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.

Why Does My Friend's House in Gurgaon Get More Sunshine on Winter Mornings?

A friend asked me why his house, located in Gurgaon, India, received more morning sunlight in winter, and more evening sunlight in summer. He looked up the angles of sunrise & sunset in summer & winter.

Here's the sunrise and sunset angles for Gurgaon that was posted.

Sunrise : 63* NE
Sunset : 297* NW

Winters :

Sunrise : 116* SE
Sunset : 244* SW

I will deal with the direction, then the angles. Notice that the sun is depicted as rising and setting in the North East and North West respectively in summer and in the South East and South West in Winter. It doesn't change direction. It is simply that in summer, the sun rides much higher in the sky than in winter. As India is in the Northern hemisphere, the position of the sun is higher, i.e. more Northerly, than in winter, when it sits more to the South. That is to say, it follows a much bigger arc, which intuitively makes sense, as the sunrise to sunset time, i.e. the total hours of sunlight, are much longer in summer. That explains the NE, NW in summer and SE, SW in winter.

Now the degrees. This confirms what I said earlier- the arc traversed in summer is much bigger- 297-63=234 degrees than in winter- 244-116= 128 degrees. The sun sits lower, i.e. more to the South in the Northern hemisphere, hence the arc is flatter and lower.

While this explains why the sun should hang around for longer in summer evenings, it certainly doesn't explain why you enjoy sunnier mornings in winter. I looked into this as well. The workings are fascinating and made lovely reading. I would be happy to share if there is any interest at all.

It is commonly believed that the winter solstice in the Northern hemisphere is the day with the most delayed sunrise and the earliest sunset. Indeed, the play of seasons and longer-shorter day length in summer-winter is a function of the earth's inclination relative to it's geometric axis. This angle of inclination ( or "declination" as it's called) is about 23.4 degrees, so that the North pole always faces the sun in summer, while the South pole faces the sun in winter. The inclined axis doesn't change direction. It always faces the Polaris, which is why it's as "Constant as the Northern Star".

However, the earth also revolves around the sun. This orbit is slightly elliptical, so that in December, the earth is closest to the Sun, called Perihelion, while in June, it is at it's furthest, called aphelion. Due to a law of planetary motion, called Kepler's second law, the earth moves faster in its orbit at perihelion, i.e. in December, than at aphelion, i.e. in June. From the vantage point of somebody sitting in the Sun, the earth will appear to be moving almost 7% faster in December therefore*. From the earth however, the Sun's movement through the sky will appear delayed. Thus, towards the end of the year, the Sun is "late". Both sunrise and sunset are later than would be predicted by the earth's declination alone. The reverse occurs in June, albeit less accentuated. That is to say, the sun is "early". Both sunrise and sunset occur earlier than would be expected from the earth's declination alone.

Thus, there are two solar phenomena determining the sunrise-sunset cycle. The first is due to the earth's declination, and can be called the "geometric effect". The second is due to the effect of the elliptical axis, and is called the "clock effect".

In practical terms, what this means is that in December, the delayed sunrise from the geometric effect is augmented by the clock effect, while the earlier sunset from the geometric effect is countered by the clock effect. Thus, say at 40 degrees North, sunset starts to occur later in the day as early as Dec 8, rather than Dec 21, while sunrise starts to occur earlier much later- around Jan 6. The effect is around 16 minutes each way.

The reverse occurs in June. As the sun is "early", sunrise occurs earlier than expected even before June 21, while the peak in late sunset is delayed until July.

It's worth saying here that the Clock effect is invariant, regardless of latitude, while the Geometric effect is more pronounced the further away from the equator you go. At the equator, because the Clock effect predominates, sunset starts occurring later and later as early as November, while it's February before sunrise starts occurring earlier. Timewise, the Clock effect is least pronounced around the equinoxes, and most pronounced around the solstices.

Practically, this means that closer to the equator (Gurgaon 28 degrees North), the Geometric effect is minimal, and the Clock effect occurs for most of the variation in sunrise and sunset. At the equator, this amounts to only around 30 minutes between summer and winter.

In more northerly latitudes ( say Nottingham 53 degrees North), the Geometric effect becomes more pronounced, accounting for the very short days in winter.

Now back to my friend's query. Why are the mornings sunnier in winter? The clock effect should not contribute more than 16 minutes to a change in the time of sunrise, but the problem with invoking it is that sunrise occurs later due to Clock effect in winter, chiming in with the Geometric effect. Hence that doesn't explain the winter morning Sun. The most likely explanation is therefore either less cloud cover in Winter or more likely a South East facing window, which captures most of the sunshine that's available. This latter explains why South facing gardens are prized in more northerly countries such as the UK.

* Kepler's second law - sometimes referred to as the law of equal areas - describes the speed at which any given planet will move while orbiting the sun. The speed at which any planet moves through space is constantly changing. A planet moves fastest when it is closest to the sun and slowest when it is furthest from the sun. Yet, if an imaginary line were drawn from the center of the planet to the center of the sun, that line would sweep out the same area in equal periods of time. For instance, if an imaginary line were drawn from the earth to the sun, then the area swept out by the line in every 31-day month would be the same. (http://www.physicsclassroom.com/class/circles/Lesson-4/Kepler-s-Three-Laws)