Nutritional and toxic myelopathies

Nutritional and Toxic
Myelopathies
DR BHAVIN J PATEL
SR NEUROLOGY
MBS HOSPITAL AND GMC KOTA

Introduction
Myelopathy:- Disease of spinal cord.

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

Pathophysiology

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

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

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

Clinical features
4) Neuropsychiatric:-
Psychiatric:- irritability, depression or mood impairment , insomnia,
pshychosis
Cognitive:- cognitive slowing, forgetfulness, dementia
Derangement in monoamine neurotransmitter production

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

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

Diagnosis
Vitamin B12 level(serum):-
Spuriously low level:- multiple myeloma, pregnancy, oc pills use, HIV
infection
 Spuriously high level:- malignancy, myeloproliferative neoplasm,
alcoholic liver disease, renal disease

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

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

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

Neuroimaging
FLAIR and T2-weighted images
might demonstrate extensive areas
of a high-intensity signal in the
periventricular white matter

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

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.

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

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

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.

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

Clinical feature
Neuropsychiatric :- depression, psychosis and mild cognitive
slowing
Haematological:- Megaloblastic anemia
Gastrointestinal:- Mouth ulcer

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

UP TO DATE:- Vit B12 and Folate deficiency

Treatment
Oral folic acid supplement Intially 3 mg/day followed by maintenance
dose of 1 mg/day.
Symptomatic treatment:- similar to B12 deficiency

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

Causes
Gastric surgery
Excessive zinc consumption
Dietary deficiency
Enteropathies
Over treatment of Wilson disease

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

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

Clinical feature
Hematological manifestation:-
Anemia with leuckopenia
Thrombocytopenia rare
Bone marrow examination may show ringed sideroblast and
erythroid hyperplasia with decreased E:M ratio

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

Neuroimaging
Increased T2 signal involving dorsal
column in cervical cord
Signal changes may involve lateral
column and central cord
No contrast enhancement

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

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

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.

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.

Causes
Pancreatic exocrine insufficiency:- cystic fibrosis
chronic pancreatitis
Cholestatic liver disease:- biliary atresia
primary biliary cirrhosis
primary sclerosing cholangitis
Malabsorption :- chrons disease
Intestinal lymphagectesia
Extensive resection
Congenital:- abetalipoproienemia or defect in chylomicron synthesis or
secretion

Clinical Feature
Spinocerebellar syndrome:-
Gait impairment
Impaired vibration and joint position
Pyramidal signs
Peripheral neuropathy:- commonly associated leads to absent DTR
Pigmented retinopathy
Myopathy
Gaze palsie
Continuum (Minneap Minn) 2015;21(1):84–99.

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.

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

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

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

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.

Clinical feature
Peripheral neuropathy:-
Commonly associated to myelopathy
Numbness and paresthesia in glove & stocking pattern
Absent DTR
Cognitive changes

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

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

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

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

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.

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.

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

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.
Dis 6(7): e1759

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
Dis 6(7): e1759

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.
Dis 6(7): e1759

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

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

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

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

Management
Investigation :-
Diagnosis made by history of exposure
Serum thiocynate level
MRI is usually normal.
Treatment:-
Same as Lathyrism

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

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)

Clinical feature
Myeloneuropathy:-
Occasional upper limb involvement wrist drop
 Glove and stocking sensory loss with depressed DTR
 In later stages spasticity with hyperreflexia occur

Management
Investigation:-
Measurement of cholinesterase activity in red blood cells (RBC) helps
confirm the diagnosis
MRI :-late phase may reveal spinal cord atrophy

Management
Treatment :-
No specific treatment.
Steroid trial can be given.
Mild cases recover over several months but severe involvement left
with neurological deficit

Chemotherapy
Acute myelopathy is a rare but devastating complication of chemotherapy
 Methotrexate, cytarabine, cisplatin, cladarabine, doxorubicin,
vincristine, cytosine arabinoside
Indirect inhibition of methionine synthesis
Direct toxicity

Clinical feature
Two type of presentation:-
Transient, flaccid, areflexic paraparesis with pain and anesthesia
Progressive spastic-ataxic paraparesis with sphincter dysfunction

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

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

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

Damage to vascular endothelial cells,
 Direct injury of oligodendroglia and myelin sheaths,
Disturbance of the intra-spinal venous drainage

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

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

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.

Diagnosis
Radiation myelopathy is diagnosis of exclusion.
Differnatial diagnosis:-
Intramedullary metastasis
 Paraneoplastic myelopathy
Chemotherapy induced myelopathy

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

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.

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.

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

Decompression myelopathy
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

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

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

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

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.

Fluororsis
Treatment:-
Surgical decompression
Water purification.

References
Bradely’s Neurology In Clinical Practise, 7th Edition
Harrison’s Principle Of Internal Medicine,19th Edition
Continuum (Minneap Minn) 2015;21(1):84–99.
Seminars In Neurology, Metabolic And Toxic Myelopathy, Volume 32, Apr 2012, Pg 123-134
Joana Ramalho,toxic And Metabolic Myelopathies, Seminars In Ultrasound, Ct, And Mri
CONTINUUM (MINNEAP MINN) 2018;24(2, SPINALCORD DISORDERS): 427–440.
Up to date.com

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

Nutritional and toxic myelopathies

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