CPC 17th April 2008

Female, 48 years old

2 years prior to admission: Proximal muscle weakness left lower extremity

1.5 years prior to admission: Weakness, on wheel chair Muscle atrophy

1 year prior to admission : Upper extremities weakness

1 week prior to admission : Quadriparesis

MRI: At 1.5 years prior to admission(lower extremities weakness with muscle atrophy)Cervical spondylosis, cervical canal stenosis C5-T1Herniated disc C 3-7

Physical therapy/ Orthropaedic surgery: C3-4 with instrument

Asymptomatic Degenerative Disk Disease andSpondylosis of the Cervical Spine: MR Imaging’

-1987 1648388Radiology ; :

<40 Yrs. Old (N = 167) >40Yrs. Old (N= 97)

Major Minor Major Minor Abnormality Abnormality Abnormality Abnormality

Herniated disc 5 (3%) 7 (4%) 1 (1%) 4 (4%)Bulging disc 0 8 (5%) 1 (1%) 5 (5%)Foraminal stenosis 5 (3%) 7 (4%) 9 (9%) 14 (14%) Disc-space narrowing 3 (2%) 18 (1 1%) 15 (16%)

21 (22%)Degenerated disc 13 (8%) NA 36 (37%) NA Spurs (spondylosis) 5 (3%) 23 (14%) 6 (6%) 33 (34%) Abnormal cords 15 (9%) 15 (9%) 1 (1%) 17 (18%)

Abnormal magnetic-resonance scans of the cervical spine in asymptomatic subjects. A prospective investigation

J Bone Joint Surg Am. 1990;72:1178-1184.

• Muscle weakness/motor predominate

• No cranial nerves involvement

• No paresthesia

• No bowel/urinary bladder/autonomic dysfunction

• Asymmetry to symmetry by clinical course

• Chronic progressive course

• Muscle atrophy

Corticospinal tract

Anterior horn cell: Amyotrophic lateral sclerosis,

Radiculoneuropathy: Demyelination disease

Mononeuritis multiplex

Neuromuscular junction: Myasthenia gravisLambert-Eaton myasthenic

syndrome

Myopathy: Polymyositis, Metabolic disorder

•Cervical spondylosis•Compressed fracture C6•HNP C 3-7, •Kyphoscoliosis•Osteopenia

Metabolic Bone DiseaseMetabolic Bone Disease

Bone turnover: Primary hyperparathyroidism Secondary

hyperparathyroidismAdynamic bone disease

Low Bone content: Osteoporosis

High bone content: Osteopetrosis Bisphosphonate

Abnormal mineralization: Osteomalacia/rickets

Causes of OsteomalaciaCauses of Osteomalacia Abnormal matrixAbnormal matrix

Abnormal vitamin D metabolismAbnormal vitamin D metabolismGastrointestinal diseaseGastrointestinal diseaseChronic liver diseaseChronic liver diseaseChronic kidney diseaseChronic kidney diseaseHypoparathyroidismHypoparathyroidism

Mineralization inhibitorMineralization inhibitorAluninum toxicityAluninum toxicityFluorideFluorideChronic metabolic acidosisChronic metabolic acidosis

Hypophosphatasia (AR)Hypophosphatasia (AR)

HypophosphatemiaHypophosphatemia

•Labs:

•BUN 9 mg %, Cr 0.4 mg %,

•Calculated creatinine clearance 151 mL/min

•Measured creatinine clearance 68.2 mL/min

•Na+ 142 mEq/L, K+ 3.7 mEq/L, Cl- 105 mEq/L, HCO3- 27 mEq/L

•Ca2+ 10.4 mg%, PO42- 1.3 mg%

•iPTH 72 pg/mL

Daily requirement = 800 mg Foods

Meat, poultry & fish Dairy products Processed foods Soda

•Etiology of Hypophosphatemia

•Internal redistribution•Re-feeding•Acute respiratory alkalosis•Hungry bone syndrome

•Decreased intestinal absorption•Inadequate intake (< 100 mg/day)•Chronic diarrhea, malabsorption•Vitamin D deficiency or resistance•Aluminum or magnesium ingestion

•Increased urinary excretion•Primary hyperparathyroidism•Secondary hyperparathyroidism•Proximal tubule dysfunction•Hereditary hypophosphatemic rickets•Onchogenic osteomalacia

Filtered Phosphate

Excreted Phosphate

Renal phosphate wasting

• 24 hours urine phosphate = 787.4 mg/day ( < 100 mg/day)

• Fractional PO42+ excretion = U PO

42+ xPcr

P PO42+ xUcr

= 26.73% (5 -10 %)

• Renal phosphate clearance = U PO42+ x V

P PO42+ x 1440

= 27.34 mL/min (5 -15 % mL/min)

Renal threshold phosphate conc (Tm PO4

2+/GFR)

Normal 2.0 – 3.5 mg% = 0.9 mg%

Lancet1975;309-10

.. GlucosuriaGlucosuria HypophosphatemiaHypophosphatemia HypouricemiaHypouricemia HypokalemiaHypokalemia AminoaciduiraAminoaciduira

Autosomal dominant, recessive, or X-linkedAutosomal dominant, recessive, or X-linked Wilson’s disease, Wilson’s disease, Galactosemia, tyrosinemia, cystinosis Galactosemia, tyrosinemia, cystinosis Multiple myeloma, amyloid, Multiple myeloma, amyloid, Heavy metal toxicity, chemotherapeutic drugs Heavy metal toxicity, chemotherapeutic drugs

(ifosfamide), imatinib mesylate(ifosfamide), imatinib mesylate

DisorderSerum

phosphateSerum

calciumALP

Vit D deficiency Low Low Elevated

Renal phosphate wasting Low Normal Normal

Chronic metabolic acidosis Normal Normal Normal

Proximal RTA Low Normal Normal

Hypophosphatasia Normal Normal Low

Bone matrix abnormality Normal Normal Normal

Hypophosphatemia with renal phosphate wasting

• Proximal RTA

• Hyperparathyroidism

• Mutation of type 2a sodium-phosphate co-transport: Absorptive hypercalciuria type III, nephrolithiasis

Hereditary hypophosphatemic rickets with hypercalciuria

• Hereditary hypophosphatemic ricket

• Tertiary hyperparathyroidism post-kidney transplantation

• Onchogenic osteomalacia: High phosphatonin:

FGF 23, matrix extracellular phosphaglycoprotein (MEPE), frizzled growth factor 4 (FRP-4)

iPTH stimulate FGF 23

Kidney Int 2003, 64 : 2272–2279

Log FGF-23

CKD, Renal bone disease, Aging

New Engl J Med 2003;348:1656

•Fibrous dysplasia

•Hemangiopericytoma

•Osteosarcoma

•Chrondroblastoma

•Chondromyxoid fibroma

•Malignant fibrous histiocytoma

•Giant cell tumor

•hemangioma

Mayo clinic 1994

Mesenchymal tumor cause TIO

•Progressive muscle weakness•Severe metabolic bone disease/Osteomalacia•Hypophosphatemia/Severe renal phosphate wasting•Groin mass

Onchogenic osteomalacia/immobilization osteoporosis

Investigation: Groin mass excision/immunohistochem staining Serum FGF-23 concentration (Octreotide labeled indium-111 scan)

Mesenchymal tumor mass

Acquired high phosphatonin (FGF-23)

Severe renal phosphate wasting

Severe osteomalacia, immobilization osteopenia

Muscle weakness