It should be noted that as a general rule 5-HT receptor agonists are used in the acute treatment of migraine whilst 5-HT receptor antagonists are used in prophylaxis. NICE produced guidelines in 2012 on the management of headache, including migraines. Prophylaxis should be given if patients are experiencing 2 or more attacks per month. Modern treatment is effective in about 60% of patients. NICE advises either topiramate or propranolol ‘according to the person’s preference, comorbidities and risk of adverse events’. Propranolol should be used in preference to topiramate in women of child bearing age as it may be teratogenic and it can reduce the effectiveness of hormonal contraceptives.

Soluble guanylyl cyclase (GC-1) is the primary receptor of nitric oxide (NO) in smooth muscle cells and maintains vascular function by inducing vasorelaxation in nearby blood vessels. GC-1 converts guanosine 5′-triphosphate (GTP) into cyclic guanosine 3′,5′-monophosphate (cGMP), which acts as a second messenger to improve blood flow.

Nitric oxide, known as an endothelium-derived relaxing factor (EDRF), is biosynthesized endogenously from L-arginine, oxygen, and NADPH by various nitric oxide synthase (NOS) enzymes and is a signaling molecule in many physiological and pathological processes in humans.
One of the main enzymatic targets of nitric oxide is guanylyl cyclase. The binding of nitric oxide to the haem region of the enzyme leads to activation, in the presence of iron.

Tumour marker CA 15-3 is mostly associated with breast cancer.

Tumour markers can be divided into:
1. Monoclonal antibodies
CA 125: Ovarian cancer, primary peritoneal cancer
CA 19-9: Pancreatic cancer
CA 15-3: Breast cancer

2. Tumour specific antigens
Prostate specific antigen (PSA): Prostatic carcinoma
Alpha-feto protein (AFP): Hepatocellular carcinoma, teratoma
Carcinoembryonic antigen (CEA): Colorectal cancer
S-100: Melanoma, schwannomas
Bombesin: Small cell lung carcinoma, gastric cancer

3. Enzymes
Alkaline phosphatase (ALP)
Neuron specific enolase (NSE)

4. Hormones
Calcitonin
Antidiuretic hormone (ADH)
Human chorionic gonadotropin (hCG)

Acute angle closure glaucoma is associated with hypermetropia, whereas primary open-angle glaucoma is associated with myopia. Glaucoma is a group of eye disorders characterised by optic neuropathy due, in the majority of patients, to raised intraocular pressure (IOP). It is now recognised that a minority of patients with raised IOP do not have glaucoma and vice versa.

Arthritis mutilans is a rare (occurs in only 5% of the patients) and extremely severe form psoriatic arthritis characterized by resorption of bones and the consequent collapse of soft tissue. When this affects the hands, it can cause a phenomenon sometimes referred to as ‘telescoping fingers.’ The associated nail changes are also characteristic of arthritis.

Normal pressure hydrocephalus is a form of communicating hydrocephalus characterised by enlarged ventricles with normal opening pressure on lumbar puncture. For diagnostic purposes, a triad of urinary incontinence, gait abnormality and dementia is necessary. It is necessary to diagnose the condition early because it is reversible by placing a ventriculoperitoneal shunt. It is most common in patients aged more than 60 years.

Diseases that cause predominantly sensory loss include diabetes, uraemia, leprosy, alcoholism, vitamin B12 deficiency, and amyloidosis.
Those that cause predominantly motor loss include Guillain-Barre syndrome, porphyria, lead poisoning, hereditary sensorimotor neuropathies, chronic inflammatory demyelinating polyneuropathy, and diphtheria.

Extrinsic allergic alveolitis (EAA) refers to a group of lung diseases that can develop after exposure to certain substances. The name describes the origin and the nature of these diseases:

‘extrinsic’ – caused by something originating outside the body
‘allergic’ – an abnormally increased (hypersensitive) body reaction to a common substance
‘alveolitis’ – inflammation in the small air sacs of the lungs (alveoli)

Symptoms can include: fever, cough, worsening breathlessness and weight loss. The diagnosis of the disease is based on a history of symptoms after exposure to the allergen and a range of clinical tests which usually includes: X-rays or CT scans, lung function and blood tests.

EAA is not a ‘new’ occupational respiratory disease and occupational causes include bacteria, fungi, animal proteins, plants and chemicals.

Examples of EAA include:

Bird fancier’s lung (BFL) is a type of hypersensitivity pneumonitis (HP). It is triggered by exposure to avian proteins present in the dry dust of the droppings and sometimes in the feathers of a variety of birds. The lungs become inflamed, with granuloma formation. Birds such as pigeons, parakeets, cockatiels, shell parakeets (budgerigars), parrots, turtle doves, turkeys and chickens have been implicated.

People who work with birds or own many birds are at risk. Bird hobbyists and pet store workers may also be at risk. This disease is an inflammation of the alveoli in the lungs caused by an immune response to inhaled allergens from birds. Initial symptoms include shortness of breath (dyspnoea), especially after sudden exertion or when exposed to temperature change, which can resemble asthma, hyperventilation syndrome or pulmonary embolism. Chills, fever, non-productive cough and chest discomfort may also occur.

A definitive diagnosis can be difficult without invasive testing, but extensive exposure to birds combined with reduced diffusing capacity are strongly suggestive of this disease. X-ray or CT scans will show physical changes to the lung structure (a ground glass appearance) as the disease progresses. Precise distribution and types of tissue damage differ among similar diseases, as does response to treatment with Prednisone.

Palmar xanthomas are found in type III hyperlipoproteinemia. Her total cholesterol level and triglyceride level support the diagnosis.

Squamous cell carcinoma like other skin cancers mostly arise on photo exposed sites. A patient usually presents with a history of a non healing lesion or wound. Confirmatory diagnosis requires a skin biopsy and histopathological screening. It is rarely metastatic and treatment of choice is surgical excision.

Cystinuria is strongly suspected because of the recurrent passing of cystine stones and otherwise non-remarkable medical history of this young adult patient. Like Cystinuria, all the conditions listed are also inherited disorders, however, the other differentials usually present in the early years of childhood, usually with failure to thrive.

A case–control study (also known as case–referent study) is a type of observational study in which two existing groups differing in outcome are identified and compared on the basis of some supposed causal attribute. Case–control studies are often used to identify factors that may contribute to a medical condition by comparing subjects who have that condition/disease (the cases) with patients who do not have the condition/disease but are otherwise similar (the controls).
An odds ratio (OR) is a statistic that quantifies the strength of the association between two events, A and B. The odds ratio is defined as the ratio of the odds of A in the presence of B and the odds of A in the absence of B or vice versa.

Blurring of vision and dry mouth are antimuscarinic side-effects that are more common with imipramine than other types of tricyclic antidepressants.

Tricyclic antidepressants (TCAs) are used less commonly now for depression due to their side-effects and toxicity in overdose. They are however used widely in the treatment of neuropathic pain, where smaller doses are typically required.

Mechanism of action: Tricyclic antidepressants impose their therapeutic effects by inhibiting presynaptic reuptake of norepinephrine and serotonin in the central nervous system (this, may give rise to seizures).

Common side-effects:
Drowsiness
Dry mouth
Blurred vision
Constipation
Urinary retention

Low-dose amitriptyline is commonly used in the management of neuropathic pain and the prophylaxis of headaches (both tension and migraine).
Lofepramine has a lower incidence of toxicity in overdose
Amitriptyline and dosulepin (dothiepin) are considered the most dangerous in overdose.

Lead poisoning is characterised by abdominal pain, fatigue, constipation, peripheral neuropathy (mainly motor), and blue lines on gum margin in 20% of the adult patients (very rare in children).

For diagnosis, the level of lead in blood is usually considered with levels greater than 10 mcg/dL being significant. Furthermore, the blood film shows microcytic anaemia and basophilic stippling of red blood cells. Urinary coproporphyrin is increased (urinary porphobilinogen and uroporphyrin levels are normal to slightly increased). Raised serum and urine levels of delta-aminolaevulinic acid may also be seen, making it sometimes difficult to differentiate from acute intermittent porphyria.

Charles Bonnet syndrome (CBS) involves visual hallucinations due to eye disease, usually associated with a sharp decline in vision. The phenomenon is seen in patients with moderate or severe visual impairment. It can occur spontaneously as the vision declines or it may be precipitated, in predisposed individuals, by concurrent illness such as infections elsewhere in the body.

It is not clear why CBS develops or why some individuals appear to be predisposed to it. It is particularly noted in patients with advanced macular degeneration. It has been suggested that reduced or absent stimulation of the visual system leads to increased excitability of the visual cortex (deafferentation hypothesis). This release phenomenon is compared to phantom limb symptoms after amputation.

CBS is much more common in older patients because conditions causing marked visual loss are more common in older people. However, it can occur at any age and has been described in children.
The prevalence is hard to assess due to considerable under-reporting, perhaps because patients frequently fear that it is a sign of mental illness or dementia. However, it is thought to occur in:
About 10-15% of patients with moderate visual loss.
Possibly up to 50% of people with severe visual loss.
Presentation:
The nature of the hallucination depends on the part of the brain that is activated. The hallucinations may be black and white or in colour. They may involve grids/brickwork/lattice patterns but are typically much more complex:

The hallucinations are always outside the body.
The hallucinations are purely visual – other senses are not involved.
The hallucinations have no personal meaning to the patient.
Hallucinations may last seconds, minutes or hours.
CBS tends to occur in a ‘state of quiet restfulness’. This may be after a meal or when listening to the radio (but not when dozing off).
Symptoms also have a tendency to occur in dim lighting conditions.
Patients may report high levels of distress, with some patients reporting anger, anxiety and even fear associated with the hallucinations.

Night sweats are a B symptom in Hodgkin lymphoma (HL) and imply a poor prognosis.

HL is a malignant proliferation of lymphocytes characterised by the presence of distinctive giant cells known as Reed-Sternberg cells. It has a bimodal age distribution being most common in the third and seventh decades of life.

Staging of HL is done according to the Ann Arbor staging system:

Stage
I: Single lymph node region (I) or one extra lymphatic site (IE)

II: Two or more lymph node regions on same side of the diaphragm (II) or local extra lymphatic extension plus one or more lymph node regions on same side of the diaphragm (IIE)

III: Lymph node regions on both sides of the diaphragm (III) which may be accompanied by local extra lymphatic extension (IIIE)

IV: Diffuse involvement of one or more extra lymphatic organs or sites

Suffix
A: No B symptoms

B: Presence of at least one of the following: unexplained weight loss >10% baseline during 6 months before staging; recurrent unexplained fever >38°C; recurrent night sweats—poor prognosis.

Immunoglobulin should be given to all seronegative women within 4 days. However, it is strongly advised to seek medical care immediately if the disease develops.

Monoclonal gammopathy of undetermined significance (MGUS)—also known as benign paraproteinemia and monoclonal gammopathy—is a pre-malignant condition not necessarily leading to its malignant form—multiple myeloma. MGUS causes increase of a serum monoclonal protein (M protein). It is not associated with ostealgia or increased risk of infections. It is often mistaken for multiple myeloma, differing from the latter in, no immunosuppression, anaemia, hypercalcaemia, lytic bone lesions, or renal failure; normal levels of beta-2 microglobulin; and stable lower levels of paraproteinemia.

Inclusion body myositis (IBM) is a progressive muscle disorder characterized by muscle inflammation, weakness, and atrophy (wasting). It is a type of inflammatory myopathy. IBM develops in adulthood, usually after age 50. The symptoms and rate of progression vary from person to person. The most common symptoms include progressive weakness of the legs, arms, fingers, and wrists. Some people also have weakness of the facial muscles (especially muscles controlling eye closure), or difficulty swallowing (dysphagia). Muscle cramping and pain are uncommon, but have been reported in some people. The underlying cause of IBM is poorly understood and likely involves the interaction of genetic, immune-related, and environmental factors. Some people may have a genetic predisposition to developing IBM, but the condition itself typically is not inherited. Elevated creatine kinase (CK) levels in the blood (at most ,10 times normal) are typical in IBM. Muscle biopsy may display several common findings including; inflammatory cells invading muscle cells, vacuolar degeneration, inclusions or plaques of abnormal proteins.

Leukemoid reaction has a high LAP score.

Leukemoid reaction refers to leucocytosis occurring as a physiological response to stress or infection which may be mistaken for leukaemia, especially chronic myeloid leukaemia (CML). Leucocytosis occurs, initially, because of accelerated release of cells from the bone marrow and is associated with increased count of more immature neutrophils in the blood (left-shift). In order to differentiate, LAP score is used. Leukocytic alkaline phosphatase (ALP) activity is high in a leukemoid reaction but low in CML.

LAP score is high in:
1. Leukemoid reaction
2. Infections
3. Myelofibrosis
4. Polycythaemia rubra vera
5. Steroids, Cushing’s syndrome
6. Pregnancy, oral contraceptive pill

LAP score is low in:
1. CML
2. Pernicious anaemia
3. Paroxysmal nocturnal haemoglobinuria (PNH)
4. Infectious mononucleosis

Elevated TSH (usually 4.5-10.0 mIU/L) with normal free T4 is considered mild or subclinical hypothyroidism.
Hypothyroidism commonly manifests as a slowing in physical and mental activity but may be asymptomatic. Symptoms and signs are often subtle and neither sensitive nor specific.
The following are symptoms of hypothyroidism:
– Fatigue, loss of energy, lethargy
– Weight gain
– Decreased appetite
– Cold intolerance
– Dry skin
– Hair loss
– Sleepiness
– Muscle pain, joint pain, weakness in the extremities
– Depression
– Emotional lability, mental impairment
– Forgetfulness, impaired memory, inability to concentrate
– Constipation
– Menstrual disturbances, impaired fertility
– Decreased perspiration
– Paraesthesia and nerve entrapment syndromes
– Blurred vision
– Decreased hearing
– Fullness in the throat, hoarseness
Physical signs of hypothyroidism include the following:
– Weight gain
– Slowed speech and movements
– Dry skin
– Jaundice
– Pallor
– Coarse, brittle, straw-like hair
– Loss of scalp hair, axillary hair, pubic hair, or a combination
– Dull facial expression
– Coarse facial features
– Periorbital puffiness
– Macroglossia
– Goitre (simple or nodular)
– Hoarseness
– Decreased systolic blood pressure and increased diastolic blood pressure
– Bradycardia
– Pericardial effusion
– Abdominal distention, ascites (uncommon)
– Hypothermia (only in severe hypothyroid states)
– Nonpitting oedema (myxoedema)
– Pitting oedema of lower extremities
– Hyporeflexia with delayed relaxation, ataxia, or both.

5–15% of the cases of polycythaemia vera progress to myelofibrosis or acute myeloid leukaemia (AML).

Polycythaemia vera (PV), also known as polycythaemia rubra vera, is a myeloproliferative disorder caused by clonal proliferation of marrow stem cells leading to an increase in red cell volume, often accompanied by overproduction of neutrophils and platelets. It has peak incidence in the sixth decade of life, with typical features including hyperviscosity, pruritus, splenomegaly, haemorrhage (secondary to abnormal platelet function), and plethoric appearance.

Some management options of PV include lose-dose aspirin, venesection (first-line treatment), hydroxyurea (slightly increased risk of secondary leukaemia), and radioactive phosphorus (P-32) therapy.

In PV, thrombotic events are a significant cause of morbidity and mortality. 5–15% of the cases progress to myelofibrosis or AML. The risk of having AML is increased with chemotherapy treatment.

The patient’s history points to absence seizures. Carbamazepine has been shown to aggravate generalized seizure types, especially absence seizures, because it acts directly on the ventrobasal complex of the thalamus which is critical to the neurophysiology of absence seizures.

Supravalvular aortic stenosis, is associated with a condition called William’s syndrome.
William’s syndrome is an inherited neurodevelopmental disorder caused by a microdeletion on chromosome 7. The most common symptoms of Williams syndrome are heart defects and unusual facial features. Other symptoms include failure to gain weight appropriately in infancy (failure to thrive) and low muscle tone. Individuals with Williams syndrome tend to have widely spaced teeth, a long philtrum, and a flattened nasal bridge.
Most individuals with Williams syndrome are highly verbal relative to their IQ, and are overly sociable, having what has been described as a cocktail party type personality.

Autosomal recessive polycystic kidney disease (ARPKD) is less common than ADPKD (dominant form) but can already present with symptoms and be diagnosed on prenatal ultrasound.

One of the most important complications in patients with PKD is being affected by berry aneurysms that may burst, causing a subarachnoid haemorrhage, which seems to be the case in this patient.

Patients with compressive neuropathy of the ulnar nerve typically describe numbness and tingling of the ulnar-sided digits of the hand, classically in the small finger and ulnar aspect of the ring finger. Among the general population, symptoms usually begin intermittently and are often worse at night, particularly if the elbow is flexed while sleeping. As the disease progresses, paraesthesia may occur more frequently and during the daytime.

When a patient fails treatment with metronidazole (Flagyl) treatment, the next course of action is to change to oral vancomycin, which is shown to be effective in the treatment of c diff colitis. Oral rifampicin is not a treatment for c diff. Oral metronidazole is not resolving her symptoms so is not the correct answer. clindamycin is a cause of c diff colitis, not a treatment. IV Vanc is not active in the gut so is not the treatment; oral is active in the gut.