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Lumbar radiculoplexopathy (amyotrophy)

–Weakness and wasting pelvic girdle and thigh

–Sensory loss in L2–L3

–Absent patellar reflex

Autonomic neuropathy

–Cardiovascular: resting tachycardia; orthostatic hypotension

–Gastroparesis: postprandial distension; gastric splash

CIDP: motor weakness

DIFFERENTIALDIAGNOSIS

Uremic polyneuropathy

Drug induced

–Antineoplastic drugs: cisplatin, vincristine

–Isoniazid

–Amiodarone

Toxic

–Chronic arsenic poisoning

–n-Hexane, methyl-n-butyl ketone

Nutritional deficiency

– Usually associated with alcoholism Paraneoplastic polyneuropathy

Hypothyroidism

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

Fasting plasma glucose, 2-hour glucose tolerance test or hemoglobin A1c for diagnosis and to assess glycemic control; may occur in “prediabetes”

Serum B12

Thyroid function

Creatinine and BUN

Syphilis testing

Serum protein electrophoresis

Vitamin D

In mononeuropathy/mononeuritis multiplex, test for vasculitis, paraproteinemia, and sarcoid.

In radiculopathy or mononeuropathy, imaging studies to exclude compressive lesions

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Diagnostic Procedures/Other

Bedside testing of vibration perception with 128-Hz tuning fork, monofilament perception of 10-g filament

Quantitative sensory testing for vibratory and thermal thresholds

– Standardized measures for assessing severity and risk of foot ulceration Electromyogram nerve conduction velocity

–Useful to confirm mononeuropathy and entrapment syndromes

–Sensitive but nonspecific index of presence and severity of diabetic polyneuropathy

–In small unmyelinated fiber painful neuropathy, test may be normal.

Lumbar puncture

– In CIDP, elevation of spinal fluid protein Skin biopsy with epidermal nerve fiber density

–Enables direct study of small nerve fibers that are difficult to assess electrophysiologically

Corneal confocal microscopy

– Noninvasive approach based on examination of corneal innervation

Test Interpretation

In nerve biopsy of peripheral nerve, Wallerian degeneration, focal axonal swellings containing neurofilaments, axonal atrophy, and demyelination are seen.

Thick neural capillary basement membrane and endothelial proliferation Obliterative microvascular lesions and perivascular inflammation

TREATMENT

GENERALMEASURES

Maintain blood glucose close to normal.

Provide appropriate footwear to prevent pressure damage to insensate feet.

MEDICATION

First Line

Management of pain and sensory neuropathy

Calcium channel modulators: gabapentin (2),(3)[A] (off-label)

– Binds Ca2+ channel–associated protein α2-δ; inhibits neurotransmitter

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release

–Dose range 300 to 1,200 mg TID, NNT ~4 to 8

–Reduce dose in renal insufficiency.

–Adverse effects: dizziness, fatigue, edema

Calcium channel modulators: pregabalin (2),(3)[A]

–Binds same calcium channel as gabapentin

–Linear pharmacokinetics and quicker onset of action compared to gabapentin

–Usual dose: 150 to 600 mg/day, NNT ~4 to 8

–Adverse effects are dizziness and edema.

Duloxetine (2),(3)[A]

–Selective serotonin and norepinephrine reuptake inhibitor

–Usual dose is 30 to 60 mg/day; NNT ~4 to 11

–Adverse effects are nausea and dizziness.

Tricyclic antidepressants (TCA) (2),(3)[A] (off-label)

–Analgesia may be related to effects on sodium channels; NNT ~2 to 5, NNH ~3 to 16

–Amitriptyline 25 to 150 mg at bedtime

–Nortriptyline (25 to 150 mg); desipramine (25 to 200 mg) less sedating than

amitriptyline but limited trial data

Anticholinergic effects, cardiac arrhythmias may occur. Management of autonomic neuropathy

–Orthostatic hypotension

Fludrocortisone (off-label)

Midodrine (off-label)

–Gastroparesis

Metoclopramide or domperidone

Erythromycin (off-label)

–Diabetic diarrhea Loperamide

Clonidine (off-label)

Octreotide (off-label)

Antibiotics for bacterial overgrowth

–Hyperhidrosis

Propantheline (off-label)

Geriatric Considerations

Anticholinergic effects of TCAs may cause urinary retention and cardiac

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arrhythmias.

Second Line

Antidepressants

–Venlafaxine (2),(3)[B] (75 to 225 mg daily) (off-label), NNT ~5 to 8 Serotonin-norepinephrine reuptake inhibitor

Anticonvulsants

–Carbamazepine (3)[C] (off-label) Blocks sodium channels

Dose 100 to 800 mg/day

Topical therapies

–Capsaicin 0.075% cream applied TID

Depletes C fibers in skin of substance P

–Lidocaine 5% (700 mg) patches applied daily to feet (off-label): Causes sodium channel blockade

–Opiate analgesia

–Tramadol (3)[B] (off-label): 100 to 400 mg/day, NNT ~3 to 7

Binds opiate receptors; also inhibits reuptake of norepinephrine and serotonin; fewer opiate side effects

–Tapentadol (3)[B]

Binds to µ-opiate receptor and inhibits norepinephrine uptake α-Lipoic acid (3)[C]

–Antioxidant properties may limit free radical–mediated damage.

–600 mg/day PO dose; limited study data on efficacy

ISSUES FOR REFERRAL

If CIDPis suspected, refer to neurologist for investigation and treatment.

ADDITIONALTHERAPIES

Transcutaneous electrical nerve stimulation

Percutaneous nerve stimulation

Electrical spinal cord stimulation

Actovegin, dextromethorphan with quinidine

C-peptide

COMPLEMENTARY& ALTERNATIVE MEDICINE

Acupuncture, Reiki, electromagnetic field treatment: no convincing trial data

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SURGERY/OTHER PROCEDURES

Electrical spinal cord stimulation

ONGOING CARE

PROGNOSIS

Generalized symmetric polyneuropathies

–Usually slow, chronic progression

–Insensitive but painless foot as pain lessens

Focal neuropathies

– Recovery over months to years

COMPLICATIONS

Claw foot deformity Neurotropic ulceration

–Painless ulcers on weight-bearing area

–Callus formation is a precursor to ulceration.

Neuropathic arthropathy

– Results in complete disorganization of joint structure in foot, Charcot joint

REFERENCES

1.Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136–154.

2.Griebeler ML, Morey-Vargas OL, Brito JP, et al. Pharmacologic interventions for painful diabetic neuropathy: an umbrella systematic review and comparative effectiveness network meta-analysis. Ann Intern Med. 2014;161(9):639–649.

3.Vinik AI. Clinical practice. Diabetic sensory and motor neuropathy. N Engl J Med. 2016;374(15):1455–1464.

ADDITIONALREADING

Bril V, England J, Franklin GM, et al. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine,

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and the American Academy of Physical Medicine and Rehabilitation.

Neurology. 2011;76(20):1758–1765.

Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162–173.

Tesfaye S, Boulton AJ, Dickenson AH. Mechanisms and management of diabetic painful distal symmetrical polyneuropathy. Diabetes Care. 2013;36(9):2456–2465.

Ziegler D, Fonseca V. From guideline to patient: a review of the recent recommendations for pharmacotherapy of painful diabetic neuropathy. J Diabetes Complications. 2015;29(1):146–156.

SEE ALSO

Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2

CODES

ICD10

E10.42 Type 1 diabetes mellitus with diabetic polyneuropathy

E11.42 Type 2 diabetes mellitus with diabetic polyneuropathy E13.42 Oth diabetes mellitus with diabetic polyneuropathy

CLINICALPEARLS

Occasionally, when glycemic control improves dramatically, as can occur when treatment for diabetes is initiated, there may be a worsening of neuropathy symptoms (described as treatment-induced neuropathy). Symptoms usually stabilize and gradually improve as glycemic control is maintained.

It is common to combine agents with different mechanisms of action in the management of neuropathic pain. Topical therapies can be combined with systemic therapies. There is limited evidence-based data to support combination therapy.

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DIARRHEA, ACUTE

Stephen M. Testa, MD Marie L. Borum, MD, EdD, MPH

BASICS

DESCRIPTION

An abnormal increase in stool water content, volume, or frequency (≥3 in 24 hours) for <14 days duration

Acute viral diarrhea (50–70%)

–Most common cause of infectious diarrhea; noninflammatory (watery)

–Frequently presents with associated nausea and/or vomiting

–Symptoms usually develop after an incubation period of ~1 day and last for

1 to 3 days; typically self-limited Bacterial diarrhea (15–20%)

–Most common infectious cause of inflammatory (bloody) diarrhea

–Incubation period variable; diarrhea caused by preformed enterotoxin presents within 1 to 6 hours of contaminated food ingestion, whereas bacterial infection typically presents within 1 to 3 days.

–Symptoms usually resolve in 1 to 7 days; antibiotic use attenuates length and/or severity of disease.

–Suspect when concurrent illness in others who have shared potentially contaminated food.

–Suspect Clostridium difficile in patients with recent antibiotic use or

hospitalization.

Protozoal infections (10–15%)

–Typically cause noninflammatory (watery) diarrhea

–Long incubation period and prolonged disease course, symptoms develop approximately 7 days after exposure and commonly last >7 days

–Suspect when outbreaks of watery diarrhea in areas with contaminated

water or food supply.

Traveler’s diarrhea (TD) typically begins 3 to 7 days after arrival in foreign location and resolves within 5 days; rapid onset, generally self-limited

EPIDEMIOLOGY

In developing countries, acute diarrhea is more common in children; no age

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predilection in developed countries

Acute diarrhea accounts for >128,000 U.S. hospital admissions and ~1.5 million annual deaths worldwide (1).

Prevalence

Second leading cause of death in children <5 years and seventh leading cause of death among all ages worldwide

Affects 11% of the general population

Rotavirus and adenovirus most common in children <2 years, bacteria are more common in children >2 years

In developing world, acute diarrhea is largely due to contaminated food and water (1).

ETIOLOGYAND PATHOPHYSIOLOGY

Bacterial

–Escherichia coli

–Salmonella, Shigella, Campylobacter jejuni

–Vibrio parahaemolyticus, Vibrio cholerae

–Yersinia enterocolitica

–C. difficile

–Staphylococcus aureus

–Bacillus cereus

–Clostridium perfringens

–Listeria monocytogenes

Viral

–Rotavirus and norovirus (most common)

–Adenovirus

–Astrovirus

–Cytomegalovirus (in immunocompromised)

Protozoal

–Giardia lamblia

–Entamoeba histolytica

–Cryptosporidium

–Isospora belli

–Cyclospora, Microspora

Pathophysiology (1)

–Noninflammatory: most commonly viral; increased intestinal secretions without disruption of intestinal mucosa; watery

–Inflammatory: generally invasive or toxin-producing bacteria; disrupts

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mucosal integrity with subsequent tissue invasion/damage; bloody stools

Viral diarrhea: changes in small intestine cell morphology including villous shortening, increased number of crypt cells, and increased cellularity of the lamina propria

Bacterial diarrhea: Bacterial invasion of colonic wall leads to mucosal hyperemia, edema, and leukocytic infiltration.

RISK FACTORS

Travel to developing countries

Failure to observe food/water precautions

Immunocompromised host

Antibiotic use

Proton pump inhibitor (PPI) use

Daycare exposure

Fecal-oral sexual contact

Nursing home residence

Pregnancy (12-fold increase for listeriosis) (1)

GENERALPREVENTION

Frequent hand washing and alcohol-based hand sanitizers; hand washing promotion may reduce incidence of diarrhea by approximately 30%.

Proper food and water precautions, particularly during foreign travel—“boil it, peel it, cook it, or forget it”

Avoid undercooked meat, raw fish, unpasteurized milk.

Rotavirus vaccine (for infants)

Typhoid fever and cholera vaccine (for travel to endemic areas)

TRAVELER’S DIARRHEA(TD) PROPHYLAXIS

Pretravel counseling on high-risk food/beverage

Consider daily prophylaxis with bismuth subsalicylate (BSS) in all travelers (can reduce the risk of TD by up to 60%).

Antibiotic prophylaxis should not be routinely used. Consider rifaximin use in patients at high risk of health-related complications of TD; fluoroquinolones no longer recommended for TD prophylaxis (2)

Probiotics, prebiotics, and synbiotics have unclear benefit as prophylaxis.

COMMONLYASSOCIATED CONDITIONS

Inflammatory bowel disease (IBD)

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Immunocompromised (HIV, malignancy, chemotherapy)

DIAGNOSIS

HISTORY

Duration of symptoms <14 days

Historical clues for dehydration: orthostatic hypotension, dizziness, increased thirst, decreased urinary output, or altered mental status

Description of stool—characteristics and output

–Frequency

–Quantity

–Character: presence of mucus, blood, or fat

–Consistency

–Floating

–Giardia associated with pale, greasy stools

Weight loss

Associated symptoms: change in appetite, abdominal pain or bloating, nausea/vomiting, or fever

Recent hospitalization or antibiotic use

Travel history

Ingestion of raw or undercooked meat, raw seafood, unpasteurized milk

Sick contacts

Immunocompromised state

Pregnancy

Daycare exposure

Sexual history (e.g., men who have sex with men [MSM], fecal-oral contact, HIV)

Nursing home residence

PHYSICALEXAM

Assess degree of dehydration (1); ill-appearing, dry mucous membranes, tachycardia, orthostatic hypotension, decreased skin turgor, delayed capillary refill, altered mental status

Fever is more suggestive of inflammatory diarrhea.

Abdomen: Assess for tenderness, distention, rigidity. Rectum: blood, tenderness, stool consistency

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