Hypersensitivity

Question 1

Which drugs are commonest causes of hypersensitivity reactions

Answer 1

Antibiotics
Antiepileptic

Question 2

Factors that influence hypersensitivity

Answer 2

State of immune activation of the subject
Dose
Frequency
Route of exposure (epicutaneous more sensitised than oral)
Duration of exposure
Sex (frequent reactions in females)
Immunogenicity predisposition

Question 3

Causes of type 2 hypersensitivity reaction

Answer 3

Beta lactams
Rifampicin
Sulfa antibiotics

Question 4

Causes of type 2 hypersensitivity reaction

Answer 4

Beta lactams
Rifampicin
Sulfa antibiotics

Question 5

Causes of type 3 hypersensitivity reaction

Answer 5

Beta lactams
Sulfa antibiotics
Minocycline

Question 6

Pathogenesis of drug induced hypersensitivity

Answer 6

Drugs (or chemicals) are too small (<1000D) to induce an immune response on their own
Immunogenic only after coupling with a carrier protein to form a hapten-protein complex
Hapten (drug) must bind irreversibly to proteins
Hapten-protein complex processed by APCs
Needs prior exposure
Nevertheless, small compounds such as drugs or metal ions were found to be able to trigger an immune response.
They may stimulate the innate immune system by covalently binding to cellular proteins and thereby transmit a danger signal, which results in stimulation of cells of the innate immune system, such as upregulation of CD40. Exceptionally, they may happen to bind to TLR7 and TLR8 directly and thus stimulate dendritic cells. This was shown for imiquimod.
b) They may stimulate the specific immune system. By forming hapten-carrier complexes, they form neoantigenic structures. This hapten-protein complex is processed and presented as hapten-modified peptide to T cells, which can react with it.1Y4,11 Modified proteins can also be immunogenic for B cells and thus elicit a humoral immune response. This hapten modification can occur with soluble proteins, cell-bound proteins, or with the major histocompatibility complex (MHC) peptide complexes themselves, leading to distinct immune responses (Fig. 1)

Drugs (or chemicals) interact directly (noncovalently) with immune receptors
Most cases this is the HLA molecule or also T cell receptor
Direct activation of T-cells without the presence of a peptide
Most data from TCR transfectants demonstrate the critical necessity of the TCR more than the HLA molecule for activation.
Also extensive data from T-cell clonotypes.
Cross-reactivity amongst memory T-cells explanation for timing of skin reactions in certain drugs. Also increased incidence in infections/auto-immune environment
Polyclonal CD8 T-cell expansion may increase the numbers of small populations of drug specific TCRs (almost all ab).
e.g. EBV and ampicillin reactivity vice versa with DRESS and latter symptoms through reactivated HHV.

Drugs nonconvalently occupy sites within the peptide-binding groove of MHC proteins
Occupation leads to alteration of the specificities of MHC-peptide binding
Self-peptides then activate T-cells inappropriately

Question 7

Clinical manifestations of Drug induced ANI

Answer 7

Rash
Joint pain
Eosinophilia
Eosinophiliuria

Question 8

Treatment of drug related ANI

Answer 8

Cessation of drug

If no improvement:
Renal biopsy
High dose prednisone eg 500mg methyl prednisone then 1mg/kg of prednisone and taper over 1month

Question 9

Managemt if tremor

Answer 9

Propanolon
Primidone
Gabapentin
Topiramate
Alprazolam
Nimodipine, clonazepam, mirtazapine, levetiracetam, zonisamide

Question 10

Adverse effects of drugs used to treat tremors

Answer 10

Propanolon: Hypotension, Brady and fatigue
Contraindicated in asthma.

Primidone: Sleepiness, tiredness

Gabapentin: drowsiness, fatigue and unsteadiness

Topiramate: drowsiness, LOW, tingling

Alprazolam: drowsiness, fatigue

Question 11

Drugs that can cause a tremor

Answer 11

▶ Alcohol**
▶ Neuroleptics*
▶ β–Agonists and sympathomimetics
▶ Lithium
▶ Valproate*
▶ Tamoxifen
▶ Ciclosporin
▶ Amiodarone
▶ Mexilitine
▶ Vincristine
▶ Adriablastine
Most of these drugs cause postural tremor. These also cause *rest tremor and **intention tremor.

Question 12

Treatment of dystonic tremors

Answer 12

Anticholinergics
Botulinum toxin injection

Question 13

Investigations for patients with dystonia

Answer 13

FBC and film for acanthocytes
Plasma caeruloplasmin (if low, Wilson’s-copper deficiency)
24 hour urine copper
Genetic testing DYT1 (young onset)
MR Brain scan
Slit lamp exam for Kayser Fleisher rings
Therapeutic trial of levodopa

Question 14

Which movement disorder improved dramatically with alcohol

Answer 14

Myoclonus dystonia

Question 15

Types of dystonia

Answer 15

Primary:
Dopa responsive dystonia
Myoclonus dystonia
DYT1 associated dystonia

Secondary:
Parkinsonism
Perinatal injury
Wilson disease
Pantothenate kinase ass/ neurodegeneration
Neuroferritinopathy
Structural pathologies

Question 16

Diagnosis for Wilson’s

Answer 16

Diagnosis depends on demonstrating a low plasma caeruloplasmin (10–20% will be nor- mal), an increased 24 h urinary copper or Keyser– Fleisher rings. If the diagnosis remains uncertain, copper level in liver biopsy can be measured.

Question 17

Treatment for Wilson’s

Answer 17

Diagnosis depends on demonstrating a low plasma caeruloplasmin (10–20% will be nor- mal), an increased 24 h urinary copper or Keyser– Fleisher rings. If the diagnosis remains uncertain, copper level in liver biopsy can be measured.

Question 18

Causes of chorea

Answer 18

1. Drug induced: levodopa and dopamine agonists, dopamine
   antagonists, and less commonly agents such as lithium, oral contraceptives and corticosteroids.
2. Genetic: Huntington’s, rarer neurogenetic conditions include neuroacanthocytosis and dentatorubropallidoluy- sian atrophy.
3. Immune mediated: Sydenham chorea, hiv
4. Metabolic: hyperthyroidism, poly- cythaemia rubra vera and in non-ketotic hyperg- lycaemia. It can also occur in liver failure, referred to as acquired hepatolenticular degeneration.
5. Structural: stroke, tumour, demyelination

Question 19

Treatment of chorea

Answer 19

Chorea and ballismus are often improved by dopamine antagonists; haloperidol has been used
for years and newer agents such as risperidone can also be used. Tetrabenazine is effective but can be associated with drowsiness and depression.

Question 20

Types of myoclonus

Answer 20

Myoclonus in epilepsy
Symptomatic myoclonus
Drug related myoclonus
Essential myoclonus
Spinal myoclonus

Question 21

What worsened myoclonus seizures

Answer 21

Carbamezapine
Phenytoin
Gabapentin
Tiagabine

Question 22

Treatment of myoclonus seizures

Answer 22

Sodium valproate

Others: lamotrigine, clonazepam, levetiracetam

Question 23

Causes of drug related myoclonus

Answer 23

Most antipsychotics: lithium,
Most antidepressants
Some antiepileptic drugs

Question 24

Symptomatic treatment for myoclonus

Answer 24

Sodium valproate
Benzos: clonazepam, levetiracetam
Ethosuzamide
Zonasemide

Question 25

Conditions to consider in an acutely ill patient with prominent hyperkinetic movement disorder—chorea, myoclonus or dystonia

Answer 25

▶ Drug induced movement disorders (perhaps given as an antiemetic or for confusion)
▶ Autoimmune encephalopathies:
▶ Agonists and sympathomimetics
– Hashimoto’s
– Anti-NMDA receptor encephalitis
▶ Encephalitis lethargica
▶ Metabolic encephalopathies especially
– Renal failure
– Liver failure
– Thyroid disease
– Hyperglycaemia
▶ Creutzfeldt–Jakob disease

Question 26

Treatment of tics

Answer 26

▶ α-agonists: clonidine (low dose 50–500 μg/ day) or guanfacine
▶ dopamine antagonists: risperidone, aripipra- zole, haloperidol. No comparative studies are available; use minimum effective dose.
▶ Others—botulinum toxin, clonazepam, tetrabenazine

Question 27

Treatment of restless leg

Answer 27

▶ some improve following a course of iron replacement
▶ dopamine agonists (only non-ergot agents such as pramipexole or ropinerole) or levo- dopa improve symptoms but may cause ‘augmentation’—an increase in symptoms as the dose is increased. They also carry a small risk of dopamine induced dyscontrol syndrome. The dose of agonists needs to be kept as low as possible and titrated against clinical effect
▶ other drugs with more limited evidence include antiepileptics, most notably gabapen- tin and pregabalin, and benzodiazapines such as clonazepam or zolpidem.

Question 28

Features/Sx of Parkinsonism

Answer 28

Bradykinesia
Rigidity
Posture instability
Remor
Depression and anxiety
Loss of smell
Constipation

Question 29

Treatment of Parkinsonism

Answer 29

Give levodopa (as it’s caused by deficiency)