NCS/EMG categorization: sensorimotor, sensory, motor, axonal, demyelinating

Clinical categorization: Acute/insidious, (non)length dependent, mononeuropathy multiplex

General sensorimotor axonal:

• 1^st pass: CBC, lytes, BUN/Cr, LFTs, B12, SPEP/UPEP, TSH, OGTT, ESR, ANA, Lipds, Vit D???
  • Note: some suggestion that isolated high TG associated with axonal polyneuropathy
  • Also TGemia noted to make DM and HIV neuropathy worse.
• 2^nd pass: MMA, lactate, celiac, immune(RF, ENA, CRP, ANCA, cryoglobulins), ACE/CXR
• Directed by history:  HIV, leprosy, lyme, B1, folate, acromegaly

Disorder	Features	Labs
B12 def (N20 toxicity. Affects b12 toxicity. Presents and treated as b12 deficiency. Case of latent motor neuropathy)		B12, methylmalonic acid elevated, folate
B1, B6 (sensory predominant)		Ask about diet B6(EtOH, isoniazid, hydralazine, penicillamine)
**asymmetric sensory neuropathy with thiamine deficiency in patient on gluten free diet
Folate deficiency	Severe malnutrition	RBC Folate
MGUS -if<1.5g/L likely MGUS -if>4 g/L likely multiple myeloma àskeletal survey for POEMS/osteosclerotic lesion, cryoglobulins, beta2-microglobulin, bone scan, bone marrow biopsy		SPEP, UPEP, immunofixation (F/U w/ skeletal survey, BMA)
Mitochondrial		Lactate, U Org.Acids, P. Amino Acids
Hypothyroid		TSH
Coeliac		Transglutaminase, antigliadin
Diabetes, IGT		OGTT
Vasculitic, Immune		ANA, RF, ENA, CRP/ESR, ANCA, cryoglobulins
Infectious -HIV -LYME -Leprosy(hypopig. Skin lesions)     -HTLV1	-Blood RF -tick bites -s. Southeast Asia, India, Africa, and Central and South America -carribean(usually with myelo)
Sarcoid		ACE, CXR
Copper deficiency	Zn supp, chelators, prox jej/gastric	Cu ceruloplasmin

?? Vitamin D felt to possibly influence DPN development:

Serum 25-hydroxyvitamin D levels and peripheral neuropathy in patients with type 2 diabetes: a systematic review and meta-analysis

*B12 deficiency linked to taking levodopa (beware parkinsons patients)

*B12 deficiency linked with metformin in diabetics

*Nienov et al 2017. Low HDL in metabolic syndrome (without diabetes) associated with polyneuropathy. BMI35+

*Nitrous oxide (illicit use) causes functional B12 deficiency – detect by elevated folate/MMA (B12 is normal)

*Abraham 2017. Uric acid levels associated with severity of dpn. Bril 2017; Urate associated with poor nerve health in obese normal.

Small Fiber Neuropathy:

• Idiopathic
• Diabetes: OGTT
• MCTD: the usual
• Ferritin (Hereditary hemochromatosis (PMID 20358215)
• B12(less so), B1??
• SPEP/UPEP – amyloidosis, IgM M protein
• HIV, HBV/HCV
• LYME??
• Celiac
• sjogren – ssa/ssb, schirmers, lip bx
• amyloid – nerve/musce/rectum/abd fat pad bx
• sarcoid – ace/cxr (African, Scandinavian)
• Autoimmune/vasculitis (ANCA, ANA, etc)???
• Paraneoplastic (AntiHu, AntiCV2/CRMP5)
• Toxic: metronidazole/linezolid, nitrofurantoin, alcohol, solvents
• Tangiers:
  • Serum
    • Hypocholesterolemia
    • Reduced or absent High Density Lipoproteins
    • Triglycerides: High
• Fabry’s disease (alpha-galactosidase A)
  • De Greef et al 2016. 0/725 isolated SFN had Fabrys. Look for other Fabry end organ
  • Japan, Sweden, Portugal endemic
  • ●Intermittent episodes of severe pain in the extremities (acroparesthesias)
  • ●Cutaneous vascular lesions (angiokeratomas)
  • ●Diminished perspiration (hypohidrosis)
  • ●Left ventricular hypertrophy of unknown etiology in young adulthood
  • ●Stroke of unknown etiology in young adulthood
  • ●Chronic kidney disease (CKD) of unknown etiology in young adulthood
  •  
  • ●Multiple renal sinus cysts discovered incidentally
• Genetics: SCN9A, SCN10A, HSAN II, III, IV
• Fat pad biopsy: Amyloid (transthyretin)

Chagas?? Case report

Amyloid: malaise, CKD, cardiomegealy, hepatomegaly

Transthyretin Amyloidosis:

Endemic in: Sweden, Portugal, East asia(Japan, China, Korea)

Adjuvant SFN testing:

1. intraepidermal nerve fiber density (IENFD). Skin biopsy samples are stained for protein growth product 9.5 (PGP 9.5, a pan-axonal antigen)
2. Corneal Confocal Microscopy – counting nerves in cornea

Pure Sensory Neuropathy:

Disorder	Features	Labs
Sjogrens		SSA, SSB, ANA
Anti-Hu/Purkinje	Paraneoplastic
B6 deficiency/toxicity (+/- motor)   B6(EtOH, isoniazid, hydralazine, penicillamine)	Acute; High dose (100 – 200 g) Chronic (0.2 – 10 g/day) -isoniazid/hydralazine, GI, chronic P.dialysis
B1(thiamine)
Toxic:	Platinum drugs, doxorubicin, etopside, taxol, nitrofurantoin
Vit E deficiency
Coeliac Disease
Anti-GD1b antibodies
Anti-Sulfatide Antibodies	GALOP Syndrome Demyelinating Mono IgM Axonal Poly IgM/IgG
Herpes zoster (localized)
Idiopathic	Pan-sensory/SFN
CIDP (Beware sensory mimic with proximal lesions)
Leprosy

Sensory Ganglionopathy

Disorder	Features	Labs
Sjogrens	50%seroneg. Lip salivary bx needed	SSA, SSB, ANA
Anti-Hu/Purkinje AntiCRMP5	Paraneoplastic
HIV/HTLV1
Chemotherapy
B6 deficiency/toxicity
GBS variant
EBV
Kennedys Disease (SBMA)	Not purely sensory though has those features on NCS
Leprosy
Mitochondrial SANDO	POLG mutation	Mito W/U
Coeliac
Anti Amphyphysin? Anti FGR3?
Assoc hepatits virus?

Treatments:

IVIg x 2 rounds

Steroids

Rituximab

MRI: increased signal dorsal columns

Malignancy screen:Ct chest/ABD/Pelvis; CEA/AFP/CA19-9/CA125; extra: transvag U/S, mammo, endoscopay

CIDP phenotype:

• Osteosclerotic multiple myeloma (SPEP,UPEP)
  • Vascular Endothelial Growth Factor(VEGF) if M protein confirmed and POEMS suspected.
• HIV, HTLV
  • Note AIDS with CMV is axonal polyradiculopathy
• Lyme disease
• Anti-MAG antibodies(if M protein with distal predominant slowing)
• MGUS(IgM M protein are usually causing immune mediated problems)
• Anti GD1b antibodies
• Chronic HCV/HBV
• CSF
  • Pleiocytosis – check for HIV, lyme, Sarcoid, lymphomatous meningitis
• sarcoid – ace/cxr
• connective tissue disease, inflammatory bowel disease
• MALIGNANCY: lymphoma, melanoma
• May be superimposed on multiple sclerosis
• Beware CMT-X which may demonstrate CB
• Syphilis (case report)

DDx of Demyelinating Polyneuropathies:

• Hereditary: CMT1, CMTX, HNPP
• Toxic: perhexilene(hexacarbons – sniffing), arsenic poisoning(24 HOUR URINE), amiodarone
• Infectious: Lyme disease, diphtheria(GBS phenotype)
• Amyloid
  • SPEP, UPEP
  • Nerve, rectum, fat pad biopsy
  • TTR(transthyretin genetic test)
• Mitochondrial(usually with ocular, not primary presentation)
  • MRI: leucoencephalopathy
  • Serum lactate
  • Urine thymidine, uridine

Vasculitis

Primary – polyarteritis nodosa (PAN), Wegener’s granulomatosis, Churg-Strauss syndrome, and microscopic polyangiitis

Secondary – rheumatoid arthritis (RA), systemic lupus erythematosis, and Sjogren’s syndrome

(SS), MCTD, type II cryoglobulinemic vasculitis associated with HCV, HIV, CMV, Sarcoidosis, nonsystemic vasculitic neuropathy (NSVN)

Other – diabetic lumbosacral radiculoplexus neuropathy (DLRPN or diabetic amyotrophy), nondiabetic lumbosacral radiculoplexus neuropathy (LRPN), and immune and inherited brachial plexus neuropathies (BPN) (or neuralgic amyotrophy and hereditary neuralgic amyotrophy).

Vasculitic work-up: CBC, metabolic panel (electrolytes, blood urea nitrogen, creatinine, and glucose), ESR, CRP, ANA, ENA, RF, PR3/c- ANCA and MPO/p-ANCA, HBV, HCV, cryoglobulins, ACE, SPEP/UPEP, HIV

-complement if suspected mixed cryoglobulinemia or SLE

Cerebrospinal fluid analysis is usually not helpful

Differential Diagnosis of Mononeuropathy Multiplex (or single nerves)

-Nerve infiltration may cause demyelination and CB

Demyelinating Neuropathies

• Multifocal Motor Neuropathy with Persistent Conduction Block
• Multifocal Sensorimotor Demyelinating Neuropathy with Persistent Conduction Block (Lewis-Sumner Syndrome) AKA MADSAM
• Hereditary Neuropathy with liability to Pressure Palsies

Vasculitic and Ischemic Neuropathies

• Systemic Lupus Erythematosis
• Rheumatoid Vasculitis
• Systemic sclerosis (Scleroderma)
• Periarteritis Nodosa
• Churg-Strauss
• Wegener’s Granulomatosis
• Paraneoplastic vasculitic neuropathy
• Nonsystemic vasculitic neuropathy
• Behçet Syndrome
• Giant Cell Arteritis
• Ischemia (thrombosed artery)

Diabetes mellitus

• Lumbosacral Radiculoplexopathy
• Truncal Radiculopathy
• Cranial Mononeuropathies
• Sensory Perineuritis

Infectious Neuropathies

• Leprosy (not vasculitis; direct infiltration) – hypopigmented lesions
• Herpes Zoster
• Lyme Disease
• EBV (brachial/LS plexus)
• HIV associated cytomegalovirus (axonal polyradiculopathy)
• Hepatitis C and cryoglobulinemia
• TB – granulomatous, hypopigmented lesions

Other causes

• Sarcoid (ACE, CXR(reticular change/hilar lymphadenopathy), ESR, RF, Ca/ALP)
  • Parotid swelling, systemic, sicca, jt pain/swelling
• Brachial Neuritis (Parsonage-Turner Syndrome)
• Monomelic Amyotrophy
• Malignant infiltration of peripheral nerve (leukemia/lymphoma)
• Neurofibromatosis
• Cryoglobulinemia (HCV, RA)
• Eosinophilic granulomatosis (CBC)
• Neuolymphomatosis (B/T/NK cells)
  • Increase CSF cells (can be normal)
  • Check for lymphadenopathy (CT chest/ABD, PET)
  • US/MRI with GAD, FNA of swollen nerve
  • Bx of rashes

Sjogrens PNS manifestations:

• Cranial neuropathy
• AIDP/CIDP
• SFN
• Sensorimotor Axonal Polyneuropathy
• Pure sensory neuropathy/ganglionopathy

Diabetes PNS manifestations:

• Distal symmetric polyneuropathy: may be SFN, axonal, classically mixed axonal/demyelinating
• DLSRPN
• Muscle infarct
• Cranial nerve infarct
• Insulin neuritis
• Truncal radiculopathy

Polyneuropathy Review of Systems:

• Travel history (Travel outside of North America in the last 5 years)
  • Carribean HTLV1
  • Leprosy ????
• Tick bites – Lyme
• Msoquito bites – WNV
• Blood borne RF (Tattoo, piercing, transfusion, STI)
  • HIV, HCV, HBV
• Restrictive diet history/gluten sensitivity :B1 (case), folate

FASCICULATIONS(Verminosis)

Drugs: steroids, neostigmine, tca, Li, isoniazid

Check thyroid, ca, po4, Hg, Vit D?

Benign:stress, fatigue, exercise, caffeine

Treat: treat sleep apnea, tegretol, Dilantin, gaba

BARIATRIC SURGERY

Cu, MMA/B12, B1, B6, E, Folate

(nutritional optic neuropathy)

CRAMPS:

Electrolytes

Anti-VGKC

AntiGAD

Anti-Amphiphysin

Episodic ataxia

Fabry disease

SCA3 (MachadoJoseph – Azores)

Statin

Foot drop

– External iliac thrombus causes sciatic neuropathy.

Essential tremor blood workup:

• Lytes, extended lytes, LFTs, RFTS, B12, TSH

Erythromelalgia: Primary (genetic) vs secondary

DDX: SCN9A, SCN10? (genetic), myeloproliferative (high plts, high RBC)

Secondary: Drugs (CCB, Bromocriptine), Rheum,

Tx: Meds: ; capsaicin, lumbar sympathetic blockade. If genetic: lidocaine, carbamazepine, mexilitine; ASA if myeloproliferative

Acute Weakness DDX:

DRUGS	FEATURES	EDX
AMIODARONE	OPTIC N. CB ataxia, ess. Tremor Vacuolar Myopathy	SM, S, M, may be rapid Ax/ demyelin
Bortezomib (Multiple myeloma)		Sensory axonal. Demyelinating
Chloroquine	(I)Myo Resp/CMO	SM Ax
Colchicine	(I)Myo	SM Ax
Dapsone		Distal M Ax
Disulfiram (antabuse)		S-M Ax
Ethambutol	Optic N.	S Ax
Isoniazid		SM Ax
Metronidazole	Recoverable CNS	S Ax, SFN
Nitrofurnatoin		GBS like Ax
Nitrous oxide (abuse)	Myeloneuropathy	SM Ax
d- drugs (HIV) d4T ddI Stavudine (d4T)Didanosine (ddI)Zalcitabine(ddC)	Painful distal (assoc myo?)	S Ax
Phenytoin		SMAx
B6	500mg/day	S Ax
Suramin (cancer/parasites)		SMAx
Tacrolimus		CIDP (rare)
Thalidomide	Cancer	S Ax
Tryptophan	Eosinophila-Myalgia Syndrome -rash, SOB, arthralgia, edema	SMAx, Dem, Dem&CB
VINCA alkyloids -vincristine et al.		S Ax