The Fallacy of Diagnosing Cardiac Involvement in Inclusion Body Myositis

Unlike polymyositis and dermatomyositis, cardiac muscle involvement in inclusion body myositis (IBM) is uncommon, and any such involvement is unlikely to be due to IBM itself. Physicians routinely check cardiac troponins in subjects with putative inflammatory myositis and there is a risk of overdiagnosis of cardiac muscle involvement, primarily in IBM, but also in other skeletal muscle disorders.

This occurs when Troponin-T is used as the marker. Unlike Troponin-I, which is specific for the heart, Troponin-T is produced by regenerating skeletal muscle fibres, and therefore could be elevated with ongoing skeletal muscle damage (and regeneration).

The same applies to CK-MB, which is also produced by regenerating skeletal muscle, and therefore is not specific for cardiac damage when there is ongoing skeletal muscle destruction. The suspicion that such elevation- for Troponin-T or CK-MB- is not due to cardiac causes, is strengthened by a normal BNP or N-terminal ProBNP and a normal Echo.

Therefore, the only safe way to rule out cardiac muscle involvement in such patients is to test for Troponin-I. Unfortunately, many labs, including ours, routinely test for Troponin-T.

Think of Spinal Muscular Atrophy 3 or 4 in Subjects with Proximal Weakness, Raised CK, Areflexia and Tremor

What is the most common monogenic cause of infant mortality?

You would be surprised to know that it is Spinal Muscular Atrophy (SMA).

SMA has a carrier frequency of 1 in 53 and affects 1 in 11,000 births.

Based on age of onset and severity, it is classified into 5 types- 0,1,2,3 & 4.

Type 0 or the prenatal type, and type 1, the infantile type, are the most severe and affected children die of respiratory failure either at birth or within a few months. Type 1 is also known as Werdnig Hoffman disease.

Type 2, also known as Dubowitz disease, has onset before 18 months and affected subjects can live to 25 years, or rarely longer.

Type 3, known as Welander-Kugelberg syndrome, can start anytime between 18 months and adulthood, while type 4 mostly starts after 35 years of age and accounts for around 5% of cases of SMA. Survival is normal in these last two types and the disease is often non-progressive.

It is SMA types 3 & 4 that I will be dealing with here, as these are the ones who can occasionally present in the Rheumatology clinic.

So what determines the type of SMA?

SMA has autosomal recessive inheritance. The putative gene is called Survival Motor Neuron or SMN, and is loocated on chromosome 5q13. Due to gene duplication, there are two SMNs-SMN1 and SMN2, which are >99% similar. SMN1 sits telomeric to SMN2.

There are rare, non-5q varieties of SMA, but most have "5q disease".

In normal subjects or heterozygotes, SMN1 produces the functional protein. SMN2 is a "defective" gene, due to a single nucleotide substitution- T-->A in exon 7. Thus, SMN2 produces a truncated, non-functional protein due to defective splicing most of the time. However, 15% of SMN2 genes produce some functional protein. There are 4 to 8 copies of SMN2 in an individual.

In SMA, both alleles of SMN1 have deletion of exon 7 in 5q13, and do not produce any functional protein at all. Therefore the small amount of functional protein produced by 15% of SMN2 genes assumes added importance. It will not come as a surprise that the higher the copy number of SMN2 genes that an individual has, the milder is the phenotype of SMA expressed. Thus SMA types 0 or 1 have 1 or 2 copies of SMN2, SMA type 2 has 2 or 3 copies, while SMN3 or 4 have 3-8 copies.

SMA3 and SMA4 present with proximal muscle weakness, complete areflexia (resembling peripheral neuropathy), raised CK and absence of respiratory weakness. They may present with difficulty climbing stairs and sometimes with falls. One unexpected feature is a fine tremor of the extremities. This is the most useful clue to the underlying aetiology.

The diagnosis may be suggested by the presence of neurogenic pattern on EMG- sharp waves and fibrillation potentials, and prolonged, high amplitude motor units. Sequencing of the SMN1 alleles on 5q13 is diagnostic, and the copy number variants of SMN2 will accord with the prognosis and type of SMA.

Recently Nusinersen, an antisense oligonucleotide has won approval for SMA in USA and some countries in Europe. It is currently being assessed by NICE. It works by increasing the amount of functional protein produced by copies of SMN2.

Think of SMA3 or SMA4 in an adult with proximal muscle weakness, raised CK, areflexia, and tremor.

An Important Clue to Protein Losing Enteropathy Causing Hypogammaglobulinaemia

Occasionally one picks up hypogammaglobulinaemia unexpectedly in a young person. Most of them look well and give no history of serious infections. Some will have lymphangiectasia, but most will have a protein losing enteropathy due to malabsorption, caused by either Crohn's disease or coeliac disease.

An important clue in such cases is low IgG and IgA, in combination with a raised IgM. As far as I know, this does not happen in any other form of severe hypogammaglobulinaemia.

Use Both Arms for Bubble Contrast Study in Brain Abscess, Not Just the Right

Subjects with brain abscess without any other risk factors, or relatively young subjects with stroke are often suspected of having a right to left cardiac shunt and undergo a bubble contrast study with agitated saline.

A minority of such subjects have the rarest form of ASD- deroofing of the coronary sinus, accompanied by a left sided superior vena cava (SVC), draining into the coronary sinus. (The coronary sinus collects venous blood from the cardiac muscle and drains into the right atrium, but occasionally, the partition separating the coronary sinus from the left atrium is absent, creating continuity between the coronary sinus and left atrium. Such subjects usually have a left sided SVC, draining into the coronary sinus).

Under such subjects, bubble contrast injected only into the right arm will bypass the left sided sided SVC and will therefore appear in the right atrium long before the left atrium, suggesting an absence of shunt. On the other hand, bubble contrast injected into the left arm will traverse the left subclavian vein and make its way into the left sided SVC, the deroofed coronary sinus and will thus appear immediately in the left atrium, revealing the shunt and thus the cause for the putative brain abscess or stroke.

Persistent left sided SVC is rare, but is still the commonest venous anomaly, affecting 0.3% of subjects in the general population and 10% of subjects with congenital heart disease.

The Ross Procedure- An Alternative to Mechanical Aortic Valve Replacement in Young Patients

Consider this problem. A young or middle aged patient needs an aortic valve replacement. Perhaps she was born with a bicuspid valve, or perhaps she grew up in the East and had rheumatic heart disease. Regardless, her aortic valve is end stage and must be replaced. She may be pregnant. What do you do?

The current practice is to give these subjects a mechanical aortic valve. Older subjects would get a tissue (bioprosthetic) valve, but the latter have shorter lives and would almost certainly necessitate replacement after 10 years or so.

Therefore, despite the daunting prospect of lifelong anticoagulation, mechanical aortic valves are preferred in younger subjects.

Donald Ross, British cardiac surgeon, thought of an alternative in 1967. Working at Guy's Hospital, London, he replaced a diseased aortic valve with the patient's own pulmonary valve- an autograft. He then put in a homograft (a cadaveric valve of human origin rather than porcine valve) in the vacant pulmonary position to complete the switch.

His rationale was that a living valve would be physiologically more suitable, the pulmonary valve would share many of the aortic valve's attributes, there would be no immunologic rejection and anticoagulation would be avoided. The background to this was that Star & Edwards had pioneered the first mechanical aortic valve prosthesis in 1960 across the pond, and two years later, Ross himself had performed an aortic valve replacement with a cadaveric graft.

He wasn't happy though. The homografts simply did not last long enough in the aortic position.

Over the next few years, the Ross procedure gained acceptance and was performed in thousands of patients. However, it gained a reputation for being a technically challenging procedure and as the new generation of mechanical valves became available, it became less popular despite the fact that 80% of transplant recipients survived 20 years or longer without re-operation.

In the current issue of JAMA Cardiology, Mazine & colleagues publish a mata-analysis that looks back at five decades of the Ross procedure. Comparing around 1500 such procedures with just over 1900 mechanical valve replacements in young to middle aged patients, they found that the Ross procedure led to reduced all cause mortality, longer survival, better quality of life, haemodynamic performance and left ventricular function than mechanical valves. Rates of major bleeding & stroke were less frequent with the Ross procedure. As expected, re-operations were marginally less common with mechanical valves. These days, most such re-operations would be in the nature of modern percutaneous procedures- TAVR.

Despite the generally held view that the Ross procedure is technically more challenging, peri-operative mortality & morbidity did not differ in the 2 groups. Subjects who had mechanical valves were at a higher risk of needing a permanent pacemaker subsequently.

The Ross procedure cannot be performed in all patients. It is best avoided in those with familial aortopathy and in those with hereditary or acquired connective tissue disease.

It took a while, but after half a century, Donald Ross's groundbreaking procedure has been finally vindicated.

Convergent Series in Medicine

There were 160,000 deaths from cardiovascular causes in the UK in 2016. If the number of deaths decreases by 5% every year, year after year, indefinitely, what is the total number of people that would have succumbed to cardiovascular causes?

This is an example of a convergent geometric series.

In general, the sum of a geometric series is given by S= a (1-r^n)/1-r, where S is the sum of the first n numbers, a is the first number in the sequence, and r is the common ratio of the sequence (the factor by which each successive number increases or decreases).

Now, can you predict what would be the sum of the series if n was infinite? Would the sum S be finite or infinite?

The answer is that it depends on the value of r, the common ratio. If r is between -1 & 1, the sum S would be a finite (convergent series), while if r is <-1 or >1, the sum would be infinite (divergent series).

If r is a fraction, the limit of the equation S= a (1-r^n)/1-r, as n approaches infinity, is S = a/1-r.

In the above example, r=0.95, as the death rate falls by 5% every year, the total number deaths in infinite number of years would be 160,000/0.05=32,00,000.

The sum of this geometric series is finite, hence it's a convergent series.

Alcohol, The Herald

Take a look at the following two situations, and see what you make of them.

In the first, a 33-year old man complains of severe left shoulder pain after drinking alcohol. He's lost weight and has night sweats.

Elsewhere, a 30 year old man has rhinorrhoea, breathlessness and wheezing every time he drinks alcohol.

The first man had Hodgkin's lymphoma. The second had Aspirin Exacerbated Respiratory Disease (AERD).

Musculoskeletal pain can be triggered by alcohol in many cancers. In one series, 40% of these were due to Hodgkin's lymphoma.

Similarly, although the usual trigger for upper & lower respiratory symptoms in AERD is aspirin or Cox 1 inhibiting NSAIDs, alcohol is a common trigger as well. The mechanism is not known.

What's Common to McLeod Syndrome & Glycerol Kinase Deficiency?

McLeod syndrome was first described in a trainee dentist, after whom the condition is named. In most cases it occurs due to truncation of the XK gene, present on Xp21. As the protein occurs on red cell membrane as a heterodimer, linked to the Kell antigen, the condition can sometimes be picked up by the Blood Bank due to the absence or attenuation of the Kell blood group antigen.

Mcleod syndrome shares many features with choreo-acanthocytosis, an autosomal recessive condition caused by defects in a protein called chorein. However, the latter does not have the blood group phenotype of McLeod syndrome- i.e. reduced or absent Kell antigen and absent XK antigen (also called Kx antigen).

McLeod Syndrome can occur alone, or as part of the contiguous gene deletion syndrome affecting neighbouring genes on the short arm of X-chromosome, leading to congenital adrenal hypoplasia, Duchenne Muscular Dystrophy (DMD), X-linked Retinitis Pigmentosa, or combinations thereof.

All documented men with McLeod syndrome have a raised CK between 400-4000 IU/l. It happens even in subjects without contiguous gene deletion, and cannot therefore be attributed to DMD.

Here's where it gets interesting. Similar elevations in CK can be seen in subjects with Glycerol Kinase deficiency, which is also coded on Xp21. This has infantile, juvenile and adult forms, and most with the adult form are asymptomatic except for 2 findings- hypertriglyceridaemia and raised CK. The infantile and occasionally, the juvenile form presents with abdominal pain, non-ketotic hypoglycemia and seizures, much like the carnitine disorders presented elsewhere in this blog.

The hypertiglyceridaemia seen in subjects with glycerol kinase deficiency is actually a pseudo-phenomenon. These subjects in fact have markedly raised serum glycerol, which tests positive in assays for triglycerides. Think of this condition when you see raised CK and high triglycerides in an adult male who is otherwise well.

Nobody knows why these two disparate conditions arising from gene defects on Xp21 should have raised CK. This is currently unexplained.

Curiously, subjects with choreo-acanthocytosis due to reduction in chorein also have a raised CK. However, this is an autosomal recessive condition and therefore cannot be attributed to the X-chromosome.

Unusual Pulmonary Function Tests- "The Non-Specific" and "Complex Restrictive" Patterns

So you thought you knew all about lung function tests, right? Well, try these two scenarios.

In the first, both FEV1 and FVC are low, and the FEV1/FVC ratio is normal. You suspect restriction. You request a TLC by whole body plethysmography, and to your surprise, the TLC is normal.

In another patient, the FEV1 and FVC are again low, the FEV1/FVC ratio is normal, and the TLC is low. However, the FVC is disproportionately reduced compared with TLC when measured against what is considered normal.

The first pattern is called the "Non-specific pattern", while the second is termed "the complex restrictive pattern".

The non-specific pattern is not uncommon- in fact, it crops up in around 10% of PFTs. These subjects were originally thought to have airway obstruction, but it's now clear that obstruction is present in only 60% of such subjects. The other 40% are due to chest wall disorders such as obesity, or neuromuscular disorders, or due to poor technique.

These two categories need differentiating with further tests such as repetition of spirometry after administration of a bronchodilator. This will identify the cohort with obstruction. A chest Xray should pick up a lung mass or pleural effusion. Obesity should be self evident, while Maximal Inspiratory Pressure, Maximal Expiratory Pressure and Maximal Ventilation Volume should identify those with neuromuscular weakness.

Fully two-thirds of subjects with the "non-specific" pattern continue to display this pattern over the years. Only a minority evolve into a frankly obstructive or restrictive phenotype on PFT.

The other pattern, called "Complex Restriction" is much more unusual, and probably accounts for less than 2% of PFTs. Here, the FVC is disproportionately reduced in relation to the TLC, with a discrepancy of >10% in relation to normal values. This pattern occurs relatively frequently in young females. It is associated with atelectasis, diaphragmatic paralysis, mosaic air trapping on imaging, bronchiectasis, BMI>40 or <18.5 and neuromuscular weakness. The term "Complex Restriction" differentiates this group from "Simple Restriction", where the FEV1 and FVC are reduced as well, but the TLC is reduced by proportionately the same extent as the FVC. While subjects with simple restriction are likely to have ILD, those with complex restriction usually do not have ILD. An excellent account can be found in the latest edition of Mayo Clinic Proceedings: https://www.mayoclinicproceedings.org/article/S0025-6196(18)30282-9/pdf

Perineural Spread of Tumour- Beware That Trigeminal Neuralgia

Perineural spread of tumours is a phenomenon that is often subtle, unobtrusive until very late and below the radar for most physicians, including oncologists. Perineurium is the second of the three nerve covers, and under the perineurium lies a potential space, where tumors can spread freely, unimpeded by immune calls, often spreading centripetally towards the brainstem, and less commonly towards the periphery. One should perhaps start by explaining the difference between perineural spread (PNS) and perineural invasion (PNI).

PNI is of two types- one that is only picked up on miscroscopic examination of the resected tumour specimen, and one that is obvious clinically or radiologicaly (usually on MRI). The former is called microscopic PNI, while the latter is called clinical PNI, named nerve PNI, or PNS.

Therefore PNS can be a clinically manifest phenomenon, presenting with numbness or paralysis, or silent, but radiologically obvious on MRI. PNS, by definition, affects large nerves.

Where does PNS crop up most often? In the head and neck, typically in territories supplies by the cranial nerves V & VII, which tend to be the most commonly affected by PNS.

Cutaneous squamous cell cancer (SCC) is the most common malignancy that leads to PNS. The second most common, in terms of ratio, is adenoid cystic carcinoma of the salivary gland. Other predisposing tumours, albeit less common, include basal cell carcimoma, salivary ductal carcinoma, ex-pleomorphic adenoma, and rarely melanoma. Mucosal (head and neck) SCC is a distinctly uncommon source of PNS.

In most cases, the tumour, usually a SCC, has been removed in the remote past, ranging from a few months to few years ago. There are no signs of metastases anywhere else in a third of cases, just in the perineural space.

One must suspect PNS when a subject with a remote history of treated SCC presents with numbness, or paresthesiae in one or more divisions of the trigeminal nerve. The most commonly affected is the maxillary branch. Symptoms are often attributed to trigeminal neuralgia. Men are affected 5 times more commonly as women. Similarly, the facial nerve may be involved, often partially. Upon exiting the stylomastoid foramen, the VII nerve splits into two divisions which then give rise to 5 branches. Usually one or more such branches are involved, for example giving rise to weakness of muscles of mastication. When the entire VII nerve is involved, an erroneous diagnosis of Bells palsy is often made. However, it is worth remembering that Bells palsy occurs acutely while VII nerve involvement in PNS occurs gradually over months.

The median interval between removal of the primary tumour and manifestation of PNS is 16 months, but can be years. Six out of 7 patients have a previous history of cancer, while around 7.5% have no previous history. In a third of cases there is no evidence of PNI in the excised original tumour. The original tumour may have been unclassifiable, treated early with radiotherapy or cryotherapy or not biopsied at all, and thus a definite history of a preceding primary may be difficult to establish, with the only evidence of the same being sun damaged skin.

MRI with neural imaging is better at diagnosis than CT, and should be used when available. Normal nerves appear isointense to the surrounding tissue on T1- and T2-weighted MRIs, but upon injury the nerves become hyperintense and thus visible on T2-weighted MRI. Survival at 5 years is 50-64%. Most patients are treated with a combination of surgery and radiotherapy.

Read the following article for a more comprehensive review.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846401/

Phaeochromocytoma/Paragangliomas Arise Against a Background of Chonic Hypoxia

Phaeochromocytomas/paragangliomas (Pheo/PGL) are tumours of the neuroendocrine system. Roughly a third of these tumours are inherited, driven by genes such as VHL, EPAS-1, EGLN-1, SDH A, SDH B, SDH C, SDH D, SDH AF, RET, and a couple of others. Several of these genes, epitomised by Hypoxia Inducing Factor (HIF), are activated in response to hypoxia. HIF-beta is constitutive, while HIF-alpha is inducible. Several of the SDH genes are also "turned on" by hypoxia. When these genes are constitutively activated in the absence of hypoxia, say due to a mutation, they are said to mimic "pseudohypoxia".

In the 1960s, it became apparent that pheo/PGL was more common in subjects with chronic hypoxia, specifically in two subgroups- in subjects with congenital cyanotic heart disease (CCHD) and in subjects living at high altitudes. Subjects with CCHD in particular, have a much higher incidence of pheo/PGL than the general population. The incidence of pheo/PGL in subjects with non-cyanotic congenital heart disease such as VSD, PDA, ASD and bicuspid aortic valve is no different than the general population.

Similarly subjects living at high altitudes have a higher risk of paragangliomas.

In the latest issue of New England Journal of Medicine, Vaidya and colleagues found that activating somatic mutations in EPAS-1, which codes for HIF-2 alpha, were present in 4 out of 5 subjects with CCHD presenting with pheo/PGL. To put this in perspective, the incidence of EPAS-1 activating mutations in subjects with pheo/PGL who do not have CCHD is only 5-6%.

In developed countries, most subjects with CCHD would have had surgical corrections such as Fontan's procedure in childhood. While the duration of uncorrected CCHD correlates positively with the risk of pheo/PGL, corrective procedures do not ameliorate risk. These tumors can arise many decades later.

Most of these subjects have striking polycythaemia. The latter is of course seen in tumours other than pheo/PGL. For example germ line mutations in VHL lead to the Von Hippel Lindau syndrome, with a higher risk of haemangioblastomas and renal cancer. Somatic mutation in VHL leads to a higher risk of renal cell cancer, and can again be associated with polycythaemia.

It is tempting to hypothesise that the hypoxia inducible genes, when chronically activated by hypoxia itself, through the agency of EPAS-1, as in CCHD, or constitutively (and inappropriately) activated by germline and somatic mutations in genes such as VHL, lead to increased risk of tumours- pheo/PGL in the case of CCHD, pheo/PGL & renal cell cancer with germline VHL mutations, and renal cell cancer in somatic VHL mutations.

It is worth clarifying here that VHL is an inbuilt inhibitor of HIF-alpha. When VHL is mutated (with inactivation), HIF-alpha becomes disinhibited and is free to act as a growth promoting gene (new blood vessels, pheo/PGL, renal cell cancer).

There is no suggestion that acquired causes of hypoxia in adulthood such as heavy smoking or chronic lung disease lead to a higher risk of pheo/PGL. It appears that the drive from hypoxia must start very early in life, such as with CCHD, in order to lead to activating mutations such as in EPAS-1, that would in turn increase the risk of pheo/PGLs.

Since many of the symptoms of CCHD mimic pheo/PGL (tachycardia, palpitation, headache, fatigue), physicians dealing with such patients should have a high index of suspicion for pheo/PGL.

Interestingly the profile of secreted catecholamines in pheo/PGL arising in CCHD is very similar to those where pheo/PGLs arise as part of an inherited syndrome due to "pseudohypoxia" mimicking mutations (VHL, SDH-x). Such subjects have high levels of noradrenaline and normetanephrines and almost normal levels of adrenaline and metanephrines.

More Snow for Britain?

Does weather fascinate you? It certainly grips me. Perhaps because I live in a smallish island (by American standards) buffeted by Atlantic currents from the West and Siberian drifts from the East. Westerly currents mean rain and warmer temperatures, while flow from the East and North is chilly. Simple, you'd think?

Well, weather forecasting is difficult, even for the best in the business. Weather patterns are stochastic, influenced by lots of different variables changing constantly, and it takes a helluva job to get it right most of the time.

So can you make money out of calling the weather right? In February 2018, BBC ditched their £3 million annual contract with the UK's venerable Met Office, which had stood for some 95 years. Instead they plumped for a private weather forecasting company called Meteo Group, founded by a Dutch meteorologist in the 1980s, now headquartered in London. There were howls of protest from traditionalists when BBC's familiar weather pages were replaced by strange charts and symbols from the pan-European group, but the BBC stood its ground.

The irony is that Meteo Group- the private company, takes its raw data from the Met Office....it then puts that data into its own models and comes up with a bespoke prediction.

Well, here's the interesting bit. This coming week, the two agencies- Met Office and Meteo Group- BBC's erstwhile and current weather Gurus- are about to go head to head. Meteo Group are predicting more snow leading up to Easter, on the premise that Siberian winds are going to linger over Britain, much to a runner's chagrin, while the Met Office are predicting cold weather, but no snow, based on their view that the Easterly stuff will work its way through but not tarry. As you can imagine, I am firmly rooting for the latter.

We shall find out soon. Who would have thought there would be so much riding on a bit of forecast?

Unripe Akee Fruit & Pivalic Acid Generating Antibiotics- Mimics of Carnitine Deficiency

In the 1950s, researchers noticed that people in Jamaica, who ate the unripe fruit of Akee tree, usually in the cold season, developed a constellation of symptoms comprising vomiting, hypoglycaemia and altered sensorium. The putative component was therefore named "hypoglycin" and later identified as methylenecyclopropane acetic acid (MCPA). It turned out that MCPA inhibited several acyl-coA dehydrogenases, namely those pertaining to isovaleryl-coA, glutaryl-coA and isobutyryl co-A. These fatty acids are complexed to carnitine and therefore lead to secondary carnitine deficiency. Plasma acylcarnitines relevant to these fatty acids are thus raised, accompanied by an increase in urinary dicarboxylic organic acids such as ethylmalonic acid and suberic acid, presumably formed by w-oxidation of the involved fatty acids, given that beta-oxidation is blocked. Thus, subjects eating unripe Akee fruit had features mimicking several disorders that shared defective beta-oxidation of fatty acids as their underlying aetiology, such as medium chain acyl-coA dehydrogenase deficiency and isovaleric acidemia (both of which are screened for in the UK through a heel prick test 5 days after birth in all neonates as part of the national newborn screening programme).

A similar picture can be seen in subjects taking prolonged courses of certain antibiotics (mostly for prophylaxis against recurrent infections). These antibiotics, namely pivmecillinam (widely used in the UK for UTI), pivampicillin (only used in Denmark), and cefditoren pivoxil (Spectracef) all have pivalic acid as one of their metabolites. Pivalic acid is excreted as pivaloylcarnitine, and thus can lead to secondary carnitine deficiency, and the familiar symptoms of nonketotic hypoglycaemia, vomiting and abdominal pain. Prolonged courses of these antibiotics is therefore inadvisable.

How to Detect Inadvertent Placement of Pacemaker Lead in Left Ventricle

Occasionally, the pacing lead meant for the right ventricle (RV) can be inadvertently placed in the left ventricle (LV) instead. There are several ways this can happen- through inadvertent transarterial catheterisation rather than transvenous, through an existing PFO or ASD, or through puncture of the interventricular septum.

Such misplacement of the ventricular lead is not benign. LV leads are thrombogenic and can be a nidus for thrombus formation and embolisation, leading to stroke.

So how can you tell?

ECG and Xray with a LAO view are the most useful.

Take a look at the following ECG. The top ECG reflects pacemaker lead inadvertently placed in the left ventricle, while at the bottom, the lead has been re-sited in the right ventricle.

Not unexpectedly, the precordial leads reflect a RBBB pattern rather than LBBB. While the RBBB pattern can persist in V1 and V2, even after repositioning the lead in the right ventricle(through open surgery- the LV lead should never be "pulled out"), V3 is the key. V3 will always be positive when the lead is in the LV, and will always be negative, when the lead is in the RV. With LV placement of lead, the frontal plane axis is usually between 0 and -90 degrees, but is often in the "northwestern" quadrant, as in this case.

This picture of apparent RBBB, suggesting a wrongly placed lead in the LV, can sometimes be mimicked even if the lead is in its rightful place in the RV. Again, V3 is the key. Even if V1 and V2 are upright (positive), V3 will always be negative with a correctly placed RV lead. The ECG can be "corrected" by placing the precordial leads one interspace lower, as in the following figure:

The lateral view on Xray is useful when the ventricular lead is in LV rather than RV. The lead is more posterior than when it is in the RV and curves away from the vertebral column, as shown in the following reference:

https://www.mdedge.com/ccjm/article/155202/cardiology/detecting-and-managing-device-leads-inadvertently-placed-left/page/0/1

Of course, such aberrant placement can be confirmed by echocardiography, but should really be picked up on the post-placement ECG.

Reference:

https://www.mdedge.com/ccjm/article/155202/cardiology/detecting-and-managing-device-leads-inadvertently-placed-left/page/0/1

The Girl with Raised CK & High Plasma Acylcarnitines

Over the years, I have got into the habit of requesting plasma acylcarnitines in subjects with raised CK. As a rheumatologist, one sees one's share of subjects with high CK. Most of them have muscle pain, some have fatigue and exercise intolerance. Largely they look well, and investigations are unrewarding.

The European Federation of Neurological Societies recommends that CK levels above the following thresholds be investigated:

Caucasian female- 325 U/l
Caucasian male- 503 U/l
Afro-Caribbean female- 600 u/l
Afro-Caribbean male- 1200 U/l

The girl in question was Caucasian, in her early twenties, and was referred with a diagnosis of ?Fibromyalgia. As physicians all over the world will be aware, this has become a popular and somewhat lazy diagnosis in almost anybody with pain, particularly in primary care. However, this particular girl had had a few admissions with vomiting and abdominal pain. Looking back through one such episode, I found that her CK was ~1500 and 800 on 2 occasions, but had not been repeated.

So I repeated her CK- it was normal. A few days later, however, her plasma acylacarnitines were reported as at least moderately raised for all fatty acid lengths- short chain, medium chain and long chain fatty acids.

So what did she have?

The most likely diagnosis in an adult with raised CK and increase in plasma acylcarnitines of all lengths is Multiple Acyl Co-A Dehydrogenase Deficiency (MADD). This is a condition that is quite responsive to riboflavin in 98% of cases and is therefore important not to miss.

MADD is just one of a number of lipid storage myopathies- the others being Neutral Lipid Storage Disorder Myopathy (NLSD-M), Primary Carnitine Deficiency (CD), and Carnitine Palmitoyl Transferase-II (CPT2) deficiency. More about those others later.

MADD is autosomal recessive, caused by deficiency of one of 3 enzymes- Electron Transfer Flavoprotein Dehydrogenase (ETFDH), or the two isoforms of ETF itself- A&B. Ninty-three percent of cases are due to ETFDH deficiency. When the deficiency is severe, such as with 2 null alleles, you get the most severe form of the disease, with congenital abnormalities (Type I) or without (type II). Such subjects present as neonates with metabolic decompensation such as vomiting, metabolic acidosis, non-ketotic hypoglycaemia, and hepatic failure with hyperammonemia, as seen in Reye's syndrome.

Type 3, with delayed onset presentation in teenage or adulthood, is the form most of us will come across. In 2014, Grunert reported that 350 such cases had been published (of all types), but it is likely that a vast majority of cases with milder phenotypes remain undiagnosed and unpublished.

Most subjects with delayed onset MADD have chronic muscle pain, muscle fatigue, subjective proximal muscle or neck weakness and exercise intolerance. A small minority have episodes of rhabdomyolysis. Subjects can remain asymptomatic. A minority present with acute metabolic decompensation with abdominal pain, vomiting, and acidosis, more commonly seen in types 1 & 2, often after episodes of stress such as fever, infection, fasting, pregnancy or labour. Chronic & acute forms can co-exist in 20% of cases.

The screening test is plasma (or serum) acylcarnitines, which will show a rise across all fatty acid lengths, i.e short, medium and long chain fatty acids (C6-C18). Corroboration can be had by measuring urinary organic acids (spot sample in non-acidified container), specifically that of glutaric acid, 2-hydroxy glutaric acid, ethylmalonic acid, 3-hydroxyisovaleric acid, adipic, suberic and sebacic acids and glycine conjugates (acylglycines). These will be raised. Hence MADD is also known as type-2 glutaric aciduria. Since the plasma acyl-coA is all bound to carnitine, serum free carnitine will be low. However, some subjects have raised plasma acylcarnitines and high urinary organic acid excretion only during periods of stress.

The confirmatory test is sequencing of the ETFDH gene, looking for mutations or null alleles. This will yield the diagnosis in 93% of cases. Muscle biopsy will show lipid containing vacuoles adjacent to normal looking mitochondria on Oil Red-O stain, but does not contribute anything extra if molecular techniques are available.

Once diagnosed, it is important to start these subjects on riboflavin in a dose of 200 mg daily. In most reported case series, riboflavin has been co-prescribed with either carnitine (3g daily) or co-enzyme A, but not both. Many subjects respond within a month, with normalisation of raised CK alongside clinical improvement of pain, fatigue and muscle power, but others may need longer.

Other lipid storage myopathies have different phenotypes. Neutral Lipid Storage Disorder Myopathy (NLSD-M) presents in adults with myopathic features, but in addition is accompanied by cardiomyopathy, fatty liver, transaminitis, high tryglycerides & VLDL, and type 2 diabetes mellitus. There may be parental consanguinity. The putative defect is in the PNPLA2 gene, with a deficit in the enzyme Adipose Triglyceride Lipase (ATGL), which catalyses the first step in the breakdown of intracellular triglycerides. Leucocytes show characteristic tryglyceride accumulation, called "Jordan's anomaly". The only effective treatment is medium chain fatty acids (these enter the mitochondria directly for beta-oxidation, without needing to be conjugated to carnitine).

Primary carnitine deficiency (CD) presents early in life, can be fatal, but is treatable if diagnosed. It presents with myopathy, cardiomyopathy, nonketotic hypoglycaemia and Reye's syndrome type hepatic failure with hyperammonemia. The defect is in the Carnitine Organic Cation Transporter gene, OCTN2. Treatment is Carnitine, in a dose of 3g daily.

CPT2 deficiency is seen in young adults or teenagers, who present with a characteristic history of recurrent rhabdomyolysis, often after exercise, fasting or fever. Some subjects develop renal failure due to myoglobinuria. Unlike the other lipid storage myopathies described above, fat accumulation in the form of lipid droplets is largely absent in muscle biopsy samples on Oil Red-O staining. Recently, bezafibrate has been shown to improve lipid shuttle in these patients in fibroblasts by activating PPAR-gamma, but clinical trials have failed to show benefit.