Differential Diagnosis in Neurology

10.16. Neuropathies Associated with Medical Illness

Hypothyroidism

• General features:
  • Concurrent hypothyroid myopathy (Hoffmann's syndrome):
    • Pseudohypertrophy; proximal weakness
    • Hyperexcitability of the sarcolemmal membrane (lumping phenomenon with percussion)
    • Axonal neuropathy >40%; CTS in approximately 30% of patients
  • Associated central nervous system signs and symptoms:
    • Decreased mentation
    • Cranial nerve V involvement (pain)
    • Cerebellar ataxia (Purkinje cell dysfunction)
    • VIIIth nerve dysfunction
• Clinical presentation:
  • Distal sensory loss
  • Burning and lancinating distal pain
  • Leg muscle cramps
  • Distal leg weakness
  • Concomitant CTS with hand paresthesias
  • Decreased relaxation phase of AJ and other reflexes
  • Hoarseness (micropolysaccharide deposition in the vocal cords)
• EMG:
  • Axonal demyelinating or mixed features
  • Decreased sensory NCVs; decreased SNAPs
  • Prolonged CMAP distal latencies
• Pathology (sural nerve biopsy):
  • Myelinated fiber loss; large > small fibers
  • Glycogen deposition in Schwamm cells, myelinated and unmyelinated axons, endothelial cells and perineurial cells
  • Axonal degeneration; some patients have demonstrated demyelination and remyelination
  • Mucopolysaccharide accumulation in synovium and connective tissue; causing CTS and Tarsal tunnel syndrome

Acromegaly

• General features:
  • 35% of patients suffer CTS; 35–45% have a peripheral neuropathy
  • CTS may be the presenting complaint
  • Enlarged sinuses; cardiac failure, arthropathy, myelopathy
  • Pituitary gland usually not enlarged; the severe endocrinopathy elicits an early diagnosis
• Clinical presentation:
  • Paresthesias of the hands and feet; legs greater than hands; decreased light touch, vibration and proprioception
  • Rare distal wasting
  • Absent reflexes
  • Concomitant proximal myopathy:
    • Type II fiber atrophy
  • Severe CTS often precedes the diagnosis:
    • Enlargement and edema of the nerve itself as well as surrounding connective tissue
• EMG:
  • 80% have CTS or subclinical NCV at the wrist
  • Decreased amplitude of sensory and mixed nerve action potentials
  • Decrease mNCV (mild)
  • Mixed axonal and demyelinating symmetric polyneuropathy
• Laboratory features:
  • Increased insulin like growth factor; somatostatin-C and growth hormone
  • CSF may be normal
• Pathology:
  • Increased connective tissue in the perineurium and endoneurium
  • Decreased myelinated and unmyelinated axons
  • Onion bulb formation

Hyperthyroid Neuropathy

• General features:
  • Cognitive dysfunction
  • Apathetic hyperthyroidism
  • Davidoff Syndrome:
    • Hyperactive reflexes
    • Babinski signs
    • Nystagmus
  • Proximal myopathy:
    • Iliopsoas often severely involved; wasting of the rhomboids
  • Thyroid storm; fever to 105° Fahrenheit, atrial fibrillation; wide pulse pressure; hypotension; most associated with increased T4; rarely increased T3 with a normal T4
• Clinical presentation:
  • Bandow's paraplegia:
    • Proximal and distal leg weakness
    • Hypotonia
    • Areflexia in the legs
  • Neuropathy:
    • Sensory signs and symptoms are mild
    • Proprioceptive loss
• EMG:
  • Slowed M/S NCVs
  • Denervation of distal musculature
• Pathology (muscle biopsy):
  • Acute denervation

Hypoglycemia Secondary to Insulinoma

• General features:
  • Rare
  • CNS symptoms of personality change and seizures predominate
  • Multiple episodes occur prior to an anterior horn cell or motor neuropathy is evident
• Clinical presentation:
  • Predominately or entirely a motor neuropathy
  • Distal and symmetrical
  • Upper limb more involved than the lower
  • Prominent wasting; no fasciculations
  • Painful paresthesias are common; no objective sensory loss
  • After treatment of the insulinomas; weakness improves; complete resolution of the sensory symptoms; wasting persists
  • More common in males greater than females
  • Neuropathy is more frequent during hypoglycemic epidoes

Hepatic Disease

• General features:
  • Peripheral neuropathy occurs in at least 20% of patients; possibly greater than 50%
  • Concomitant CNS and PNS neurological complications:
    • Hepatic coma (3 stages)
    • Optic neuritis; changing pupil signs
    • Wernicke/Konakoff Syndrome
    • Acquired hepatolenticular degeneration
    • Acute increased intracranial pressure (severe acute liver failure)
    • Complications of coagulopathies
    • Dementia
    • Choreoathetosis
    • Spastic paraparesis
    • Seizures
    • Reversible decortication and decerebration
    • CTS
    • Type II muscle atrophy
• Clinical presentation:
  • Length dependent
  • Distal sensory loss; small fiber greater than large fiber modalities
  • Loss of distal reflexes
  • Correlation of severity of the neuropathy and liver disease
  • Autonomic neuropathy; possibly parasympathetic > sympathetic fiber
• EMG:
  • Length-dependent decrease of SNAP and CMAP; normal NCV
  • Concomitant CTS
  • Some patients concomitant IgA or IgM monoclonal gammopathy
• Pathology:
  • Confounding factors are diabetes mellitus or alcoholism
  • Segmental demyelination; no active demyelination or inflammatory cells; thinly myelinated fibers that are affected may reflect axonal degeneration and regeneration; short internodes suggest demyelination

Primary Biliary Cirrhosis

• General features:
  • Incidence not known; primarily case reports
• Clinical presentation:
  • Mild distal sensory neuropathy
  • Case report (asymmetrical sensory neuropathy)
  • Severe itching:
    • Class of skin C-fiber involvement carry the itch modality
• EMG:
  • Normal motor NCVs
  • Decreased sensory NCVs
• Pathology:
  • Myelinated fiber loss
  • Xanthomatous infiltration of the fascicles

Viral Hepatitis

• General features:
  • Type A and B viral hepatitis
• Clinical presentation:
  • GBS presentation in both A and B hepatitis
  • Occurs after the onset of jaundice; may rarely proceed jaundice
  • Mild sensory neuropathy
• EMG:
  • Slowing of NCVs during episodes of severe hepatitis B
• Pathology:
  • Segmental demyelination

Tropical Sprue

• General features:
  • Far East India and the Caribbean
  • Nutritional deficiency and bacterial contamination of the small bowel
  • Improvement with folic acid
  • Stages:
    • Fatigue, asthenia, bulky stool
    • After months of true malnutrition disease; weight loss glossitis, stomatitis, cheilosis and hyperkeratosis
    • Anemia and megaloblastosis
• Clinical presentation:
  • Predominant distal sensory paresthesias

Adult Celiac Disease (Gluten Enteropathy)

• General features:
  • Intestinal mucosa affected; villous atrophy, columnar to cuboidal change of absorbing cells; infiltration of the laminae propria with plasma cells and lymphocytes; jejunum greater than ileum
  • Increased HLA-B8 and DW3
  • Patients with IgA deficiency are predisposed
  • Antibodies to gliadin
• Clinical presentation:
  • Distal dying-back neuropathy; fluctuates depending on gluten exposure
  • Associated with myelopathy and cerebellar degeneration
• EMG:
  • Axonal feature
• Pathology:
  • Axonal degeneration

Vitamin E Deficiency

• General Features:
  • Dietary (associated with severe diarrhea and malabsorption)
    • Difficult to achieve pure vitamin E deficiency nutritionally
  • Alpha tocopherol transporter deficiency
• Clinical features:
  • Primarily dorsal column dysfunction
  • Cerebellar degeneration
  • Posterior column sensory loss
  • Peripheral large fiber neuropathy

Chronic Obstructive Pulmonary Disease

• General features:
  • Associated with severe COPD with weight loss
• Clinical presentation:
  • Mild distal sensory neuropathy
  • Associated with Type II fiber muscle atrophy of proximal muscles

Sarcoidosis

• General features:
  • Granulomatous multisystem disease most frequently affecting the lung (hilar adenopathy or infiltrative pattern) heart, joints, skin, ocular and reticuloendothelial systems
  • CNS involvement:
    • Pituitary; chiasm, posterior hypothalamus; any location in the parenchyma; stroke presentation
    • Dural involvement
    • Uveitis and bilateral VIIth nerve palsy (Hereford's syndrome)
    • Myelopathy from involvement of the dura with compression of the spinal cord
    • CSF; sugar 30–40 mg/dL ; protein 80–150 mg/dL and lymphocytic pleocytosis
    • Rarely cranial nerve VIII and II are involved
• Clinical presentation:
  • Neuropathy may occur as isolated manifestation or as part of generalized disease
  • Mononeuritis multiplex
  • Sensory loss over the trunk; may be associated with dysesthesias or pain, posterior column dysfunction
  • Symmetrical polyneuropathy
  • Rare acute GBS like presentation
  • Chronic forms may have little associated systemic disease
  • Peripheral neuropathy occurs in approximately 15% of patients
  • Patients with mononeuritis multiplex may have anesthetic trunk areas (intercostal neuritis)
• EMG:
  • Decreased motor nerve amplitudes
  • Absent sensory responses SNAPs
  • Slowed m/r NCVs; rare conduction block
  • Denervation of affected muscles
• Pathology:
  • Localized granulomatous nerve infiltration; noncaseating granuloma within the endoneurium of peripheral nerves, roots and cranial nerves
  • Angiopathy a component of the pathology

Critical Illness Polyneuropathy

• General features:
  • Exact incidence is unknown; appears common in patients that have been in the ICU for greater than four weeks
  • Need to distinguish it from concomitant acute myopathy (Type II fibers; thick myosin; corticosteroid induced myopathy; neuromuscular blocking agents)
• Clinical presentation:
  • Occurs in patients with sepsis and multiorgan failure (cardiac, pulmonary, renal, liver)
  • Quadriparesis
  • Difficulty weaning from the respirator
  • Reduced or absent deep tendon reflexes
  • Less clear sensory deficit
  • Often concomitant encephalopathy
  • Residual weakness in distal muscles
• EMG:
  • Reduced CMAP and SNAP amplitudes
  • Normal distal latencies and NCVx
  • Denervation
• Pathology:
  • Axonal degeneration

Neuropathy of Renal Failure

• General features:
  • Present in 80% of severely uremic patients; large percentage may be asymptomatic but demonstrable by NCV abnormalities
  • Primarily related to the duration and severity of the renal failure
  • Males more often affected than females
  • Stable or improves with dialysis
  • Improves following successful renal transplantation
• Clinical presentation:
  • Insidious onset; rarely acute or subacute
  • Sensory neuropathy; painful tingling of the feet; burning; band-like constrictions around the toes
  • Restless legs; muscle cramps
  • Impaired position and vibration sensibility; there may be small fiber predominant variant
  • May have marked muscle wasting; concomitant Type II atrophy of proximal muscles
  • Distal lower extremity weakness of anterior tibialis, extensors of the toe and eversion
  • Decreased or absent deep tendon reflexes
  • Orthostatic hypotension, impotence and constipation are common
  • Increased incidence of CTS
  • Arteriovenous shunt placement in the arm may cause ischemic high median neuropathy
  • CTS may be secondary to deposition of beta2-migroglobulin (systemic amyloidosis as consequence of the renal failure)
  • Ulnar and peroneal compressive neuropathy may occur concomitantly
• EMG:
  • Decreased motor and sensory NCVs
  • No correlation between NCVs and clinical signs of neuropathy
  • After transplantation there may be rapid improvement of NCV followed by consistent improvement over time
  • Progressive reduction of SNAPs and CMAPs
  • Prolonged F-wave latencies
  • Denervation and reinvention noted by needle EMG in distal muscles
  • Small parasympathetic fiber abnormalities (R-R variability) greater than sympathetic fiber loss
• Laboratory:
  • Creatinine clearance of less than 10 ml/minute has decreased NCV
  • serum PTH inversely correlated with NCV
  • CSF
    • Usually normal; may have slight increase in protein
• Pathology:
  • Axonal degeneration
  • Some segmental demyelination and remyelination

Primary Hyperoxaluria

• General features:
  • AR (primary hyperoxaluria Type I)
  • Accumulation of calcium oxalate crystals in cutaneous arterioles, kidneys and eyes
• Clinical presentation:
  • Rapidly progressive motor and sensory neuropathy
  • Occurs despite hemodialysis
  • Livedo reticularis
  • Retinopathy
  • Renal and liver transplant are beneficial
• EMG:
  • Axonal feature
• Pathology:
  • Calcium oxalate within endoneural blood vessel walls and axon cylinders
  • Axon loss
  • Demyelination

Hyperlipidemia

• General features:
  • Rare
  • Serum cholesterol moderately increased, triglycerides levels are very high
• Clinical presentation:
  • Slowly progressive
  • Pain in the feet without proximal extension or hand involvement
  • No weakness or autonomic symptoms
  • 50% of patients have decreased ankle jerks
• EMG:
  • Axonal features (subclinical) in greater than 30% of patients with hypertriglyceridemia
• Pathology (nerve biopsy):
  • Axonal degeneration

Sicca Complex

• General features:
  • Rare
  • Probable autoimmune etiology
• Clinical presentation:
  • Diffuse patchy loss of sweating over the body surface
  • Panautonomic dysfunction
  • Greater than 50% of patients; mixed pattern of autonomic dysfunction with abnormal sudomotor, cardiovagal and adrenergic function
  • Autonomic neuropathy with distal sensorimotor neuropathy
  • Rare in association with extraglandular disease
  • Extractable nuclear antigen ENA; SSA-SSB Ag noted in 20% of patients

CREST Syndrome

• General features:
  • Calculosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasis are the major systemic features
• Clinical presentation:
  • Onset of neuropathy may occur up to 25 years after the first symptoms of scleroderma
  • Multiple mononeuropathy
• EMG:
  • Infarction of individual nerves
• Pathology:
  • Necrotizing vasculitis
  • Axonal degeneration