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Polyneuropathy Differential -  Outlines in Clinical Medicine on Physicians' Online 2001

Polyneuropathy Mnemonic "DANG THERAPIST"

• D diabetic
• A alcoholic
• N nutritional (Vitamins B6, B12)
• G Guillain-Barre syndrome
• T toxic (lead, arsenic, vinblastine, others)
• He hereditary
• R recurrent
• A amyloid
• P porphyria (motor involvement, intermittent)
• I infections (AIDS, mononucleosis, leprosy, diphtheria)
• S systemic (CVD, uremia, dysproteinemia)
• T tumor (paraneoplastic)

Peripheral Neuropathy

Etiologic Categorization:  Metabolic , Toxic , Immune Mediated , Vascular , Infectious , Heritable , Entrapment (compression)

Pathology of Peripheral Nerve Damage:
(Distal) Axonal Degeneration (usually toxic, vascular, metabolic) - dying back
Demyelination (usually immune/inflammatory)

Nerve Fiber Type Involvement :
Focal Neuropathies
Sensorimotor Polyneuropathy
Motor (predominantly) Polyneuropathy
Sensory (predominantly) Polyneuropathy
Autonomic Neuropathy

Laboratory Evaluations

• Screening with serum or urine as needed
• Focused on nerve conduction studies (NCS) and electromyography (EMG)
• Nerve biopsy (such as sural nerve) may be required
• Grading Peripheral Neuropathy:
  Grade 1 - Grade 2 - Grade 3 - Grade 4
• Radicular (Nerve Root) Disease usually considered separately (see below)

B. Chronological Categorization of Diseases

Acute Onset Monophasic (days):
Guillain-Barre Syndrome ; Porphyric Neuropathy ; Diptheria associated polyneuropathy

Subacute Onset (weeks):
Many toxins ; Nutritional neuropathies ; Carcinomatous neuropathy ; Uremic neuropathy

Relapsing:
Chronic inflammatory demyelinating polyneuropathy (CIDP) & Refsum's Disease

Chronic (months-years):
Diabetic ; Chronic inflammatory ; Charcot-Marie-Tooth (hereditary sensorimotor neuorpathies)

C.  Focal Neuropathies

Nerve Entrapment Syndromes:
Carpal Tunnel Syndrome; Ulnar Nerve Palsy (Cubital Tunnel Syndrome) ; Brachial Plexus Lesions ; Radial Nerve Syndrome ; Tarsal Tunnel Syndrome ; Meralgia Paresthetica - lateral femoral cutaneous neuropathy ; Morton's Neuroma

Mononeuritis Multiplex:
Typically vascular etiology ; Vasculitides - including polyarteritis nodosum ; Cholesterol Emboli Syndrome ; Central Nervous System Disease causing focal deficits ; Multiple Sclerosis ; Sarcoidosis ; Central nervous system vasculitis ;
Syringomyelia

Radiculopathy (usually compression syndromes):
Cervical, Lumbar, Usually due to bone abnormalities in spine or vertebral disc disease

D. Sensorimotor Polyneuropathies (Generalized)

• Alcoholic Neuropathy
• Diabetic Neuropathy
• Nutritional Deficiency: Vitamin B12 Deficiency
• Toxin Neuropathy
• Metabolic Disorder
• Inflammatory Neuropathies (see below)
• Critical Illness Polyneuropathy - likely nutritional/metabolic/toxin components

E. Inflammatory Neuropathies

Demyelinating
Acute - Guillain Barre Syndrome (GBS)
CIDP - often associated with monoclonal gammopathies
Hereditary

Multifocal Motor Neuropathy
Weakness and muscular atrophy  & Responds to IVIg

Infection
Varicella Zoster ; Poliomyelitis ; Leprosy ; Lyme Disease

Autoimmune Etiology
Polyarteritis Nodosa
Rheumatoid Arthritis
Other Vasculitis

Gammopathy and Neuropathy

• Paraproteinemias are frequently associated with chronic progressive neuropathies
• Direct toxicity of immunoglobulin deposition on neurons may occur
• Amyloid deposition may also contribute
• Focal and Diffuse Myeloma
• Waldenstrom's Macroglobulinemia
• Amyloidosis
• Cryoglobulinemias
• Lymphoma
• Chronic Lymphocytic Leukemia
• Giant Lymph Node Hyperplasia

F. Predominantly Motor Neuropathies

1. Guillain-Barre Sydnrome and CIPD
2. Acute intermittant porphyria
3. Lead neuropathy
4. Heritable motor-sensory neuropathies
5. Motor Neuron Disease (neuronopathy):
   ALS
   Infantile Motor Neuron Diseases
   Poliomyelitis and Postpolio Syndrome
   Autoimmune Syndromes

G. Predominantly Sensory Polyneuropathies

Global Loss:
Diabetic polyneuropathy (see below)
Monoclonal gammopathies, dysproteinemias, paraproteinemias, cryoglobulinemia
Tabes dorsalis

Primary Loss of Pain and Thermal Sensibility
Small fiber losses
Diabetic polyneuropathy (see below)
Amyloid Deposition
Hereditary sensory neuropathies
Lepromatous leprosy

Ataxic Neuropathies
Primary loss of joint position and vibration sensation
Carcinomatous sensory neuroapthy
Sjogren Syndrome
Chemotherapeutic Agents: cisplatin
Metronidazole
Vitamin B6 overdose
Friedreich's Ataxia
Sensory abnormalities may predominate in neuropathy with paraproteinemias

H. Diabetic Neuropathy

Complex interplay of multiple etiologic mechanisms

• Metabolic and vascular abnormalities
• Hypertension increases progression of neuropathy
• Improved glycemic control associated with reduction in progression of neuropathy
• Proliferative microvascular disease is likely a major contributor
• Increased capillary leakage and arteriovenous shunting also play a role
• Basement membrane thickening (glycated biomolecules) also found

Types

• Rapidly reversible hyperglycemic neuropathy
• Distal Symmetric Sensory Neuropathy

Mononeuropathy (multiplex)

• Autonomic neuropathy (common)
• Subacute Proximal Neuropathy (uncommon)

Distal Symmetric Sensory Neuropathy:

• Predominantly affects sensory and autonomic function
• Most common type of diabetic neuropathy
• Distal axonopathy of dying-back type is most likely pathology

Mononeuropathy:
Cranial, thoraco-abdominal, and limb neuropathies
Proximal lower limb motor neuropathy (diabetic amyotrophy) can occur
Local vascular insufficiency with nerve ischemia is most likely underlying problem
Focal inflammatory and vasculitic pathologies may occur

Diabetic Amyotrophy

• Acute, monophasic, painful lower limb weakness and areflexia
• Minimal sensory loss
• Axonal destruction

Subacute Diabetic Proximal Neuropathy

• Proximal muscle weakness associated with reduced or absent lower extremity reflexes
• Axonal degeneration and some demyelination on NCS and biopsy
• Autonomic failure is commonly found
• Sural nerve biopsy shows demyelination; less commonly inflammation
• CSF protein is typically increased
• Active treatments were sometimes used (similar to CIDP)
• Disease frequently self-limiting
• This entity may be severe variant of bilateral lumbosacral radiculoplexopathy

Treatment

• Tight glucose control prevents progression of neuropathy [5]
• ACE inhibitor trandolapril showed improvement in NCS/EMG studies in type 1 DM [16]
• Intensive therapy with various ACE-I + Vitamin E + Vitamin C in Type II DM with microalbuminuria reduced progression of neuropathy >60% over three years [17]
• Urinary Retention - often responds to cholinergic agents such as bethanechol
• Gastroparesis
• Cisapride (Propulsid®) 10-20mg po tid-qid is best tolerated  
  Also responds to erythromycin 750mg po qd (inexpensive but poorly tolerated)
• Fecal Incontinence See outline "Anorectal Problems"
• Capsaicin cream (0.075%) for 8 weeks sometimes relieves painful neuropathy
• Tricyclic antidepressants and carbamazepine effective in some patients
• Mexilitine for painful diabetic neuropathy is fairly effective
• Dose: 75-150mg po tid
  • Contraindicated in long QTc, cardiac arrhythmias
  • Side effects include confusion, fatigue, nausea
• Gabapentin (Neurontin®)
• Various effects on brain neurotransmitters, particularly g-AminoButyric Acid (GABA)
  • Dose: 900-3600 mg qd divided (2-3 times)
  • Generally well tolerated with excellent efficacy in diabetic pain reduction
  • Side effects: diziness, somnolence, confusion (all <8%)

Failed Therapies

• Gangliosides
• Gamma-linolenic acid
• Acetyl-L-carnitine (levocarnitine)
• Antioxidants
• Tolrestat (Alredase®) has been withdrawn from the market

I. Toxin (Drug) Associated Neuropathies

• Amiodarone, Thalidomide, DDI, Stavudine (d4T), DDC, Chemotherapeutic Agents, Dapsone, Disulfiram, Gold Salts, Isoniazid, Metronidazole, Phenytoin (Dilantin), Suramin

J. Chemotherapy Associated Peripheral Neuropathy

• Vinca Alkyloids - vincristine (less so with vinblastine)
• Paclitaxel (Taxol®)
• Topoisomerase Inhibitors : Etoposide & Etanidazole
• Carboplatin
• High Dose Cytosine Arabinoside (HiDAC)
• Bone Marrow Transplantation - may be severe; multiple causes

K. HIV Peripheral Polyneuropathy

Mononeuritis Multiplex (CD4>500/µL or <50/µL)

Distal Symmetrical Polyneuropathy

• Similar to diabetic sensory neuropathy
• EMG shows distal axonopathy
• Analgesics, tricyclic agents, anticonvulsants and capsaicin may be effective

Inflammatory Demyelinating Polyneuropathy (CIDP related)

• CD4<50 or >500/µL
• Often associated with cerebrospinal fluid (CSF) abnormalities
• Responses to glucocorticoids, plasmapheresis, intravenous Ig reported

Non-inflammatory Neuropathy, Sensorimotor (early and late) Disease

Autonomic Nervous System

CMV Polyradiculopathy (Cauda equina syndrome)

• Patients with CMV infection in cauda equina region
• All symptoms of cauda equina destruction may occur
• Includes pain, lower extremity weakness, and incontinence
• Treatment: Foscarnet or Ganciclovir or both
• Neither amitriptyline nor acupuncture were effective against pain for this syndrome

L. Other Systemic Diseases

Peripheral Vascular Disease

Uremic Neuropathy

Thyroid Disease

• Mainly hypothyroidism causing carpal tunnel syndrome
• Hypothyroidism also increases peripheral nerve symptoms from other causes

Acromegaly

• Usually due to pituitary adenoma
• Nerve entrapment syndromes, particularly carpal tunnel syndrome

M. Radicular (Nerve Root) Disease

Nerve roots pass through thecal sac to neural foramina

Narrowing of the neural foramina can lead to root dysfunction

Bone spurs, disk prolapse or herniation are the most common causes of radiculopathy

Weakness and pain are the most common presenting symptoms

Commonly Affected Regions and Weakness

• Cervical C5, C6, and C7
• Lumbar L4 and L5
• Sacral S1

Sites of Weakness

• C5: shoulder abduction
• C6: elbow flexion
• C7: elbow extension, wrist flexion and extension, and hand grip
• C8: hand grip, hand intrinsic muscles
• L2-3: hip flexion
• L5-S1: hip extension and ankle plantar flexion
• L3-4: knee extension
• L4-5: knee flexion and ankle dorsiflexion

04192001