4. Vitamin B 12 Deficiency
Water soluble vitamin
RDA:- 2.4 μg for men and non-pregnant women
-2.6 for pregnant women
-2.8 μg for lactating women
-1.5–2 μg for children up to 18 years.
Total-body cobalamin content:- 2 to 5 mg in adults
Sources:- eggs, meat, milk, and many other animal proteins
Harrison’s principle of internal medicine, 19th edition, pg 640
7. Clinical features
Fatigue, generalised weakness
Neurological manifestations:-
1) Myelopathy:-
Subacute combined degeneration was first used by Russell an colleagues
in 1900
Slowly progresive myelopathy
Mild sensory symptoms with loss of vibration and proprioception
sense(POSTERIOR COLUMN)-First manifestation
Cobalamin Deficiency: Clinical Picture and Radiological Findings: Nutrients 2013, 5, 4521-4539
8. Clinical features
Weakness of lower limb(PYRAMIDAL)
Bladder bowel also can occur
Signs:-
Spasticity with abnormal tendon reflexes
Positive Babinski response
Impaired position and vibration sense
Ataxia with positive rhomberg sign
Lhermitte sign
Cobalamin Deficiency: Clinical Picture and Radiological Findings: Nutrients 2013, 5, 4521-4539
9. Clinical features
2) Peripheral neuropathy(25%):-
Paresthesia and numbness
Autonomic involvement- urinary frequency, constipation and erectile dysfunction
Subclinical neuropathy
3) Optic neuropathy:-
Bilateral painless subacute progressive vision loss
Central or centrocecal scotoma
10. Clinical features
4) Neuropsychiatric:-
Psychiatric:- irritability, depression or mood impairment , insomnia,
pshychosis
Cognitive:- cognitive slowing, forgetfulness, dementia
Derangement in monoamine neurotransmitter production
11. Clinical features
Associated conditions:-
Megaloblastic anemia:-
•Shortness of breath, chest pain, edema
•Pallor and jaundice
Gastrointestinal:-
•Glossitis..
•Abdominal pain and diahorrea- malabsorptive state
Skin hyperpigmentation
12. Diagnosis
Vitamin B12 level(serum):-
Low serum cobalamin levels may be the only information needed to confirm the
diagnosis.
Above 300 pg/ml:- normal
200-300 pg/ml :- borderline
<200 pg/ml:- deficient
14. Diagnosis
MMA and Homocysteine level:-
Indication:- Borderline or inconclusive vit B12 level
- Clinical discordant with B12 level
Normal values are assay specific.
Typical normal range:- MMA 70-270 nmol/l
-Homocysteine:- 5-15 micromol/l
Spurious high level:- MMA- renal insufficiency, methylmalonic aciduria
-Homocysteine- hereditary homocysteinemia
15. Diagnosis
CBC and Blood smear:-
Low Hb with Macro-ovalocytosis (MCV>100 Fl)
Mild leuckopenia and/or thrombocytopenia
Hypersegmented neutrophils
Low reticulocytes count
Howel jolly bodies and cabot ring
16. Diagnosis
Neuroimaging:-
Increased T2 signal intensity, commonly confined to posterior or
posterior and lateral columns in the cervical and thoracic spinal
cord
Sometimes, enhancement is noted.
The abnormal MR signals might disappear on follow-up after months
19. Diagnosis
Electrophysiological study:-
NCV:- Unveil the sensori-motor polyneuropathy, due to both demyelination
and axonal degeneration. ( 76% axonal and 24% demyelinating)
VEP:- to rule out subclinical optic neuropathy
Additional test:-
Schilling test ( historical value)
Autoantibodies to intrinsic factor
20. Treatment
Parenteral:- 1000 mcg cobalamine given parenterally for 1 week f/b 1000
mcg once a week for month f/b 1000 mcg once a month for life long
(cyanocobalamine)
Oral:- 1000-2000 mcg once a day for life long.
Symptomatic treatment:-
Baclofen
Antipshychotic
Pregabalin
Gait training
CONTINUUM (MINNEAP MINN) 2018;24(2, SPINALCORD DISORDERS): 427–440.
21. Monitoring
Haematological response:-
Decrease marker of hemolysis (LDH, indirect bilirubin):- 1-2 days
Increase reticulocyte count:- 3-4 days
Increase Hb:- 1-2 week
Disappear hypersegmented neutrophils :- within 2 week
Resolve leuckopenia and thrombocytopenia:- 2-4 week
Cobalamin Deficiency: Clinical Picture and Radiological Findings: Nutrients 2013, 5, 4521-4539
22. Monitoring
Neurological response:-
Symptomatic improvement started wthin 1-2 week, maximum upto 3 month and
may occur upto 1 year.
50% complete improvement, 40% partial improvement and 10% residual severe
neurologic deficit.
EEG, visual and somatosensory evoked potentials and P300 latency abnormalities
readily improve with treatment
Cobalamin Deficiency: Clinical Picture and Radiological Findings: Nutrients 2013, 5, 4521-4539
23. Folate deficiency
Normal body stores of folate:- 5 to 10 mg
RDA:- 200 to 400 mcg
Source of folate:- green vegetables, citrus fruits, legumes, dairy and other
animal products, seafood, and grains
Populations at risk include alcoholics, premature infants, and adolescents.
Harrison’s principle of internal medicine, 19th edition, pg 643
26. Clinical feature
Neurological manifestation:-
Myelopathy(SACD):-
Similar presentation to B12 deficiency
Onset is acute and rapid progression
Less common and less severe
Peripheral neuropathy:- Equal prevalence of autonomic involvement
A. Okada et al. / Journal of the Neurological Sciences 336 (2014) 273–275
27. Clinical feature
Neuropsychiatric :- depression, psychosis and mild cognitive
slowing
Haematological:- Megaloblastic anemia
Gastrointestinal:- Mouth ulcer
A. Okada et al. / Journal of the Neurological Sciences 336 (2014) 273–275
28. Diagnosis
Serum folate level:-
Above 4 ng/ml:- normal
From 2 to 4 ng/ml:- borderline
Below 2 ng/ml:- low
Blood sample should be taken empty stomach and before blood
transfusion
RBC folate level :- < 150ng/ml s/o folate deficiency
A. Okada et al. / Journal of the Neurological Sciences 336 (2014) 273–275
30. Treatment
Oral folic acid supplement Intially 3 mg/day followed by maintenance
dose of 1 mg/day.
Symptomatic treatment:- similar to B12 deficiency
31. Copper deficiency
Neurologic manifestations had been described in the veterinary literature as
swayback.
In 2001, Schleper and Stuerenburg:- myelopathy that occurred postgastrectomy
Pathophysiology:- important cofactor in several key enzymatic pathways that
are critical to the function of the bone marrow and the nervous system.
Mayo Clin Proc. :October 2006;81(10):1371-1384
33. Clinical feature
Neurological manifestation:-
Myelopathy:-
Subacute onset slowly progressive
Gait impairment (sensory ataxia)
Impaired position and vibration sense
Weakness of limbs and spasticity
Brisk reflex with extensor planter
Bladder involvement rarely occur
Mayo Clin Proc. :October 2006;81(10):1371-1384
34. Clinical feature
Peripheral neuropathy:-
Paresthesia in stocking pattern with impaired pain and temperature
Wrist and foot drop can occur
Brisk knee with absent ankle
Can occur without or before myelopathy
Optic neuropathy:- subacute bilateral visionloss
Myopathy and cognitive impairment
Mayo Clin Proc. :October 2006;81(10):1371-1384
36. Diagnosis
Serum copper and ceruloplasmin level:-
Both decreased in copper deficiency
24 hr urinary excretion of copper is less sensitive
Ceruloplasmin is acute phase reactant:- increased in inflammatory
condition
24 hr urinary zinc level
Vitamin B12 level
Mayo Clin Proc. :October 2006;81(10):1371-1384
37. Neuroimaging
Increased T2 signal involving dorsal
column in cervical cord
Signal changes may involve lateral
column and central cord
No contrast enhancement
38. Electrophysiological study
NCV:- Axonal sensorimotor polyneuropathy
-Pure motor polyneuropathy
-Pure sensory neuropathy
EMG:- myopathic changes present in 20% of patient
VEP:- to rule out optic neuropathy
Mayo Clin Proc. :October 2006;81(10):1371-1384
39. Treatment
Copper supplement:-
Oral or parenteral :- copper gluconate or chloride
Regimen:-8 mg/d for 1 week followed by 6 mg/d for 1 week followed by 4
mg/d for 1 week then 2 mg/d
-Intravenous 2mg elemental copper given for 5 days and then periodically.
Periodic monitoring of copper is required
In case of zinc induced deficiency:- discontinuation of zinc use
Mayo Clin Proc. :October 2006;81(10):1371-1384
40. Prognosis
Response of the hematologic parameters (including bone marrow
findings) is prompt and often complete
Recovery of neurological signs and symptoms seen in association with
copper deficiency varies.
Subjective improvement in sensory symptom is prominent.
Progression is typically halted.
Mayo Clin Proc. :October 2006;81(10):1371-1384
41. Vitamin E deficiency
Rare cause of myeloneuropathy
RDA:- 15 mg/d dietary alpha tocoferol
Source:- many grains, leafy vegetables, nuts, and seeds
Pathophysiology: exactly not known
Vitamin E is an antioxidant that prevents peroxidation of membrane fatty
acids
The American Journal of Clinical Nutrition 36: , pp 1243-1249.
44. Diagnosis
Serum vitamin E:-
Based on low vitamin E levels
Normal value 0.8 to 1.2 mg/dl
Hyperlipidemia or hypolipidemia can affect vitamin E levels
Corrected by dividing serum vitamin E levels by the sum of serum
triglycerides and cholesterol.
45. Neuroimaging
MRI Brain with spinal cord:-
Cerebellar atrophy as well as hyperintensity in the posterior columns of
the spinal cord on T2-weighted images.
NCV:- axonal sensory neuropathy
Genetic testing may be helpful in
childhood cases
46. Treatment
Oral replacement of vitamin E is the treatment of choice
Dosages ranging from 800 IU/d to 1200 IU/d
Parenteral replacement may be needed in severe cases.
Correction of serum levels does not always result in clinical
improvement of symptoms
Continuum (Minneap Minn) 2015;21(1):84–99.
48. Nitrous oxide(N2O)
Nitrous oxide (laughing gas):-
Anesthetic commonly used in surgical and dental procedures.
Used as a recreational drug for its mood-elevating effects
Pathophysiology:- N2O causes irreversible inactivation of vitamin
b12
American Journal of Emergency Medicine (2012) 30, 1016.e3–1016.e6
49. Clinical feature
Can occur after chronic use or single exposure in b12 deficient
person.
Myelopathy:-
Can mimic SACD
Acute or subacute onset and rapid progressive
Early presentation by sensory ataxia followed by weakness
Abnormal sensory examination with pyramidal signs.
American Journal of Emergency Medicine (2012) 30, 1016.e3–1016.e6
50. Clinical feature
Peripheral neuropathy:-
Commonly associated to myelopathy
Numbness and paresthesia in glove & stocking pattern
Absent DTR
Cognitive changes
American Journal of Emergency Medicine (2012) 30, 1016.e3–1016.e6
51. Diagnosis
Only clinical diagnosis based on history of exposure
Investigations:-
CBC shows High MCV
Vit B12 level :- low or normal
MRI cervical spine:- Identical changes may be seen similar to SACD
52. Treatment
Vit B12 given parenterally 1000 mcg OD for 5 days followed by
weekly for 2 month at least.
Administration of exogenous methionine may also be required
Prophylactic administration of vitamin B12 given weeks before
surgery who will receive N2O anesthesia
53. Heroin myelopathy
Abuses via IV or inhalational route
Pathophysiology:-
Hypersensitivity reaction
Direct toxicity
Vasculitis
Ischemia
Joana Ramalho,Toxic and Metabolic Myelopathies, Seminars in Ultrasound, CT, and MRI
54. Clinical feature
Resembles acute transverse myelitis
Usually involve thoracic segment but may extent upto cervical
region
Sudden onset flaccid paraparesis or quadriparesis
Sensory loss
Urinary disturbances
Joana Ramalho,Toxic and Metabolic Myelopathies, Seminars in Ultrasound, CT, and MRI
55. Diagnosis
Clinical diagnosis based on history of heroin used after ruling out other causes
Neuroimaging :-
MRI is frequently normal.
Hyperintense lesions on T2-WI and FLAIR images affecting the posterior and
lateral columns, pontomedullary region and ventral pons may be seen
CSF:- occasionally pleocytosis with elevated protein
Pathological examination of involved spinal segment shows extensive necrosis.
Joana Ramalho,Toxic and Metabolic Myelopathies, Seminars in Ultrasound, CT, and MRI
56. Treatment
Treatment is largely supportive.
Use of IV corticosteroids or plasma exchange is not proven to be effective.
The prognosis for recovery is often poor, although some patients may recover
completely.
Many patients develop residual spastic paraparesis and sensory deficits and not
all patients survive.
57. Lathyrism
Lathyrus sativus, also known as Khesari dal(in India)
or grass pea
Serving as a staple food for the poor farmers in
countries like India,Bangladesh, Nepal.
Age:- 15-45 yr
Toxic amino acid b-N-oxalylamino-L-alanine
Degeneration is most prominent in pyramidal tracts
that are responsible for lower extremity function.
Ngudi DD, Research on Motor Neuron Diseases Konzo and Neurolathyrism: Trends from 1990 to 2010. Negl Trop
Dis 6(7): e1759
58. Clinical feature
Three modes of presentation of neurolathyrism
The commonest being a sudden onset of leg weakness
Some patients complain of a subacute onset of walking difficulty.
Gradual progression of spastic paraparesis extending over months.
On examination hyperreflexia with severe spasticity
Sensory and bowel-bladder involvement are not uncommon.
Ngudi DD, Research on Motor Neuron Diseases Konzo and Neurolathyrism: Trends from 1990 to 2010. Negl Trop
Dis 6(7): e1759
59. Clinical feature
Stages of neurolathyrism
Latent stage:- Weakness of lower limb and spasticity
-Movement at knee and ankle joint restricted and painful
No stick stage:-
Flexion of knee is more marked and certain amount of inversion of foot
Tendency to walk on toes
Ngudi DD, Research on Motor Neuron Diseases Konzo and Neurolathyrism: Trends from 1990 to 2010. Negl Trop
Dis 6(7): e1759
60. Clinical feature
One and two stick stage:-
Above described symptoms become more
marked
Pt require crunches or stick to walk.
Crawler stage:- knee become completely
flexed so erect posture and walking become
impossible
Atrophy of thigh and leg muscles.
Ngudi DD, Research on Motor Neuron Diseases Konzo and Neurolathyrism: Trends from 1990 to 2010. Negl Trop
Dis 6(7): e1759
61. Management
Investigation:-
Clinical diagnosis
MRI study are negative
Treatment:-
Supportive with measures to reduce spasticity :-Physical therapy
Medication
Assistive devices
Prevention by proper preparation of the grass pea and combining it with other
cereals
62. Konzo
Konzo means “tired legs” in the native language of the
Yaka tribe of Congo in Africa
Consumption of poorly processed cassava root that
contains cyanide
Cyanide is also absorbed through skin or the
respiratory tract
Highest levels are typically found in the liver, lungs,
blood, and brain
Nzwalo H, Cliff J (2011) Konzo: Cassava, and Cyanogen Intake to Toxico-Nutritional Neurological Disease
63. Clinical feature
Acute intoxication symptoms due to cyanide:-
Tachypnoea, tachycardia, dizziness, headache, abdominal pain,
Vomiting,diarrhea,
Mental confusion, and convulsions
Without any recognizable motor sequelae
Generally 4–6 hours after ingestion of meals containing cassava
Nzwalo H, Cliff J (2011) Konzo: Cassava, and Cyanogen Intake to Toxico-Nutritional Neurological Disease
64. Clinical feature
Acute symmetric paraparesis
Transient non motor symptoms like paraesthesia,
cramping pain or low back pain
Variable upper limb involvement
On examination spasticity with hyperreflexia
Contracture may develop in later stages.
Additional neurological manifestation like optic neuropathy or pseudobulbar
dysarthria may occur
Nzwalo H, Cliff J (2011) Konzo: Cassava, and Cyanogen Intake to Toxico-Nutritional Neurological Disease
65. Management
Investigation :-
Diagnosis made by history of exposure
Serum thiocynate level
MRI is usually normal.
Treatment:-
Same as Lathyrism
Nzwalo H, Cliff J (2011) Konzo: Cassava, and Cyanogen Intake to Toxico-Nutritional Neurological Disease
66. Organophosphate poisoning
Most common complication is an acute intoxication with a cholinergic crisis
Some patients develop organophosphate induced delayed myelopathy and
neuropathy, also known as organophosphate-induced-delayed neurotoxicity
(OPIDN)
Pathophysiology:-possibly due to phosphorylation and subsequent aging of
neurotoxic esterase in the nervous system
More common with triorthocresyl phosphate
Continuum (Minneap Minn) 2015;21(1):84–99.
67. Clinical feature
OPIDN may occur In absence of the cholinergic or intermediate phase
Myeloneuropathy:-
Distal paresthesias and cramping muscle pain.
Progressive leg weakness and wasting
Foot drop( high stepage gait)
Continuum (Minneap Minn) 2015;21(1):84–99.
70. Management
Treatment :-
No specific treatment.
Steroid trial can be given.
Mild cases recover over several months but severe involvement left
with neurological deficit
71. Chemotherapy
Acute myelopathy is a rare but devastating complication of chemotherapy
Methotrexate, cytarabine, cisplatin, cladarabine, doxorubicin,
vincristine, cytosine arabinoside
Pathophysiology:-
Indirect inhibition of methionine synthesis
Direct toxicity
Joana Ramalho,Toxic and Metabolic Myelopathies, Seminars in Ultrasound, CT, and MRI
72. Clinical feature
Two type of presentation:-
Transient, flaccid, areflexic paraparesis with pain and anesthesia
Progressive spastic-ataxic paraparesis with sphincter dysfunction
73. Diagnosis
Chemotherapy-induced myelopathy is a diagnosis of exclusion
Differential diagnosis:- malignancy, viruses, radiation, and paraneoplastic
myelopathy
Neuroimaging:-
Initial imaging examination is often normal.
Symmetric increased T2 signal in dorsal and lateral columns of the cord
Abnormal contrast enhancement
Long-term outcome is cord atrophy
74. Treatment
No specific treatment
Prevention:-
Preservative-containing chemotherapeutic agents or diluents should not be
used intrathecally
Multiple and frequent intrathecal therapy should be avoided
Monitoring of methotrexate concentration in CSF
Immediate discontinuation of intrathecal methotrexate
Treatment and supplementation of derivates of folic acid
75. Radiation myelopathy
Radiation myelopathy is defined as injury caused by ionizing radiation
Two main reasons for spinal cord exposure to radiation
An intentional delivery to treat primary or secondary lesions
Its inevitable inclusion in a radiation field
Joana Ramalho,Toxic and Metabolic Myelopathies, Seminars in Ultrasound, CT, and MRI
77. Radiation myelopathy
Factors affecting spinal cord sensitivity:-
Total radiation dose, radiation dose per fraction, time between applications
Length and volume of spinal cord
Concomitant chemotherapy
Hypertension, diabetes
Congenital and acquired spinal cord abnormalities,
Pre-existing CNS injury
Joana Ramalho,Toxic and Metabolic Myelopathies, Seminars in Ultrasound, CT, and MRI
78. Clinical feature
1) Acute transient radiation myelopathy (most common)
Occur after 2- 4 mth latent period
Characterized by Lhermitte‘s sign with no other abnormalities
2) Acutely developing paraplegia or quadriplegia
Secondary to ischemia and/or hemorrhage of the spinal cord
Joana Ramalho,Toxic and Metabolic Myelopathies, Seminars in Ultrasound, CT, and MRI
79. Clinical feature
3) Lower motor neuron disease:-
Presumably caused by selective anterior horn-cell damage
4)Delayed radiation myelopathy (DRM)
Occur after latent period of 9-18 mths.
Chronic progressive radiation myelopathy
Bowel- bladder involvement may occur.
May fatal when involve cervical cord.
80. Diagnosis
Radiation myelopathy is diagnosis of exclusion.
Differnatial diagnosis:-
Intramedullary metastasis
Paraneoplastic myelopathy
Chemotherapy induced myelopathy
81. Diagnosis
Diagnostic criteria for DRM include
(1) The affected spinal cord segment must be in the irradiated zone
(2) Symptomatology must correspond to the radiated spinal cord segment,
(3) Latency period should be more than six months
82. Diagnosis
Neuroimaging:-
In acute transient radiation myelopathy:- normal MRI
In DRM :- initially MRI shows cord swelling with increased T2 signal intensity
with enhancement
Chronic stage cord atrophy
PET-CT:- Done to differentiate from primary spinal cord lesion and metastasis.
CSF:- Usually normal but occasionally mild elevation of protein with
pleocytosis.
83. Treatment
Acute radiation transient myelopathy:- treated with steroids
- complete recovery
DRM:-
No specific treatment
Steroid may derive short term effect
Other therapies like anticoagulation, pentoxyfylin and vitamin E used
with limited benefit.
84. Decompression myelopathy
Decompression sickness is a clinical syndrome caused by alterations in
environmental pressure.
Pressure resulting in liberation of inert gas bubbles in tissues or blood
Two types of decompression illness:
Type I :- characterized by joint pain, skin marbling, small patchy
hemorrhage and lymphatic Obstruction
Type II:- characterized by CNS involvement
- spinal cord involvement 77%
Robert N. Schwendimann, MD Neurol Clin 31 (2013) 207–218
85. Decompression myelopathy
Pathophysiology:-
Pathophysiological mechanism is not totally understood.
Embolization of arterial bubbles via a right-to-left shunt,
Development of bubbles within the spinal cord,
Embolization of the epidural vertebral venous system causing congestion
and venous cord infarctions
Robert N. Schwendimann, MD Neurol Clin 31 (2013) 207–218
86. Clinical feature
Most common:- subjective sensory abnormalities distributed according to
the dermatomes
More characteristic presentation:-
Numbness in the limbs
Progressive ascending level of both sensory and motor deficits
Often accompanied by disturbances of bladder function
87. Management
Diagnosis relies on clinical history, physical examination and MRI findings
MRI:- demonstrate patchy areas of increased T2 signal intensity in the white-
matter tracts
Treatment:-
Hyperbaric oxygen therapy treatment of choice
20 -30% patients have incomplete recovery.
Boussuges score more than 7 are independent predictive variables for poor
clinical recovery
88. Fluororsis
Fluorosis occurs when large amount of fluoride naturally present in water
was consumed.
Clinical feature:-
Back pain and stiffness
Neurological manifestation(10%):-
Cord compression and radiculopathy
Hearing loss due to sclerosed auditory canal
Entrapment neuropathy
Seminars in neurology, metabolic and toxic myelopathy, volume 32, apr 2012, pg 123-134
89. Fluororsis
Investigation:-
Increase ALP and PTH level
Normal calcium and phosphorus
Urinary fluoride level is not reliable
MRI- s/o osteosclerosis and ligamentous calcification causing multiple
level compression
Calcification of interosseous membrane of forearm.
Seminars in neurology, metabolic and toxic myelopathy, volume 32, apr 2012, pg 123-134
93. Subacute myelo-optic neuropathy
Clioquinol (iodochlorhydroxyquin) is an antifungal- antiprotozoal
drug used to treat intestinal parasitic diseases
Subacute onset of lower limb paresthesias and spastic paraparesis
with optic atrophy
Clioquinol-induced neurotoxicity may be a consequence of copper
deficiency
Editor's Notes
Intramyelin edema
Characteristically associated with conditions that are the source of multiple nutrient deficiencies
Anti oxidant
cytochrome- c oxidase for electron transport and oxidative phosphorylation in the mitochondrial respiratory chain
hypersensitivity is the predominant explanation since the myelopathy may occur after a period of abstinence
systemic toxins typically involve the nervous system more diffusely along with other organs
when going to sleep or when awakening from sleep. Usually after heavy manual work or prolong walk
processing methods including roasting , soaking prior to boiling, germination, and autoclaving
May precede paraparesis Disapper in week
Form fine motor impairment to spastic tetraparesis causing autonomous ambulation impossible
may occur soon after intrathecal injection
seen after weeks of a series of intrathecal treatments
caused by radiation induced blood vessel damage
Various combinations of motor and sensory deficits occur
it reduces the bubble volume and increases concentration of dissolved oxygen in ischemic tissues