Vitamin syndromes

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VITAMIN & NUTRITION RELATED SYNDROMES

Copper deficiency
Selenium deficiency
Vitamins
A: Retinoids
B1: Thiamine
B2: Riboflavin
B₁₂ deficiency
Biotin
D
E
Deficiency
Intoxication
Niacin
Pyridoxine
Deficiency
Intoxication

MULTIFACTORIAL
Alcoholism
Celiac disease
Critical illness polyneuropathy
Cuban neuropathy
Postgastroplasty
Strachan's

Also see: GI disorders

Thiamine (B1) deficiency (beri-beri)

Thiamine

Biochemistry

Metabolically active form
- Thiamine pyrophosphate (TPP): Hydroxyl group is replaced by diphosphate ester group
- TPP is a coenzyme for two types of enzymes: Cleave a C-C bond adjacent to a carbonyl group
  - α-Ketoacid dehydrogenases
  - Transketolases
- TPP dependent enzymes also require a divalent cation, commonly Mg⁺⁺
Enzyme systems
- α-ketoglutarate dehydrogenase: Krebs cycle
- Pyruvate dehydrogenase: Pyruvate ® Acetyl CoA
- Transketolase: Pentose monophosphate shunt

Sources: Yeast, Pork, Legumes, Cereal grains, Rice (Whole grain)

"A certain very troublesome affliction, which
attacks men, is called by the inhabitants Beri-beri
(which means sheep). I believe those, whom this
same disease attacks, with their knees shaking
and legs raised up, walk like sheep. It is a kind
of paralysis, or rather Tremor: for it penetrates
the motion and sensation of the hands and feet
indeed sometimes the whole body..."

Jacobus Bonitus, Java, 1630

Clinical features
- Extraocular movement paresis
- Peripheral neuropathy¹⁰
  - Onset
    - Progression: Variable; Acute (< 1 month) 50%; Chronic (> 1 year) 20%
    - Weakness (Legs): 50%
    - Sensory loss (Legs): 50%
  - Distribution: Symmetric; Legs > Arms
  - Weakness
    - Distal > Proximal
    - Legs (Foot dorsiflexors) & Hands (Wrist extensors; 80%)
  - Sensory loss: Large & Small fiber modalities
  - Pain
    - Burning feet; Lancinating pain; Calf tenderness
    - Frequency: Some patients
  - Autonomic neuropathy: With severe disease
    - Orthostatic hypotension
    - Bladder: Flaccid
    - GI: Gas retention
  - Tendon reflexes: Reduced or Absent
- Cranial nerve weakness (Occasional): Laryngeal (Hoarseness), Face & Tongue
- Cerebellar degeneration
- Encephalopathy
  - Acute: Wernicke's disease
    - Mental status change: Confusion; Memory loss; Agitation
    - Ataxia: Especially truncal
    - Ocular: Paresis; Nystagmus; Retinal hemorrhages
  - Chronic: Korsakoff's psychosis
    - Memory disorders
    - Dementia
- Systemic
  - Cardiac failure (Wet beri-beri): Congestive; Tachycardia; Edema
  - Infantile: Acute cardiac failure
  - Anorexia: Weight loss
- Associated or causative disorders
  - Alcoholism
  - Malnutrition: Polished rice; HIV infection; Systemic malignancy; Anorexia nervosa
  - Dialysis
  - Malabsorption & repeated vomiting: Gastric resection; Pregnancy
  - Diet with thiaminases: Raw fish (carp)
  - Infantile beri-beri: Breast-feeding infants whose mothers are thiamine deficient
Diagnosis
- Transketolase activity: Whole blood or Erythrocyte
- Increased RBC Transketolase activity after addition of thiamine diphosphate (TPP)
- Urine thiamine excretion: 24 hour
Other lab
- Serum pyruvate: High
- Nerve conduction: Motor & Sensory axon loss
Pathology
- Axonal loss: Especially large axons
- Subperineurial edema
- No segmental demyelination
Treatment: Thiamine
- Acute
  - Immediate: 100 mg/ml solution; Give 100 mg iv before glucose
  - Follow-up: 100 mg i.m. for 3 to 5 days
- Chronic therapy: 50 mg i.m. for 2 weeks, then, Thiamine 50 mg p.o. per day
- Prophylactic: Treat with thiamine before giving i.v. glucose
- Response: Oculomotor change best; Dementia & Neuropathy less well

Riboflavin

Riboflavin (B2) related syndromes

Riboflavin Deficiency: ? Burning feet syndrome
Riboflavin Sensitive myopathies
- Multiple acyl–CoA dehydrogenase deficiency (Glutaricaciduria IIA)
- ? Myopathic carnitine deficiency
- ? MELAS: With Idebenone
- Mitochondrial: tRNA Leu mutation (T3250C)
  - Genetics
    - Heteroplasmic
    - T3250C Mutation may also present with
      - Fatigue syndrome
      - Cardiomyopathy
  - Onset: 1 year
  - Clinical
    - Weakness: Proximal & Neck extensor
    - Lumbar lordosis
    - Normal EOM
  - Family history: Sibs with early death
  - Biochemistry: Complex I deficiency

Niacin (Nicotinic acid) deficiency

Biochemistry

Nicotinamide
- Niacin: Includes Nicotinic acid & Nicotinamide
- Metabolically active forms:
  - Nicotinamide adenine dinucleotide (NAD)
  - NAD phosphate (NADP)
- Associated enzymes carry out oxidation & reduction reactions
- Sources: Meat, Liver, Fish, Legumes, Coffee & tea
Sources: Meat, Liver, Fish, Legumes, Coffee & Tea
Pellagra
- Niacin deficiency: Isoniazid; Alcoholism
- Diarrhea
- Dermatitis
- CNS: Dementia; Hyperreflexia; Startle myoclonus
- ? Neuropathy related to other associated vitamin deficiencies
Associations
- Hartnup's disease
- Carcinoid syndrome
Treatment: Niacin 40 to 250 mg qd

Pyridoxine intoxication

Pyridoxine

Sensory neuropathy/neuronopathy
- Syndromes
  - High doses (180 g): Acute sensory neuronopathy
    - Paresthesias: Diffuse
    - Sensory loss
      - Proximal & Distal
      - Sensory ataxia
    - Autonomic dysfunction
    - Strength: Normal
    - Recovery: Poor
  - Lower doses (0.2 to 10 g/day): Chronic neuropathy
    - Progressive, distal, sensory
    - Tendon reflexes: Reduced distally
    - Latency until symptoms: Shorter with higher doses
    - Pathology: Distal axonal loss
    - Recovery: Good
Nutritional data
- With intake up to 200 mg/day
- Minimum daily requirement: 0.6 to 1.3 mg/day

Pyridoxine deficiency

Pyridoxine sources
- Grains (enriched)
- Chicken
- Fruit & Vegetables: Orange & Tomato juice, Banana, Avocado
At risk populations
- Malnutrition: Alcoholics, Prisoners, Refugees
- Infants of B₆ deficient mothers
- Increasing age
- Patients using Isoniazid, Penicillamine & Hydralazine
  - Slow acetylation of isoniazid
  - Isoniazid & hydralazine cause increased excretion of pyridoxine in urine
Clinical
- Polyneuropathy
  - Distal, symmetric
  - Sensory > motor
  - Pain & Paresthesias
  - Axonopathy
- CNS
  - Infantile seizures
    - Pyridoxine responsive: Normal pyridoxine levels
    - Deficient diet: Breast milk feeding from undernourished mothers
  - Adults: Depression; Irritability; Confusion
- Skin: Pellagra-like rash
Diagnosis
- Erythrocyte glutamic pyruvate transaminase ± pyridoxine
- Measure tryptophan metabolites (xanthenuric acid) after tryptophan loading
- High serum & CSF pyruvate
Prophylaxis in isoniazid treatment & pregnancy: 30 to 300 mg/day

Vitamin B₁₂ (cobalamin) deficiency

Causes Clinical features Testing	Vitamin B₁₂

Clinical features
- Polyneuropathy
  - Sensory change: 2° spinal or peripheral nerve lesions
    - Early: Paresthesias
    - Loss especially of large fiber modalities
    - Distal
  - Motor: Later in course; Distal
  - Reflexes
    - Tendon: Reduced or absent at ankles
    - Plantar: Upgoing
  - Autonomic: Postural hypotension
- CNS
  - Spinal cord: Earliest locus of involvement
    - Major cause of sensory & motor disability
    - Posterior column fiber loss
    - Spasticity in legs
    - Similar clinical features to N₂O toxicity
  - Other CNS
    - Cognitive impairment in adults: Leukoencephalopathy on MRI
    - Mental retardation or encephalopathy in childhood syndromes
    - Sensory: Reduced smell & taste
    - Gait ataxia
- Anemia: Megaloblastic; Due to reduced DNA synthesis
- Gastrointestinal: Glossitis; Diarrhea
- Fingernails: Hyperpigmented
Testing
- Serum
  - Low B₁₂
    - Clinically significant: < 100 pg/ml
    - Suspicious: < 200 pg/ml
  - High homocysteine & methymalonic acid
    - Confirm biological significance of low B₁₂ levels
- MRI
  - Hyperintense T2 lesions in posterior columns (50%)
  - Lesions resolve after 8 to 12 months of therapy
- Evoked potentials
  - Somatosensory: Abnormal tibial & median
  - Motor: Normal in most
Pathology
- Spinal cord
  - Multifocal axonal loss & demyelination
  - Localization
    - Cervical & thoracic
    - Posterior column > Anterolateral & Anterior
- Peripheral nerve: Axonal loss; Occasional ± demyelination
Treatment: 1 mg i.m. q 3 months
Prognosis: Stabilization, or Some improvement
- Paresthesias
  - Resolve within weeks
  - Rarely transient exacerbation after treatment
- Myelopathy changes slowly if at all
Causes of B₁₂ deficiency: Normal body stores last 3 to 4 years
- Gastrointestinal malabsorption
  - Deficient intrinsic factor production
    - Post-gastrectomy
    - Antibody vs parietal cells⁶: Pernicious anemia
      - Onset: Median = 60 years; Female slightly > Male
      - Antibody targets: Gastric H⁺/K⁺-ATPase
        
        Catalytic α subunit, and
        Glycoprotein β subunit
      - Regions of stomach affected: Fundus & body; Not antrum
      - Mechanisms of B₁₂ deficiency
        
        Reduced intrinsic factor production 2° parietal cell loss
        Antibodies to B₁₂ binding site on intrinsic factor: Prevent formation of complex that is normally carried to terminal ileum & absorbed
      - Associated immune disorders: Thyroiditis; Diabetes; Addison's; Ovarian failure; 1° hypoparathyroidism; Graves; Vitiligo; Myasthenia gravis; Lambert-Eaton syndrome; Common variable immunodeficiency with low Ig or IgA (younger patients)
      - Associated neoplasia: Gastric carcinoma (1% to 3%)
      - Family history: 20% of relatives also have pernicious anemia; Especially 1st degree females
      - Gastritis treatment: Corticosteroids; Azathioprine
  - No digestion of cobalamin-R-binder complex
    - Pancreatic insufficiency
  - Consumption of cobalamin in GI tract
    - Intestinal bacterial overgrowth
  - Poor absorption by distal ileum
    - Sprue-related disorders
    - Autosomal recessive disorders
  - Parasitic infection: Diphyllobothrium latum
- Dietary inadequacy in vegetarians
  - Sources: Meat & dairy products
- Congenital disorders of B₁₂ binding proteins
  - Vitamin B₁₂ R-binding protein deficiency
    - Neurological B₁₂ deficiency syndromes in adults
  - Gastric intrinsic factor deficiency
    - Congenital anemia & jaundice
  - Transcobolamin II deficiency
    - Megaloblastic anemia; Diarrhea; Immunodeficiency; Mental retardation
- Abnormalities of synthesis of active forms of B₁₂
  - Methylcobalamin deficiency, types E and G
    - Neurological (CNS) & hematological B₁₂ deficiency syndromes
    - In children
  - Adenosylcobalamin deficiency
    - Episodic ketoacidosis; Encephalopathy; Neutropenia; Osteoporosis
  - Combined methylcobalamin & adenosylcobalamin deficiency
    - Types I and II
    - Mental retardation; anemia; ± myelopathy in slowly progressive cases
  - Nitrous oxide exposure
    1. Oxidizes cobalt in cobolamin: Methylcobalamin inactivated
    2. Inhibits conversion of homocysteine to methionine:
    3. Reduced supply of S-adenosylmethionine
- Abnormal release of B₁₂ from lysosomes

Vitamin E deficiency

Vitamin E (α-tocopherol)

Vitamin E
- Mixture of tocopherols
- α-tocopherol most potent
- Antioxidant
  - Prevents peroxidation of polyunsaturated membrane fatty acids
  - ? Relationship with vitamin E
- Recommended daily allowance: Males 10 mg; Females 8 mg
- Absorbed & incorporated into chylomicrons in small intestine
Causes of deficiency
- Transfer protein disorders
  - A-β-lipoproteinemia
  - Vitamin E transporter deficiency
- Malabsorption
  - Chronic cholestasis
  - Cystic fibrosis
  - Chronic bowel disease: Celiac; Whipple's; Inflammatory; Tropical sprue; Chronic pancreatitis
  - Surgical: Post gastrectomy; Short bowel syndromes
  - Chylomicron retention disease
- Reduced intake
  - Malnutrition
  - Total parenteral nutrition: May be associated with selenium deficiency
Clinical
- Polyneuropathy
  - Sensory loss
    - Large fiber modalities
    - Sensory ataxia
  - Tendon reflexes: Absent
  - Electrodiagnostic
    - Sensory potentials: Usually small; May be normal
    - Abnormal somatosensory evoked potentials
- Myopathy: 1 patient
  - Related to high dose cholestyramine treatment
  - Weakness: Generalized
  - Serum CK: High
  - Muscle pathology: Small ovoid inclusions (H&E purple; GT pink; Acid phos +)
- CNS
  - Ophthalmoplegia
  - Spinal
    - Posterior column snesory loss
    - Extensor plantar responses
- Systemic: A-β-lipoproteinemia
  - Retinitis pigmentosa
  - Acanthocytosis
Pathology
- Dorsal root neurons: Early loss of distal region of central projection
- Spinal cord: Loss of fibers in posterior & Clarke column
- Axonal dystrophy (swellings) in cuneate & gracile nuclei
Diagnosis
- Vitamin E levels: Undetectable or very low levels in serum
- Other: Fat malabsorption ® Fatty stools; Low serum carotene
Treatment: Vitamin E supplementation
- A-β-lipoproteinemia: 100 to 200 mg/kg/day in childhood ? + vitamins A & K
- Malabsorption: 1 to 4 g/day

Hypervitaminosis E

Weakness: Proximal
Myalgia
Serum CK: High
Muscle
- Necrosis
- GT stain: Paranuclear accumulation of red granular material
  - Inclusion staining pattern: NADH-TR, Acid phosphatase, Esterase

Vitamin D deficiency⁵

1,25-Dihydroxy Vitamin D₃

Function
- Steroid hormone
- Active form: 1,25-dihydroxy vitamin D₃ (Calcitriol)
- Action via intracellular receptor
- Regulates Ca⁺⁺ & Phosphorus homeostasis
Clinical: Similar to 1° hyperparathyroidism
- Epidemiology
  - Dietary deficiency more common in
    - Northern Europe & US
    - Elderly patients
    - Immigrant populations
    - Infants: Vitamin D deficiency rickets
  - Other predisposition to vitamin D deficiency
    - Pigmented skin
    - Reproductive age females
      - High parity
      - Breast feeding, prolonged
    - Clothing: Wearing long sleeved dresses & veils (Females)
- Myopathy (50%)
  - Weakness
    - Distribution: Proximal; Symmetric; Arms > Legs
    - Severity: Mild to Moderate (4 of 5)
    - Gait disorder: Common
  - Muscle wasting
  - Myalgia
  - Muscle physiology
    - Reduced Force generation
    - Delayed relaxation
  - Course: Slow progression over months
- Tendon reflexes: Normal
- Carpopedal spasm
- Bone
  - Pain: Back, Hips or Lower limbs
  - Osteomalacia or Rickets (See Spinal disorders)
- Treatment
  - Vitamin D
    - Ergocalciferol: Oral (50,000 U 1x/week x6) or IM
    - Vitamin D: Oral 2000 to 3000 IU/Day for 6 weeks
  - Ca⁺⁺ supplementation: > 1 g/day
  - Disease course after treatment
    - Improvement in strength & reduced pain over weeks to months
Laboratory
- 25-Hydroxyvitamin D reduced (< 20 nmol/l)
- Parathyroid hormone: Increased
- Alkaline phosphatase: Often increased
- Serum CK: Normal
- Serum Phosphate: Low
- Serum Ca⁺⁺: Normal or Low (≤2.1 mmol/l)
- Radiographic: Osteomalacia; Pseudofractures (28%)
- EMG
  - Normal or Myopathic (Small polyphasic action potentials)
  - No spontaneous activity
- Muscle biopsy
  - Normal or Non-specific changes
  - Muscle fiber atrophy
Vitamin D deficiency: Other causes
- Vitamin D malabsorption
  - Dietary deficiency
  - Reduced Sun exposure
  - Malabsorption: Post-surgical; Bowel disease
  - Renal: Tubular acidosis; Chronic failure
  - Anticonvulsants
- Osteogenic osteomalacia
  - Onset: Mean 4th decade; Range 5 to 63 years
  - Clinical: Bone pain; Muscle weakness
  - Neoplasm: Mesenchymal; Bone & Soft tissue; Limbs, Head & Neck
  - Lab: Hyperphosphaturia, Hypophosphatemia, Normal serum Ca⁺⁺, Decreased serum 1,25-dihydroxyvitamin D₃

Biotin deficiency

Biotin

Biotin
- Cofactor required in carboxylation enzymes
  - Acetyl-CoA carboxylase
  - Pyruvate carboxylase
Deficiency: Causes
- Prolonged antibiotic therapies: Deplete intestinal fauna
- Excessive consumption of raw eggs
  - Eggwhite protein avidin binds biotin & prevents absorption
Onset
- Subacute encephalopathy & confusion
- Dysarthria & Dysphagia
- ± Facial nerve palsy: Supranuclear
- ± External ophthalmoplegia
Late features
- Spastic paraparesis
- Mental retardation
- Dystonia
MRI: Central necrosis of the head of the caudate ± Putamen
Treatment: Biotin (5-10 mg/kg/day)

Retinoid (Vitamin A derivatives) toxicity

Drugs: Etretinate; Isoretinoin
Discomfort
- Hyperesthesias & paresthesias
- Muscle cramps
- Myalgias & arthralgias
- Fatigue
Weakness
- Proximal
- Mild; Occasional
CNS: Pseudotumor
Systemic: Hepatitis
Serum CK: Normal or High
Muscle: Minor change
- Variation in fiber size
- Occasional necrotic fiber
- EM
  - Elliptical bodies between muscle fibers
  - Simplified neuromuscular junctions

Cuban epidemic neuropathy¹

Nomenclature: Similar to Strachan's syndrome in prisoners of war
Epidemiology
- Age: 25 to 64
- Male slightly > Female
- Risk factors
  - Tobacco use (Especially cigars)
  - Nutrition reduced
  - Cassava consumption
- Protective
  - Lycopena non-vitamin A antioxidant in tomato, guava, watermelon & red fruit
  - Riboflavin
- Causes: ? Reduced B-group vitamins, carotenoids & sulfur-containing amino acids
Clinical
- Optic neuropathy: Cecocentral scotoma (Bilateral); Photophobia; Color vision reduced
- Sensory-neural hearing loss: High tone
- Polyneuropathy
  - Symmetric
  - Sensory
  - Painful dysesthesias in hands & feet
  - ± Foot drop
- Gait disorder
- Autonomic: Urinary incontinence
- Myelopathy: Dorsolateral; Spasticity in legs
Laboratory
- Neuropathy: Axonal loss, Large > small fiber loss; Axonal regeneration
- CNS: Reduced Myelinated axons in Posterior column
Treatment: B-group vitamins
Prognosis
- Recovery in most with early treatment
- Visual field defects may persist

Bariatric surgery (Postgastroplasty) syndromes: Polyneuropathy +

Epidemiology
- Surgery: For morbid obesity
- Frequency of neuropathy: 5% to 10% of Gastric bypass surgeries
Associated with
- Malnutrition
- Surgical procedures
  - Gastrojejunectomy
  - Gastric stapling
  - Gastroplasty
  - Gastrectomy
  - Jejunoileal bypass: Higher risk
- Vomiting
  - Severe protracted
  - May be chronic after gastrectomy (68%)
- Weight loss
  - Degree: Mean 28%; Range 11% to 48%
  - Rapid
- B12 deficiency
- Copper deficiency
Neuropathy types⁹
- Polyneuropathy: Sensory-predominant
- Mononeuropathy
- Radiculoplexus neuropathy
Polyneuropathy
- Onset
  - Course
    - Chronic: 75%
    - Acute or Subacute: 25%
  - Numbness & paresthesias: Distal then proximal in legs
- Sensory loss
  - Distal ± Proximal
  - Modalities
    - Large fiber: Joint position & Vibration
    - Small fiber
  - May simulate myelopathic pattern
- Pain: 60%
  - Feet or Lower back
  - Less prominent than in nutritional (Cuban) neuropathy
- Weakness: Some patients
  - Distal or Proximal
  - Legs > Arms
- Hyporeflexia (66%)
- Autonomic: Uncommon
  - Hypotension: Syncope
- Progression: May develop quadriparesis
- Laboratory
  - Nerve conduction studies: Axonal loss
  - Pathology
    - Nerve
      - Axonal loss
      - Inflammation: Perivascular; Endoneurial & Perineurial
    - Muscle
      - Type 2 muscle fiber atrophy
      - Denervation: Angular muscle fibers
  - Serum albumin: Reduced
  - Serum transferrin: Reduced
Sensory polyneuropathy
- Onset: Years after surgery
- Distal
- Symmetric
- Paresthesias
- Slowly progressive
Mononeuropathy
- Median nerve at wrist: 75%
- Onset course
  - Rapid: 50%; More often in nerves other than median
  - Slow: 50%
Radiculoplexus neuropathy
- Frequency: 5%
- Locations: Cervical & Lumbosacral
- Onset course: Rapid
- Pain: All
- Electrodiagnostic: Axonal loss
Myelopathy: Postero-lateral spinal cord
- Weakness: Paraparesis
- Sensory loss
  - Spinal sensory level
  - Posterior column involvement: Prominent
CNS
- Encephalopathy: Wernicke-Korsakoff like disorder
  - Confusion
  - Memory loss
  - Eye movement disorders
- Affective disorders
- Optic neuropathy
  - Acute onset
  - 1 to 3 years after surgery
- D-lactate disorder: Bacterial overgrowth
Dumping syndrome
- Clinical features: "Neurohormonally mediated symptoms"
  - Facial flushing
  - Lightheadedness
  - Palpitations
  - Fatigue
  - Diarrhea
- Associations
  - Frequency: Up to 70% of patients after Roux-en-Y gastric bypass
  - Typically triggered by ingestion of concentrated sugar
Electrophysiology
- EMG: Denervation
- Nerve conduction studies
  - Axonal loss
  - Sensory + Motor involvement
Prevention: Nutrition counseling
Treatment
- Parenteral nutrition
- Vitamins: Thiamine +
- ? Reversal of surgery
Prognosis
- Death 8%
- Good resolution of signs 35%

Selenium Deficiency^3,4

Selenium
- Trace essential element
- Sources: Meat; Fish; Cereals
- Component of selenoproteins: Glutathione peroxidases; Iodothyronine 5'-deiodinases
- Deficiency produces
  - Glutathione peroxidase activity: Reduced
  - Oxidative damage
  - Reduced levels of selenoproteins
  - Increased toxicity of drugs & toxins: Nitrofurantoin; Paraquat
Deficiency & other syndromes
- Myopathy: Long term parenteral nutrition; Chronic bowel disease; Other dietary deficiency
- Epidemic cardiomyopathy
  - 2° Reduced dietary selenium in pregnant women & children in Keshan, China
  - ? Associated with Coxsackie B infection
- Selenoprotein disorders
  - Congenital muscular dystrophy with rigid spine: SEPN1
  - Hyperthyroxinemia: DIO1
- Selenium toxicity: Nail & Hair loss; Gastroenteritis; Dermatitis
- Animal disorders
  - "White muscle" or "Yellow fat" disease in horses, cattle & Guinea pigs
  - Probably related to concurrent selenium & vitamin E deficiency
Myopathy
- Causes of deficiency
  - Malabsorption: Chronic bowel disease
  - Dietary deficiency
    - Especially in regions with low selenium in soil: New Zealand; China; Central Africa
    - Parenteral nutrition: Long term; Critical illness
  - Chronic disorders with oxidative stress: HIV infection; Alcohol abuse
- Clinical
  - Muscle pain: Proximal
  - Weakness: Proximal, Symmetric
  - Frequency: Occurs only in minority of selenium deficient patients
- Laboratory
  - Serum CK: High or Normal
  - Serum selenium: Low
  - Vitamin E levels: Commonly low
  - Muscle biopsy
    - Muscle fiber atrophy
    - Vacuoles
    - Thinned myofibrils
    - Mitochondria: Enlargement; Reduced Number
- Treatment: Selenium supplementation
  - Most helpful with malabsorption & parenteral nutrition
  - Latency to improvement: 4 weeks
Cardiac disease: Arrhythmia; Cardiac failure

Copper deficiency

MRI: Copper Deficiency
Posterior column T2 signal

Acquired
- Predisposition
  - Zinc: High levels
    - Increased intake
      - Chronic over years
      - Sources
        
        Zinc supplements
        
        Coins
        
        Denture creams
    - Idiopathic
  - Molybdenum excess
  - Gastric bypass surgery
  - Chemotherapy: Tetrathiomolybdate
  - Copper chelating agents: Penicillamine; Clioquinol
  - Hyperhomocysteinemia¹²
  - Deficient copper intake
    - Total parenteral nutrition
    - Infancy
- Clinical syndrome: Myelopathy⁷
  - Sensory
    - Loss: Vibration; Joint position
    - Paresthesias
    - Gait: Sensory ataxia
  - Motor: May be normal other than gait
    - Spasticity
    - Leg dysfunction: Upper motor neuron pattern
    - Gait: Spastic-Ataxic
  - Reflexes
    - Tendon reflexes: Increased
    - Plantar responses: Extensor
  - Course: Progression over years
  - Laboratory
    - MRI: T2 signal increased
    - Early pathology: Axonal swelling
  - Treatment: Stabilization; Little improvement
- Clinical syndrome: Lower motor neuron syndrome + Sensory loss¹¹
  - Clinical
    - Weakness
      - Asymmetric
      - Proximal & Distal
      - Gait disorder
    - Sensory loss: Large fiber modalities
    - Reflexes
      - Tendon: Brisk; May be reduced distally
      - Plantar: Upgoing
  - Electrodiagnostic
    - EMG: Diffuse denervation
    - NCV
      - CMAP: Small; Asymmetric
      - SNAPs: Normal
  - Muscle biopsy
    - Acute denervation: Angular muscle fibers; Targets
    - ? Mitochondrial complex IV reduced activity
- Clinical syndrome: Neuropathy
  - Sensory-Motor
  - NCV: Axonal loss
- Clinical syndrome: Optic neuropathy
- Hematologic features
  - Sideroblastic anemia
  - Neutropenia
  - Myelodysplastic syndrome
- Treatment
  - Copper supplementation: Cupric sulfate (2 mg IV for 5 days)
  - Stop zinc intake
  - Paresthesias often improve
Inherited disorder: Menkes syndrome
Animal disorders
- Ataxic myelopathy
  - Swayback: in utero
  - Enzootic ataxia: Neonatal
  - Pathology: Cavitation of cerebral white matter
  - Pathogenesis: ? Cytochrome oxidase dysfunction
- Animals
  - Ruminants: Lamb
  - Goats: Cerebellar syndrome
  - Moose (Sweden)
- External link: Copper Development Association
Copper-containing enzymes
- Superoxide dismutase
- Mitochondrial Complex IV

Copper toxicity

Clinical syndrome: Wilson's disease
Mechanism: Mitochondrial enzyme toxicity ⁸
- Facilitates formation of oxygen radicals (ROS)
- Inhibition of pyruvate dehydrogenase (PDH) & α-ketoglutarate dehydrogenase (KGDH)

Critical Illness Neuropathy

Controversial syndrome
Very ill patients in intensive care (ICU) often develop mild polyneuropathy
- Distal
- Symmetric
- Sensory > Motor
Severe weakness in ICU is rarely 2° to "Critical illness polyneuropathy": Most have Myosin-loss myopathy
- Clinical features of myosin-loss myopathy
  - Sub-Acute onset
  - Respiratory failure
  - Weakness: Severe; Proximal > Distal
- Electrodiagnostic studies
  - NCV may mimic an axonal neuropathy with small CMAPs
  - Small CMAPs are 2° to inexcitability of muscle, not axonal loss
  - Sural sensory potentials may be reduced or absent
    - 2° to sensory neuropathy
    - Does not indicate severe loss of motor axons
  - EMG of proximal muscles rarely shows clear evidence of denervation
- Biopsy of a proximal muscle is required for diagnosis of myosin-loss myopathy
  - Small, sometimes angular muscle fibers: Usually type 2 muscle fiber atrophy, not denervation
  - ATPase stain at pH 9.4: Muscle fibers with reduced or absent staining

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1. Curr Opin Neurol 1998;11:539-544
2. Textbook of Clinical Neurology 1998 pp 798-809
3. JNNP 1999;67:829-830
4. Muscle Nerve 1998;21:637-639, 2003;Online January
5. Arch Int Med 2000;160:1199-1203, Can J Neurol Sci 2009;36:336-339
6. Immunology Today 2000;21:348-354
7. Neurology Today 2003;61:273-274, Arch Neurol 2003;60:1303-1306; Arch Neurol 2003;60:1782-1785
8. Ann Neurol 2004; Online March
9. Neurology 2004;63:1462–1470
10. Ann Neurol 2003;54:19-29
11. Muscle Nerve 2006;34:789-793
12. Neurobiol Dis 2006;23:725-730

Some illustrations from MW King

7/8/2009