Clinical Snippets

December 2024

Clinical Snippets December 2024

1. Empagliflozin and ketoacidosis

The December 2024 Prescriber Update includes a reminder on the risk of ketoacidosis associated with use of SGLT2 inhibitors (empagliflozin in NZ) whether or not they are being used for treatment of diabetes.  Key messages and prescribing considerations include:

• Patients taking SGLT-2 inhibitors are more likely to develop ketoacidosis when other risk factors are present, including acute illness, infections, surgery, pancreatic disorders, insulin dose reduction, insulin insufficiency, severe dehydration, reduced caloric intake, low carbohydrate diet, heavy alcohol use and a history of ketoacidosis.
• Inform patients taking SGLT-2 inhibitors about ketoacidosis risk factors, signs and symptoms. Blood glucose levels may be normal or only mildly elevated. Symptoms may be non-specific and include nausea, vomiting, malaise, anorexia, abdominal pain, excessive thirst, shortness of breath, dizziness or confusion. Advise patients to seek medical attention immediately if they experience ketoacidosis symptoms, irrespective of blood glucose levels.
• Consider monitoring ketones and temporarily discontinuing SGLT-2 inhibitors in clinical situations known to predispose patients to ketoacidosis. Refer to local clinical guidelines for further advice, including management before surgery/procedures and during acute illness.
• Ketoacidosis may be prolonged in patients with T2DM, despite stopping SGLT-2 inhibitors.

Healthify has excellent resources for users of empagliflozin including a printable information sheet in a variety of languages that covers risks of ketoacidosis. 

2.  Decision to fund fosfomycin in the community

Pharmac has decided to fund fosfomycin (branded as UroFos) in the community from 1 November 2024. This decision will allow New Zealanders to access funded fosfomycin treatment in the community, reducing the need for people to be treated for urinary tract infections (UTIs) in the hospital.  Dose for an adult is 3 as a single dose – comes as a sachet which the patient mixes with water (see NZF).  Special authority is required with initial application from any relevant practitioner. Approvals are valid for 2 months for applications meeting the following criteria:

Both:

• Patient has an acute, symptomatic, bacteriologically-proven uncomplicated urinary tract infection (UTI)/cystitis with Escherichia coli; and

Either:

• Microbiological testing confirms the pathogen is resistant to all of: trimethoprim, nitrofurantoin, amoxicillin, cefaclor, cefalexin, amoxicillin with clavulanic acid, and norfloxacin; or
• The patient has a contraindication or intolerance to all of: trimethoprim, nitrofurantoin, amoxicillin, cefaclor, cefalexin, amoxicillin with clavulanic acid, and norfloxacin that the pathogen is susceptible to.

3.  Latent autoimmune diabetes

I have received a complaint recently regarding delayed diagnosis of latent autoimmune diabetes of adults (LADA) in a patient in his 40’s with history of Graves disease who was diagnosed with type two diabetes and had two years of poor glycaemic control despite metformin and SGLT2 inhibitors before the correct diagnosis was made and insulin therapy commenced.  A BPAC article on management of type 2 diabetes notes at least 5-10% of adult-onset diabetes is not type 2 and this can result in suboptimal treatment.   LADA occurs when there is progressive autoimmune-mediated destruction of pancreatic beta cells commencing in adulthood, and has feature of both type 1 and type 2 diabetes (sometimes called type 1.5 diabetes).  Features that might raise suspicion of the condition include:

• Symptoms of insulin deficiency at diagnosis e.g. polyuria, polydipsia, weight loss
• Rapid deterioration in glucose levels/HbA1c
• Ketoacidosis (NB: Ketoanaemia or ketonuria without acidosis are weak discriminators between the types of diabetes)
• Normal or low BMI at diagnosis
• Personal or family history of autoimmune disease
• Family history of type 1 diabetes

Most cases of LADA are associated with positive anti-GAD antibodies and reduced C-peptide levels.  HealthPathways recommends if both are anti-GAD and anti-IA2 antibodies are negative and you still suspect a type 1 diabetes picture, seek specialist diabetes advice about arranging anti-ZnT8 antibodies.  Management principles are similar to that for general diabetes management although use of sulfonylureas is thought to accelerate beta cell loss and earlier progression to insulin therapy. The linked reference notes the main challenge is to distinguish patients with LADA from those with T2DM. By definition, patients with T2DM have absent autoantibodies to islet cell antigens, normal or elevated fasting, and stimulated C-peptide and usually do not require insulin for an extended period. Clinicians should consider screening for LADA in patients with T2DM who do not achieve adequate glycemic control within a reasonable period after compliance with therapy. This is particularly true if they are not obese, lack the features of the MetS, or they, or their first-degree relatives, have other autoimmune disorders, including Hashimoto thyroiditis, Graves disease, celiac disease, rheumatoid arthritis, or pernicious anemia.

4.  HINTS Test for vertigo

One reasonably common are of complaints I see is missed or delayed diagnosis of posterior circulation stroke, with a contributing factor being assessment of central vertigo as peripheral.  While most vertebrobasilar strokes are also accompanied by other signs (such as diplopia, dysarthria, dysphagia, motor and sensory deficits) a proportion of cerebellar strokes present only with vertigo and subtle incoordination on examination. A positive HINTS exam has been reported to have a high sensitivity and specificity for the presence of a central cause of vertigo.

The HINTS exam is only used on a subset of the patients who present with:

• Persistent vertigo over hours or days
• Nystagmus
• A normal full neurological exam

HINTS is comprised of three core components: head impulse test, evaluation of nystagmus, and a test of skew.  An excellent 8-minute video that illustrates the tests including abnormal results is available on Youtube.

5.  Treating yourself and those close to you

MCNZ has updated their statement on treating yourself and those close to you.  

• Allowance made for one-off management of minor ailments
• Accommodating the challenges faced by doctors in rural, remote and under-served communities
• Emergency situations

The statement notes that in those circumstances when treatment is provided, you must inform the patient’s general practitioner (with the patient’s consent).  There are some situations where you must not treat yourself or those close to you:

• Issuing medical certificates, death certificates and conducting third party medical assessments
• Providing psychotherapy
• Providing recurring treatment or ongoing management of an illness or condition
• Performing complex procedures
• Performing sensitive examinations
• Prescribing medication with a risk of or misuse, controlled drugs, and psychotropic drugs (except in an emergency) 

6.  ADHD changes

The ADHD landscapes is changing.  From 1 December 2024, Pharmac removed the renewal criteria for methylphenidate, dexamfetamine and modafinil, medicines used to treat ADHD and narcolepsy. This means that once an initial special authority approval for stimulant medicines has been granted, a doctor or nurse practitioner can continue to prescribe it.  From the same date, lisdexamfetamine will be funded when prescribed for people with ADHD who meet certain eligibility criteria, outlined in the Pharmac information page.  The Goodfellow Unit has scheduled a half-day online webinar event on 22 February 2025 that aims to provide an in-depth exploration of ADHD care, from initial assessment to long-term management – you can register here.  The Unit also has multiple existing podcasts/webinars on various aspects of ADHD diagnosis and management via their searchable database. 

7.  Pertussis

A whooping cough epidemic has recently been declared in NZ and it is timely to review our part in supporting pregnant patients/hapu mama to receive pertussis and influenza vaccines during pregnancy.  An interactive Geohealth Tool allows you to examine vaccination rates in your region by year, vaccine and ethnicity up to 2021.  For Hamilton City in 2021, pertussis vaccination rates for hapu mama were 46% for NZE, 13% for Maori, 27% for Pacifika and 49.4% for Asian ethnicity.  IMAC includes the following additional pertussis advice: 

• Advise pregnant people of the current increase in pertussis cases and strongly recommend the free Boostrix vaccination with every pregnancy. The vaccine is funded from the second trimester of pregnancy and recommended from 16 weeks. Vaccination during pregnancy is 92% protective against infant death from pertussis.
• Encourage all members of the extended whānau, including infants, children and older people to check they are up to date with all immunisations, especially their pertussis boosters – funded for people aged 4 years (Infanrix-IPV), 11 years, 45 years and 65 years (Boostrix). Some whānau may wish to privately purchase a booster (Adacel/Boostrix) if a newborn baby is expected to join the household.
• Ensure all babies receive on-time 6-week immunisations.
• Ensure pathways are in place to identify, diagnose and notify cases as well as seek public health advice for vaccinating close contacts, as recommended.
• Encourage all staff, including reception, administrative and retail, to ensure they are up to date with immunisations (in particular pertussis and measles). Booster vaccinations of Boostrix every 5 years are recommended for all lead maternity carers and healthcare workers who are in regular contact with infants.
• Notify the Medical Officer of Health as soon as you suspect a case of pertussis.

8.  Medical Aspects of Fitness to Drive

On 25 November 2024, Waka Kotahi published the 2024 edition of MAFTD.  A summary of changes is available and worth reviewing (15 pages).   Legal and other obligations to which the health practitioner undertaking the driver’s examination and completing certification are subject to include:

• To use the guide when doing a medical examination
• To give NZTA medical reports as soon as practicable of persons unfit to drive, or who should only drive subject to conditions, and are likely to continue to drive after being advised not to. Delays in sending or not giving enough information can create a road safety risk.
• When issuing a medical certificate, to give NZTA written notice as soon as practicable that the applicant isn’t medically fit to drive. Delays in sending or not giving enough information can create a road safety risk.
• Always advise your patient about the impact their medical condition, disability or treatment, may have on their ability to drive. Give this advice to them in writing as well as verbally.
• Recommend any temporary driving restrictions to the patient where appropriate. This could be not driving for a specific amount of time or not driving at night.
• Discuss with your patients any recommendations you’ll make to NZTA around their fitness to drive, including licence conditions, potential suspension, or revocation of their licence.
• Advise patients on their responsibility to report their condition to NZTA if their long-term or permanent injury or illness may affect their ability to drive safely.
• Include ongoing consideration of their fitness to drive while you treat, monitor, and manage the patient’s medical condition.

9.  Unexpected weight loss

Issue 247 of GP Research Review included a recently published paper in the BMJ looking at the predictive value that unexpected weight loss had for cancer, according to patient age, sex and clinical features.  The study population included 326,240 adults who presented to primary care with unexpected weight loss in England, between 2000-19. Within 6 months of presentation, 4.8% of all patients were diagnosed with cancer, of whom 98.9% were aged ≥40 years, and 96.3% ≥50 years. The most common malignancies were lung cancer (22.8%), bowel cancer (15.6%) and gastro-oesophageal cancer (12.4%). It was concluded that for men aged ≥50 years and women aged ≥60 years, the presence of unexpected weight loss alone warrants referral for invasive investigation, as the positive predictive values for cancer were above the recommended NICE threshold of 3%. Invasive investigation was also recommended for younger patients who presented with unexpected weight loss and concurrent clinical features (various symptoms and signs listed in the paper). Some of the concurrent clinical features with strongest associations with malignancy were bloating, dysphagia, chest signs, abdominal or rectal mass, VTE, pelvic mass (women) and iron deficiency anaemia (men). The blood test results associated with cancer included raised platelets (positive likelihood ratio 3.48), low albumin (3.24), raised CRP (3.13) and raised total white cell count (3.01).  Reviewer’s comment: It is the doctor’s dilemma! A patient presents with unexplained weight loss, a few non-specific blood results just outside normal parameters, and nothing else. How often do we as GPs see that?

10.  Quickies

• A recent Medscape article looked at evidence for pharmacological agents used in post-Covid syndrome and listed the most promising (with cited references) as:  low dose naltrexone; SSRIs; modafinil; antihistamines.  
• Goodfellow Unit has a learning module on Doxy-PEP to reduce chlamydia and syphilis risk, completion of which is eligible for professional development points. 
• A reminder from Medsafe (Prescriber Update) that aciclovir and valaciclovir can accumulate in the presence of renal impairment and cause neurotoxicity (confusion, agitation, hallucinations or seizure).  NZ Formulary gives specific dosing instructions for various eGFR ranges.
• The October issue of GP Voice  included links to a one-page summary regarding management of patient with possible MS relapse.  The MS Health Pathways section has more comprehensive advice including links to patient resources.  Both refer to use of methylprednisolone, not prednisone, if treatment of a relapse is required with dose recommendation differing between the two resources.  New Zealand Formulary recommends a dose of 1000mg once daily for three days or 500mg once daily for five days.  Tablets are available in 100mg strength. 

Clinical Snippets November 2024

Clinical Snippets November 2024
 
1.  Eyesore
I have recently looked at a complaint regarding delayed diagnosis and treatment of acanthamoeba keratitis.  The patient presented with an irritated red right eye after showering in a residence on tank water and with her contact lenses in place.  The patient was treated initially as a bacterial conjunctivitis with chloromycetin drops changed to fucithalmic and Maxitrol ointment (steroid/antibiotic combination) when the symptoms worsened.  An optometrist detected severe keratitis when the patient presented for a second opinion and urgent referral was made to an ophthalmologist.  There were further delays waiting for results of PCR testing on a corneal swab before appropriate treatment was commenced and after many months of treatment including corneal transplant the patient was left with a nonfunctional phthisical eye. 
A referenced resource notes that up to 93% of cases occur in contact lens wearers, and approximately 5% of cases of contact lens associated keratitis are secondary to AK.  While the condition is rare (reported rates ranging from 1-33 per million contact lens wearers), early detection and treatment offers the best chance of recovery.  Several risk factors contribute to the occurrence of AK, including inadequate contact lens hygiene, overnight wear, prolonged use, lens use during activities like swimming and showering, exposure to contaminated water, trauma, the use of contaminated contact lens solution and orthokeratology.
 
AK typically manifests unilaterally, although it may rarely occur in both eyes. A defining characteristic of AK, even in its early stages, is severe pain disproportionate to the clinical findings believed to be triggered by the activity of trophozoite-derived proteases. Patients commonly complain of reduced vision, eye redness, a foreign body sensation, photophobia, tearing, and discharge. Symptoms may fluctuate in intensity, ranging from mild to severe.  Alarmingly, 75% to 90% of patients with early AK are initially misdiagnosed, underscoring the importance of considering AK in patients where symptoms persist for several weeks without improvement despite strict adherence to a daily regimen of topical antibiotics or antivirals. Approximately 39% of patients with AK do not respond to initial therapy. Individuals with more severe clinical presentations or a history of corticosteroid use before diagnosis face a higher likelihood of treatment failure.
 
Health Pathways section on the red eye emphasises the importance of an adequate eye examination including visual acuity and corneal staining when the history might suggest keratitis.  Keratitis red flags include painful, red eye in a contact lens wearer and severe pain that is inconsistent with clinical signs in a contact lens wearer.  The initiation of topical ocular steroids in primary care is open to discussion. 
 
2.  Syphilis again
The September Waikato Public Health Bulletin included a reminder regarding the increasing prevalence of syphilis in the community.  The 2023 STI Annual 2023 Dashboard and supplementary report demonstrate a 45% increase in syphilis cases in Aotearoa since 2022. In Waikato, there were 98 cases reported throughout 2023, an increase from 57 in 2022. The highest number of cases continue to be reported in men who have sex with men (MSM), and the 30-39 and 40+ year age group. There are increasing case numbers reported in men who have sex with women (MSW), particularly in Waikato.
Untreated syphilis in pregnancy can lead to adverse outcomes including stillbirth, premature birth, and neonatal death. The incidence of congenital syphilis is inequitable, with Māori and Pacific whānau disproportionately impacted.  Access to timely antenatal care is important to ensure early identification and treatment of syphilis in pregnancy.  
 
Consider testing for syphilis in patients with unusual skin rashes, oral, genital or perianal ulcers, lymphadenopathy, hepatitis and/or neurological symptoms. Syphilis can affect any body system and cause end organ damage in its secondary stage.
 
The NZSHS has produced a statement on the use of doxy-PEP (postexposure doxycycline prophylaxis).  Three randomised controlled trials among cisgender men who have sex with men and transgender women who have sex with men at risk of bacterial STIs have shown a relative risk reduction of 70 to 80% for syphilis and 70 to 90% for chlamydia in those randomised to take a single dose of 200mg doxycycline within 72 hours after a possible exposure.  Efficacy against gonorrhoea is highly variable (0-50%) dependent on local resistance patterns.   The statement outlines those situations where you might consider prescribing doxy-PEP including relevant precautions.   
 
3.  B12 and metformin
AI have recently reviewed a case of late diagnosis of symptomatic Vitamin B12 deficiency in a patient with T2DM on metformin.  A 2022 UK drug safety update gives useful information on the topic including:
 metformin can commonly reduce vitamin B12 levels in patients, which may lead to vitamin B12 deficiency
the risk of low vitamin B12 levels increases with higher metformin dose, longer treatment duration, and in patients with risk factors for vitamin B12 deficiency
Existing low B12 levels (lower end normal range)
People at risk of decreased absorption (elderly, inflammatory bowel disease, gastric resection or autoimmune conditions)
Strict vegan and some vegetarian diets
Concomitant use of medications known to decrease B12 absorption (proton pump inhibitors, colchicine)
test vitamin B12 serum levels if deficiency is suspected (for example, in patients presenting with megaloblastic anaemia or new-onset neuropathy) and follow current clinical guidelines on investigation and management of vitamin B12 deficiency (eg Health Pathways).
Other symptoms of low vitamin B12 levels may include mental disturbance (depression, irritability, cognitive impairment), glossitis (swollen and inflamed tongue), mouth ulcers, and visual and motor disturbances.
consider periodic vitamin B12 monitoring in patients with risk factors for vitamin B12 deficiency
administer corrective treatment for vitamin B12 deficiency in line with current clinical guidelines (oral vs IM – debated); continue metformin therapy for as long as it is tolerated and not contraindicated
 
4.  Itraconazole and heart failure
Another recent case I have reviewed involved a patient with heart failure secondary to cardiomyopathy being prescribed itraconazole for severe tinea corporis and developing a marked exacerbation of his heart failure.  He was not warned of the risk of exacerbation and the prescriber was not aware. 
NZF presents a ‘blue box’ precaution:

The MCNZ statement on Good prescribing practice (revised Feb 2024) includes:  Be familiar with the indications, adverse effects, contraindications, major drug interactions, appropriate dosages, monitoring requirements, effectiveness and cost-effectiveness of the medicines that you prescribe.  How is this requirement s best achieved in a time constrained environment?
 
5.  BP cuff position
A recent Medscape article reviewed a crossover, randomized trial published in JAMA last month looking at the effect of arm position on blood pressure readings.  Guidelines for BP measurement recommend arm support on a desk with the mid-cuff at heart level. The study found that supporting the arm on the lap overestimated systolic BP (SBP) by 3.9 mm Hg and diastolic BP (DBP) by 4.0 mm Hg. When the arm hung at the side, readings overestimated SBP by 6.5 mm Hg and DBP by 4.4 mm Hg, with consistent results across subgroups.  The conclusion:  Commonly used, nonstandard arm positions during BP measurements substantially overestimate BP, highlighting the need for standardized positioning.
 
6.  Low dose naltrexone
A September NZ Doctor article reviewed the use of low dose naltrexone in post-Covid syndrome and some other conditions.  Key points were: 
In low doses (typically 3–4.5mg daily), naltrexone appears to modulate neuroinflammation and increase endorphin production, resulting in improved immune system modulation.
Low-dose naltrexone has shown promising results in fibromyalgia/chronic fatigue syndrome, chronic pain, Crohn disease, multiple sclerosis and long COVID, although the quality of evidence is generally low.
While further research is needed, given the limited choice of effective therapies for functional syndromes, LDN is a relatively safe and, in many cases, effective treatment when first-line options fail.
The article examines the evidence base for use of LDN in the various conditions described.  Note: Naltrexone is produced as a 50mg tablet and LDN requires compounding by a pharmacy or compounding laboratory.  Cost is around $115 for 100 days’ supply direct from CompoundLabs (compoundlabs.co.nz); if ordered via a local pharmacy, they may add an extra charge.  The drug is only subsidised if prescribed through and alcohol and drug service for management of alcohol dependence (SA1408) and  note is being used of label outside the indications of opioid and alcohol dependence management. 
 
7.  Endometriosis and ovarian cancer risk
Issue 243 of GP Research Review reported a large population-based study published in JAMA looking at the relative risk of ovarian cancer in women with endometriosis (n=78,893) versus a control group without.
Overall, 597 women had ovarian cancer, and the mean age at first diagnosis was 36 years. Compared to women without endometriosis, those with endometriosis had a 4.2-fold increased risk of ovarian cancer even after adjustments for sociodemographic factors, gynaecologic surgical history and reproductive history.  The risk was most marked for type 1 cancers (aHR[1] 7.48).  Women with ovarian endometriomas and/or deep infiltrating endometriosis had a near 9.7-fold increased risk for all ovarian cancers, with aHR of almost 19 for type 1 cancers. 
Type 1 cancers are composed of low-grade serous cancers, endometrioid and clear cell cancers, and mucinous cancers. This group tends to grow locally, metastasize late, and behave in a more indolent fashion. Type 2 cancers are composed of high-grade serous cancers, carcinosarcomas, and undifferentiated carcinomas. These are highly aggressive malignancies that generally present at an advanced stage.
 
8.  ACC claim numbers
In early September 2024 ACC announced an improvement to their claim approval notification process. Most kiritaki/clients will receive a text message from ACC confirming a claim approval decision, date of injury and ACC45 claim number. They will no longer receive a posted letter. Kiritaki can use their claim number straight away when seeking treatment.  Those under 16 years or without a mobile contact number will continue to receive claim details by mail. 
 
9.  Goodfellow Gems
Gem 225 – Twenty Winks Sleep Questionnaire.  This questionnaire asks about sleep patterns and provides personalised recommendations to help improve your patient’s sleep. There are 20 questions about sleep habits, lifestyle and health.
 
Gem 226 – This looks at the 2024 update on modifiable risk factors for dementia published by the Lancet Commission on dementia prevention.  Two new factors (LDL cholesterol (7% contribution) and visual loss in later life (2%)) have been added since the 2020 update.  The accompanying infographic might be useful when discussing lifestyle improvements with your patients.
 
10.  Health Equity
Issue 111 of Maori Health Review looked at a study published in the NZMJ on the impact of continuous glucose monitors in reducing disparities in glycaemic metrics for Maori Tamariki with recently diagnosed type 1 diabetes.   At the time of the study of 206 children diagnosed over 12 months 2020-2021, CGM use was 56.7% for Māori and 77.2% for European children. At 12 months post-diagnosis, HbA1c was 10.8 mmol/mol (95% CI 2.3-19.4 mmol/mol; p = 0.013) higher in Māori vs European children without CGM, but was similar between ethnic groups in those using CGM.  Hopefully the disparity in numbers accessing CGM will reduce since the devices have become funded. 


[1] Adjusted hazard ratio