NEUROTICS

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NEUROTICS
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• 1) CEREBRAL
• a) CNS DEPRESSANTS - e.g., Alcohol, GA,
  Opioid analgesics, Sedatives, Hypnotics.
• b) CNS STIMULANTS e.g., CAD, Caffeine,
  Amphetamine, Methylphenidate.
• c) DELIRIANTS Dhatura, Cannabis, Cocaine,
  Atropa belladona, Hyocyamus.

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• 2) SPINAL
• e.g. Strychnos nux vomica,
• Gelsemium.
• 3) PERIPHERAL
• e.g. Conium , Curare.

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ALCOHOL
5

• ETHYL ALCOHOL
• METHYL ALCOHOL
• ETHYLENE GLYCOL
• ISOPROPYL ALCOHOL

6
INEBRIANTS

• Inebriant produces Intoxication
• Light headedness, confusion, disorientation,
  drowsiness.
• Prolonged sleep recovery
  Hangover (headache, irritability, lethargy,
  nausea abdominal discomfort).

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ETHYL ALCOHOL

• C2H5OH
• Transparent , colourless, volatile liquid with
  spirituous odor and burning taste.
• Absolute Alcohol 99.95
• Rectified Spirit 90
• Industrial Methylated Spirit 95Wood Neptha
  5
• 
  (Methyl alcohol)
• Fermentation of sugar by yeast -- till (15 vol)
• Beverages Alc Water Congeners (0.5)
  
  
• add
  flavour

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• Proof spirit at 10.5C weighs exactly 12/13
  part of an equal measure of D.W.
• Underproof and Overproof
• of Alc content x 2 Proof
• One unit 8 gms

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Percentage by Volume

• Vodka 60- 65
• Rum, Liquors 50-60
• Whisky , Gin, Brandy 40-45
• Port, Sherry 20
• Wine , Champagne 10 15
• Beers 5- 8
  

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• Consumption 1-2 drinks per day
• Safe Limits of Alcohol 210g in men per
  
  week
  140g in women
• Arrack Liquor distilled from - palm, rice,
  sugar or jaggery etc. (40-50) and may be mixed
  with Chloral hydrate and KBr for greater kick.
  

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ABSORPTION

• Requires no digestion
• Immediately by Simple diffusion
• 20 from Stomach , 80 from Small intestine.
• 60 absorbed in 30-60 min, 90 in 60-90 min.
• Detected in blood within 2-3min.
• Max.conc.in blood within 45-90min. (mainly1hr).

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Factors Increasing Absorption

• Carbonated drinks
• Warm
• Conc. 10-20
• Absence of congeners
• Without food
• Gastrectomy
• Drugs (which increase gastric emptying )
• eg. Cimetidine, ranitidine, etc.

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Factors Decreasing Absorption

• Cold
• Conc. 10 (Dilution e.g. Beer)- takes double
  time
• 40 - Pyloric Spasm
• - Reduced gastric
  motility
• - Irritation of mucosa
  mucus secretion

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• Food (Fat and Protein)
• - Fatty meal - delays by many hours
  . - Mixed meal
  -reduces max conc. by ½
• Diseases Achlorhydria , Chronic gastritis
• Drugs (which reduce gastric emptying)
• eg. Aspirin, Atropine, etc.

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Distribution

• More Alveolar air (diffusion)
• Water content
• Less RBC
• Fat (Adipose tissue, Obese,
  Females)
• Venous (10 less than Arterial)
• Equilibrium
• - Capillary Arterial Brain
  (1-3min)
• - Venous ( 1 hr)

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• Females have 25 higher blood alcohol conc. for
  the same amount consumed d/t -
• - small volume of distribution
• - small aqueous compartment
• - more variable absorption from gut
• - lower activity of gastric ADH enzyme
• - faster hepatic clearance
• - higher conc. of acetaldehyde
• - poor solubility in body fat

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EXCRETION

• All routes.
• 10 is excreted.
• 5 - Breath
• 5 - Urine
• Traces- Sweat , saliva, milk, tear and feaces.
• Skin glands Odour

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METABOLISM

• 90 is Metabolised
• - 90 of which is oxidised in Liver.
• - 10 is metabolised by Cytochrome
  P4502E1 .
• Alcohol
  Acetaldehyde
• dehydrogenase (ADH)
  dehydrogenase
• Alcohol Acetaldehyde
  Acetic acid (or
  NAD Acetyl
  CoA)
• By- Fructose
  Krebs
  - Enzymes (Chronic alcoholic)
  cycle
• By Liver damage
  CO2 H2O
• Acetate can form glycogen , protein ,fats and
  cholesterol.
• A Diabetic who is Ketogenic will produce fat .
• 
  
  

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• Disappears from blood at 10-15 ml/hr
  
  
  (15mg/100ml/hr)
• Elimination varies 12-27mg/100ml/hr (Av18mg)
• Fast - With large dose
• - Chronic alcoholics
  (30-40mg/100ml/hr)
• Slow - Liver damage
• 10 of metabolized is deposited in tissues as
  lipids (cholesterol and neutral fat)

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ACTIONS

• Endogenous (Metabolism or bacterial activity in
  GIT)
• Stimulant and selective depressant (Primarily RAS
• Effects - Frontal lobes (mood changes)
• - Occipital lobes (visual
  disturbances)
• - Cerebellum (loss of
  coordination)
• Like hypoxia on neural cells ( reduces activity)
• Depresses cells of Conduct , Judgement
• Self criticism with release of
  inhibitory tone
  (unrestrained behavior).
• ?Brain function ?Vitals

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• Generalized vasodilatation (Skin)
  Hemorrhage
• Hypnotic.
• Diaphoretic Sensation of warmth
  Heat loss.
• Tachycardia Bradycardia
• (at lower conc.)
  (at higher conc. 300mg)
• Toxic to every organ, d/t acetaldehyde or change
  in redox potential.
• Blocks metabolism and increases levels of some
  drugs.
• Moderate consumption ? HDL LDL

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• ? Appetite (?salivary gastric juice)
• Carminative (Brandy)
• Diuresis (d/t ?ADH)
• Spirituous liquor Heamorrhagic
  gastritis
• Mixing of drinks ?Gastric emptying
• Fasting blood Alcohol 0.001mg
• IN VINO VERITAS

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Causes of Death

• CNS Depression (respiratory centre)
• Aspiration of vomit
• Chronic effects of Alcohol.

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ACUTE POISONING

• 1) STAGE OF EXCITEMENT (50-100mg)
• Feeling of well being slight excitation.
• Action , emotion speech are less restrained.
• Lowering of inhibitions.
• Inc. confidence and lack of self control.
• Forgets good manners and is careless.
• At 30mg - impaired cognitive function ,
  motor coordination sensory
  perception.
• At 50mg - slurring of speech, unsteadiness,
  drowsiness, impaired reasoning memory,
• decreased perception concentration .

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• ?Visual acuity at conc. 20mg in abstainers
• 20-33mg in moderate
  drinkers
• 40-70mg in heavy
  drinkers.
• Judgment motor control
• 
  affected at 25-50mg.
• Altered time space perception.
• Pupils Dilated.
• 40-100mg ALCOHOL GAZE NYSTAGMUS.
• 50-100mg loss of inhibitions laughter.
• 100-150mg slurred speech, unsteadiness
  nausea.

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• Mental concentration is poor judgment is
  impaired.
• ? Attention Recall memory.
• ? Sensitivity to pain (at 80mg).
• ? Reaction time (at 50mg).
• ? Sexual desire impaired performance
• (prolonged intercourse without ejaculation).

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2)STAGE OF INCOORDINATION (150-250MG)

• Sense perception skilled movements are
  affected.
• Alteration in conduct.
• Carefree, cheerful, ill-tempered, irritable,
  excitable, quarrelsome , sleepy, etc.
• In coordination in fine skilled movements
• ( altered speech and fine finger movements)
• Nausea and Vomiting.
• Alcoholic smell (in breath).
• Face flushed , Pulse rapid, Temp Subnormal.
• ? Sense of touch, taste, smell hearing.

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3) STAGE OF COMA

• Motor sensory cells affected deeply
• Speech thick and slurring
• Coordination is affected giddy, stagger
  falls.
• Pulse rapid,
• Temp Subnormal
• Pupils contracted, Dilate on pinching or
  slapping, with slow return (Mc Ewan Sign).

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• Micturition Syncope
• At night
• Loses consciousness d/t upright posture
• Munich Beer Heart
• Cardiac dilation and hypertrophy
• Hang over
• Recovers from deep sleep in 8 10 hrs
• Wakes with acute depression nausea,
• abd. discomfort, irritability, lethargy and
  headache.

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• Death - at 400mg
• - below 400mg in
• chr. debilitating disease
• severe arteriosclerotic
  heart disease
• pulmonary emphysema
• chronic lung disease with
  hypoxia.
• Low blood alc. levels seen in
• - Prolong coma causing hypoxic brain damage
• - Prolong survival after heavy drinking.

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• Fatal Dose
• 150 250 ml of Absolute alc. consumed in 1
  hr
• Fatal period
• 12-24 hrs
• Tolerance
• is acquired, lost by out of practice
• d/t- tissue sensitivity or rate of
  absorption
• restricted by liver damage

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Treatment

• Evacuation of stomach bowel with Gastric
  Lavage.
• Keep warm
• 1 ltr. N.S. with 10 Glucose, 100 mg Thiamine and
  15 units of insulin
• Nerve stimulants (Caffeine and Strychnine)
• Oxygen
• Dialysis Hemo or Peritoneal

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Post mortem appearance

• Alcoholic odour in cavities
• Stomach - Acute inflammation with coating of
  mucus
• Brain, Liver Lungs congested with smell of
  alc.
• Blood fluid and dark
• Brain Meninges Oedematous congested
• Cloudy swelling in parenchymatous organs

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Chronic poisoning

• Addicts are the people who cannot stop drinking
  for long or develops withdrawal symptoms if they
  stop drinking.
• It results in impaired social or occupational
  functioning.
• They suffer from nausea, vomiting, anorexia ,
  diarrhoea , jaundice, tremors of the tongue and
  hands, loss of memory, impairment of judgment,
  coma, death.

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Post mortem appearance

• Sign of malnutrition present.
• The GI mucosa is reddish brown and congested.
• Liver is congested and enlarged with weight
  approximately 2kg . The surface is pale and
  greasy .
• Later cirrhosis develops and liver becomes
  smaller and contracted with weight 800-1200gm.
• Kidneys show granular degeneration
• Heart shows fatty degeneration and patchy
  fibrosis.

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Treatment

• 1. Disulfiram 250mg OD .
• It inhibits aldehyde dehydrogenase.
• It causes accumulation of aldehyde in blood and
  tissues .
• Aldehyde causes unpleasant symptoms such as
  flushing , palpitation , anxiety ,sweating ,
  nausea , vomiting ,abdominal cramps ,due to which
  patient dislikes alcohol.
• Disulfiram like reaction is caused by
  metronidazole.

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• 2. Citrated calcium carbamide -50 mg OD
• 3. Chlorpromazine -25-50 mg 6 hourly
• 4. Clonidine 60-180 mg/hr iv
• 5. Chlormethiazole

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Drunkenness

• The state of an individual whose mind is affected
  by the consumption of alcohol.
• Drunkenness is a consequence of drinking
  intoxicating liquors to such an extent as to
  alter the normal condition of an individual and
  significantly reduce his capacity for rational
  action and conduct. It can be asserted as a
  defence in civil and criminal actions in which
  the state of mind of the defendant is an
  essential element to be established in order to
  obtain legal relief.

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Medical examination of Drunkenness

• Exclusion of injuries and pathological state
• 1.Severe head injury
• 2.Metabolic disorder
• 3.Neurological condition
• 4.Drugs like insulin, barbiturate, morphine
• 5.Pre-existing psychological disorder like
  hypomania
• 6.High fever
• 7.Exposure to CO

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Medical examination of Drunkenness

• B. History
• C. General behaviour-
• 1.general manner
• 2.state of dress
• 3.speech
• 4.self control
• D. Memory and mental alertness
• E. Hand writing
• F. Pulse - usually rapid, full and bounding

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• G. Temperature-raised
• H. Skin-dry
• I. Mouth
• J. Eyes-
• 1.General appearance-lid swollen and red
• 2.Visual activity-reduced
• 3.Intrinsic muscle-pupil (equal or unequal dilate
  or contracted, reaction to light (may be unequal,
  brisk slow and absent)
• 4.Extrinsic muscle- test for convergence,
  strabismus, and nystagmus.

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• K. Ears - examine for any impairment
• L. Gait-examine for manner of walking, reaction
  time to a direction to turn, manner of turning,
• M. Stance-whether the examinee can understand
  with his eye closed and heel together (Romberg's
  sign)
• N. Muscle incordination-finger nose test
• O. Reflexes-test for knee and ankle reflex
• P. Pulmonary, cardiac and alimentary
  system-general examinations for presence or
  absence of any disease.

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Laboratory Investigation-A. Urine

• Conc. of alcohol is 25 higher than in blood
  collected in same time.
• First sample should be taken as soon as possible
  while second sample should be taken 25 to 30
  minutes later.
• Multiplication of alcohol concentration in the
  second urine specimen by 0.75 gives an
  approximate value of blood alcohol level, during
  the time that this specimen was being secreted.

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B. Collection of blood

• Spirit must not be used for cleaning the skin,
  and syringe must be free from any traces of
  alcohol.
• Skin should be cleaned with a solution of 11000
  mercuric chloride or washed with soap and water.
• Blood sample should be preserved by addition of
  100 mg. of sodium fluoride and 30 mg. potassium
  oxalate for 10ml.followed by shaking. this
  prevent loss of alcohol by glycolysis and
  bacterial action.
• Collection of post-mortem sample-the best place
  to obtain blood is from femoral or iliac veins or
  axillary veins.
• In embalmed bodies alcohol can be estimated
  either in muscle or vitreous.

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Widmarks formula

• a
  prc
• aweight of alcohol in gm.in the body
• pbody wt in kg
• rconstant (0.68 for men and 0.55 for women)
• c concentration of alcohol in blood (in mg. per
  kg.)
•  
• For urine analysis the
  formula is
• a
  3/4 prq
• q is alcohol concentration ( mg. per kg.) in
  urine

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Methods of determining blood alcohol

• Kozelka and Hine Macro-method
• Cavett test Micro test
• Other techniques
• Direct injection gas chromatography
• Enzyme- spectrophotometric assay
• Oxidation techniques

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C.Breath

• Breath analyser machines operate on the principle
  that alcohol absorbs radiation in the infrared
  region.
• Concentration of alcohol in deep lung air
  dependent on concentration in arterial
  blood.2100-2300ml of alveolar air contains same
  amount of alcohol as one ml. of blood (Henrys
  law)

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• 60 100 ml of breath
• Drunkotester, drunkometer, intoximeter,
• alcometer, alcotest, or breathalyser.
• Residual alcohol disappears from mouth in 20
  minutes.
• Test should be repeated after 20 minutes.

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D.Saliva

• Mouth should be thoroughly washed with water
  and about 5 ml of saliva collected in a test tube
  containing 10 mg. of sodium fluoride.

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E. Vitreous

• At equilibrium for every unit of alcohol in
  blood there are 1.2 unit of alcohol in vitreous,
  as it has high water content

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Medical terminology

• Below 10 mg Sober
• 10 to 70 mg Drinking
• 80 to 150 mg Under the influence
• 150 to 300 mg Drunk or intoxicated
• 300 to 400 mg Stupor
• 400mg and above Coma and death

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Hazards of alcohol

• Alcohol is associated with domestic violence,
  child abuse and suicide.
• Personal risk are
• 1.He may die of exposure
• 2.On inhalation may cause pneumonia
• 3.Inhale his vomit or dentures
• 4.May fall and sustain a head injury
• 5.May fall into water and drowned

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Alcohol palimpsests (alcoholic blackout)

• it is a condition seen among alcoholics, and
  rarely in non addictive drinker, after drinking a
  moderate amount of alcohols. this behaviour
  resembles the blackouts in anoxaemia. this may
  results in loss of memory of a period of drinking
  spell, or in some cases, the inability to recall
  what happened over a period of days.

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Alcohol and traffic accident

• Safe driving is interfere due to
• 1.increase in reaction time
• 2.creates false confidence
• Impairs concentration, dulls judgement and
  degrades muscle coordination
• It decreases visual and auditory acuity
• Below 50mg-in majority driving not affected
• At 60 mg-risk of accident double in compare
  to sober driver
• 80-100mg-risk of accident increase 12 fold
• Over 150mg-risk become 20 times

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• Statutory limit in India is 30 mg (S.185, MOTOR
  VEHICLE ACT,1988).the punishment for offences
  fine up to 2000rs or 6 month imprisonment or
  both, and for subsequent offence fine up to 3000
  or imprisonment up to 2 years or both.

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Alcohol withdrawal

• Symptoms appear 12 to 48 hrs after reduction in
  alcohols intake. most common symptoms is tremor
  and shakes. the essential feature is coarse
  tremors in hand tongue and eyelid in association
  with at least one of the following-
• a)nausea and
  vomiting
• b)malaise and
  weakness
• c)hypertension
  ,tachycardia and sweating
• d)anxiety,
  depressed mood and irritability
• e)transient
  hallucination and illusion
• f)headache and
  insomnia.
• Withdrawal seizures are typically single and
  generalised and usually develop 6 to 48 hrs after
  last drink. About 1/3 rd of these patient will
  develop delirium tremens unless preventive
  measures are taken.

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Pathology- Delirium Tremens

• Results from long continued action of poison on
  the brain. it occurs in chronic alcoholics due
  to1)temporary excess2)sudden withdrawal of
  alcohol
• 3)Shock after receiving an injury such as
  fracture of a bone
• 4)Acute infection, such as pneumonia,
  influenza, erysipelas,etc.
• Typically begin 72 to 96 hour the last drink.

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Main symptoms

• are coarse muscular tremors,insomnia,restlessness,
  loss ofmemory,psychomotoragitation,confusion,disor
  ientation,fear,tendency to commit suicide. other
  symptoms are diarrhoea, dilated pupil,tachypnoea
  and hypertension.
• Death occurs in 5 to 15 cases due to cerebral
  oedema, cardiac failure and shock.
• Treatment-20 mg of chlordiazepoxide, or 100 mg of
  diazepam are given 4 times a day.anticraving
  agent like acamprostate,naltrexone and
  fluoxetine.

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Alcoholic polyneuritis and korsakoffs syndrome

• Symptoms are weakness and pain in the
  extremities, wrist and foot drop, loss of deep
  reflex, tenderness of muscle.

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• Alcoholic Paranoia-there are fixed delusion but
  not hallucinations.
• Acute alcoholic hallucinosis -persistent
  hallucination develop with in 48 hrs after
  cessation of alcohols
• Alcoholic epilepsy -seizures occurs after a day
  or more after termination of drinking session.

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Wernickes encephalopathy

• Results from a hypothalamus, cerebellum
  midbrain lesion due to heavy drinking.
• Vit-B1 deficiency occurs

62

• Cardiac dysrhythmias- tachyarrhythmia's are
  common because of high adrenergic activity.
• Marchiafavas syndrome -degeneration of corpus
  callosum may occur.
• Mallory-Weiss syndrome -ruptured oesophagus with
  mediastinitis

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• Malnutrition
• Gastric and Peptic Ulcer
• Cirrhosis
• Myocarditis
• Pancreatitis
• Mental illness
• Disturbance in tryptophan metabolism

64

• Holiday Heart Syndrome
• Wet Berri-berri- Inc. H.R. ,Raised JVP,
  Vasodilation, peripheral edema PND.
• Boer Haeve Syndrome Spontneous transmural
  rupture of esophagus (typically in forceful
  emesis).
• Zieve Syndrome
• -Occurs after withdrawl of alcohol from
  prolong alcohol abuse.
• -Hemolytic anemia, spur cells and
  acanthocytes, hyperlypoproteinemia jaundice.

65
Alcohol and Criminal behaviour

• S.510,IPC
• Misconduct in public by a drunken person is
  punishable with imprisonment up to 24 hrs.

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Alcohol and Sudden death

• Sudden death may occur due to cardiac
  dysarrhythmias and cardiopulmonary arrest.

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Alcohol after death

• 1. If death occur due to trauma- A post-mortem
  alcohol estimation in Subdural blood clot will
  give true picture.
• 2.No appreciable loss by evaporation or any other
  means
• 3. With advance putrefaction, the entire content
  of the vascular system including alcohol is
  destroyed. Analysis of brain gives best results.

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• 4.Ethanol and other alcohol can be produced
  during putrefaction by fermentation of
  carbohydrate and proteins of the body (usually 20
  to 30 mg/100ml).this may occur due to enzyme,
  bacteria, yeast, fungi
• The commonest organism is E. coli.

69

• 5.The longer the interval after death and higher
  the temperature, the more is produced.
• 6.Alcohol conc. in excess of 0.2 would indicate
  alcohol consumption prior to death.

70
Methyl alcohol

• Also known as wood alcohol
• It is present in antifreeze , paint removers ,
  dyes, adhesives and varnish .
• Absorption absorbed from stomach, intestine ,
  lungs and skin.
• Rate of oxidation is 1/5th of that of ethanol.
• Accumulates in blood with repeated small doses
  and remains in blood for 3 -4 days.
• 80mg/100ml of blood is dangerous level.

71

• Methanol ? Formaldehyde ? Formic acid
• Liver (x 33
  ) ( x 6 )
• 
  Metabolic Acidosis
• 
  Retinal Toxicity
• Formate may inhibit cytrochrome oxidase, inc
  lactate.
• It is distributed according to water
  content, and conc in vitreous body optic nerve.
  
• 
  

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• Signs and symptoms
• Same as ethyl alcohol but inebriation is not
  prominent.
• Symptoms are N/V , severe cramps in abdomen,
  headache , dizziness , neck stiffness ,
• The effect on CNS is more intense and prolonged
  Delirium and Coma (for 2-3 days)
• Toxic effect on liver and kidney (acute tubular
  necrosis).

73

• Metabolic acidosis (d/t lactic other acids )
• Anionic acidosis
• Pupils are dilated and fixed
• Visual disturbances like photophobia , blurred or
  misty vision (snowfield vision), central and
  peripheral scotoma , decreased light perception ,
  concentric diminution of visual field for color
  and form.
• Sudden failure of vision or complete blindness is
  due to optic neuritis and atrophy.

74

• Fatal dose 60-200ml
• Fatal period 24-36 hrs
• Elimination 3-5 through lungs
• 12 through kidneys
• Cause of death Acidosis

75
Treatment

• 1. G.Lavage. with 5 bicarbonate soln.
• 2. Activated charcoal
• 3. Antidote Ethanol , 10 100 ml as iv
  infusion , level of 100-150 mg is maintained at
  all times.
• 4. Alternatively 60ml Ethyl alcohol in 200 ml
  fruit juice is given per orally.
• 5.Haemodialysis is treatment of choice in severe
  poisoning.

76

• 6. Methyl pyrazole (4MP or fomepizole) It is
  competitive inhibitor of alcohol dehydrogenase.
• 15mg/kg f/b 10mg/kg after 12 hours for 4
  doses
• 7. Folinic or folic acid 50-75mg every 4
  hourly
• 8. Sodabicarb to treat the metabolic acidosis
• 9. Place the patient in left lateral position and
  head down to avoid aspiration of vomitus

77

• PM appearances Cyanosis is marked
• Absence of PM clotting of blood
• Pyridine may give the skin a purple colour
• The mucous membrane of stomach and duodenum is
  congested and inflamed
• Small or large intestine or both are contracted
  and resemble thick pipe with narrow lumen
• Lungs brain bladder are congested.
• Liver shows fatty changes
• Kidneys show tubular degeneration
• MLI poisoning is mostly accidental

78
Questions

• 1.Widmarks formula are used for estimation of
• Cyanides
• Alcohol
• D.D.T
• Teeth

79

• 2.Optic atrophy can be caused by.....poisoning
• Phosphrous
• Ethyl alcohol
• Methyl alcohol
• Lead

80

• 3.Fetal dose of methanol
• 15ml
• 30-60 ml
• 60-250ml
• 500ml

81

• 4.Morbid jealousy is diagnostic of
• Cocaine
• Cannabis
• Alcoholism
• Barbiturate

82

• 5.Macewan sign is seen in
• Alcohol
• Organophosphorus
• Dhatura
• Barbiturate

83

• 6.Best method of treatment of methyl alcohol
• Calcium gluconate
• Ethyl alcohol
• Amphetamine
• 1 ammonia

84

• 7.In chronic alcoholism which of the following is
  seen
• Delirium tremens
• Wernikes syndrome
• Korsakoff psychosis
• All of the above

85

• 8.The fatal dose of absolute alcohol
• 30 ml
• 60 ml
• 90 ml
• 150 ml

86

• 9.Which of the following is not useful in methyl
  alcohol poisoning
• Gastric lavage
• Dialysis
• Ethyl alcohol
• High dose of Vit. B12

87

• 10. Wernickes encephalopathy is due to-
• Vitamin B1 deficiency
• Vitamin B2 deficiency
• Vitamin B6 deficiency
• Vitamin B12 deficiency