or both?
Temporal clue: Acute = GBS or vasculitis. Subacute = toxic or nutritional. Chronic = DM, CMT, or CIDP. Relapsing = CIDP or porphyria.
Small vs large fiber: Normal NCS does NOT exclude neuropathy. Small-fiber disease needs skin biopsy (IENFD).
UMN alert: Brisk reflexes + sensory loss = combined system degeneration. Check B12, copper, HIV, MRI spine.
Hereditary clue: Pes cavus + family history + signs > symptoms + childhood onset = hereditary neuropathy. Check genetics.
Treat the treatable: GBS and CIDP (IVIg), vasculitis (steroids and cyclophosphamide), B12 deficiency (replacement). Diagnose early.
Half are idiopathic: Approximately 50% of sensory polyneuropathies have no aetiology found despite full workup (CSPN - cryptogenic sensory polyneuropathy). This is a diagnosis of exclusion.

Sources: Harrison's Principles of Internal Medicine, 22nd Edition (Chapter 457) | Textbook of Family Medicine, 9th Edition (Chapter 41)

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