too many clinicians method pathology 

means the solution,

the final answer to the problems in the 

diagnosis of neuromuscular diseases.

Yet like all other methods 

of examination,

his pathology of the muscle tissue has 

its restrictions.

And it's just one of the many ways of reaching a 

diagnosis.

Muscle tissue has only a limited range of 

histological changes in reaction to disease.

But on the other hand,

this number is so large that it is 

impossible to show you every way of 

reaction.

Therefore,

I have chosen a few pathological changes that 

illustrates very well the possibilities and 

the restrictions of muscle pathology.

I shall demonstrate some special fibers like 

target fibers,

rink fibers and ragged red fibers and 

some special morphological features like the 

formation of cuba integrates 

cars,

roads and the focal loss of cross 

variation.

On this slide.

You see the five main methods 

of examination and neurovascular 

diseases and I want to 

put forward to you that the order 

is completely arbitrary 

and there is no one of 

these methods that is more important 

than the other.

But I will talk about pathology 

and that will be history,

pathology,

enzyme,

history,

chemistry and when necessary.

I'll show you some slides of the 

electron microscopic features.

The first slide shows you a 

target fiber called by DR King Engel in 

1961 target fiber because it looks 

like a target and especially this guy.

Graham ST,

glamorous tye.

Graham ST staying at the 

core of this target stains 

bread.

Right?

Then you see the target fiber with 

an enzyme,

histone chemical reaction oxidative enzyme.

And then you see that the center of the target 

is not stained at all.

That is because there are no mitochondria in the 

center of these targets.

Sometimes you will find many of these 

targets like here in the ordinary paraffin slides 

stained for or 

hear the cry state section.

And then you see many of these targets.

But in some cases you 

only find one or two of these targets.

And in all cases you can say when you see targets 

that it is a 

involvement of the lower motor 

neuron.

You cannot say that when there is an 

involvement of the lower motor your 

neuron,

you always see targets.

But when you see them then you 

are allowed to say that this must be a 

disease where the lower motor 

neuron is involved.

Another special 

fiber is called the linked fiber.

This is a fost relay staining.

And then you see these rings and the cytoplasmic 

masters like here you see you're running ever and 

Maya Federal through the psych a pleasant.

And when you look upon these 

fibers in longitudinal sections in 

the tristate stained sections.

Then you see these psycho plastic masses and the rink 

fibers and here for instance is a high 

oxidative enzyme activity in 

this cycle plastic mass,

rink fibers are called rink fibers 

because it looks if they have a ring 

around them.

But actually this is not a ring with a 

spiral and there's an aberrant Maya Federal 

running like a spiral along the 

longitudinal axis of this fiber.

And of course it's not often that you 

cut just in the plane of this 

spiral.

And then you can actually see see the 

spiral.

More often it happens that you cut through the 

spiral and then you only see 

part of these aberrant maya 

fables.

When you cut a ring 

fiber transfer sections,

then you of course don't see a close ring 

because it is not a ring but a 

spiral.

And you always find somewhere 

a place where the spiral begins 

or ends like seen here in this 

transfer section of this particular muscle 

fiber.

This is an E.

M.

Of a rink fiber.

And you can see the event Maya fables running 

around this transfers 

section of the main fiber 

mass.

And here is a 

example of linked fibers 

and our and cytoplasmic masses in 

10 autopsies.

Then on elderly,

normal people without any neuro muscular 

diseases.

And you see here on the left side the blue 

missiles and here the other missiles.

And these missiles have a lot of rink 

fibers and psycho plastic masses.

And here on the left hand side there are 

only a few missiles containing one or 

several rink fibers.

The difference between the left and the 

right group of missiles is 

that here all the missiles have a tenderness 

insurgent to bone.

And these missiles do not have any 

tenderness insurgent to bone.

When you take a missile of a guinea 

pig that normally does not 

contain any rink fibers and you 

make it a missile like in the normal human 

just by doing a sonata me.

Then after half a year you will see these 

ringed fibers develop and then you just 

cut the missile fiber,

the missile on a as a whole.

Then again after half a year,

you see these rink fibers and cytoplasmic 

masses appear.

So if you see in 

a biopsy,

ring fibers.

And then I think pathology 

is very low in rank 

because actually ring fibers are 

not pathological in every case because 

normal people can have them.

And furthermore you can say that rink 

fibers will develop in any 

case when the normal continuity of the 

missile fibers has been disrupted by 

pathological process.

For instance replacement of the missile 

by fed tissue.

Often people say that in 

my atomic dystrophy you see many 

ring fibers and that happens to be true.

But on the other hand,

my atomic dystrophy is one of the few neuro 

muscular diseases that you can easily 

recognize just by physical examination 

and so you don't need in this particular 

disease.

A biopsy to confirm 

your diagnosis.

Another kind of rings scene 

are these Granules around some of these 

muscle fibers,

sip psychological collections 

of Granules and in longitudinal 

sections,

you will see that again 

there are many of these Granules 

present in the cycle Emel region.

Sometimes the whole of the 

fiber of part of the fiber is 

involved.

And all these Granules happen to be a 

mitochondria.

When you do a tri gram stain modified,

try gram stain on christ eight 

sections.

Then you see these collections of 

mitochondria are stained red and 

therefore they are called ragged red 

fibers.

Right.

Red fibers have a very 

high oxidative enzyme activity because 

they consist of a 

collection and increase of uh 

mitochondria.

And this is a higher magnification 

showing you the 

particular pattern that has gone.

And all of the fibers 

are have a very high 

oxidative enzyme activity.

Because most of the fibers a 

fiber has been replaced by 

mitochondria.

This is an example of a paraffin slide.

And here again you see this tri gram staining 

technique with this venue.

Als And when you see a similar fiber like this 

in crime state section then of course all 

of the fiber has a very 

very high oxidative enzyme 

activity.

Uh ultra structural.

You see there is a collection of 

of mitochondria abnormal in 

shape and often the cursed 

are thickened.

And here again you see the very 

bizarre formation and 

shape of this mitochondria.

Most of the times in these particular 

collections the mitochondria are 

enlarged as well.

And often you will find these 

particular uh so called para 

crystalline inclusions or parking lot 

inclusions.

And these again are by no means 

very specific for this 

group of diseases.

Uh sometimes these diseases 

or myopathy czar called mitochondrial myopathy.

But the only thing they have in common is a 

increase of collections of 

mitochondria and you can have all 

kinds of muscular involvement,

all kinds of other manage stations.

And so when you see these 

mitochondria,

you cannot say this is a mitochondrial disease.

You only say that this is a 

myopathy with abnormal mitochondria.

And then there are many possibilities left for a 

correct diagnosis in these cases.

Another red 

collection in the diagram stain 

is the formation of so called tubular 

agra grades.

And here you see this 

these two braga grades are only 

found in the dark fibers.

Type two fibers.

This is an A.

T.

P.

S.

A.

T.

P.

A staining.

And here again you 

see that in the light fibers there 

are there are collections 

of tubular Agra greats with a very high 

oxidative enzyme activity.

That is to say when you use any D.

H.

Oxydol reductase 

methods on the other hand,

the typical so called mitochondrial 

enzyme like 16 

hydrogen has no 

increase of his 

activity in this particular fibers.

These are the type to fibers and here are the tubular 

aggregate but they have no increase 

of their this particular enzyme 

activity.

And the same is true for this particular enzyme.

Here are dark fibers are type two fibers and again 

no activity is seen in these 

regions.

So apparently these are not 

mitochondria 

and there are two bills 

like seen here at the ultra structural level 

and therefore they are called tubular agra 

grids.

Uh people still 

think that these are derived from 

mitochondria.

but other people think that they 

consist of a market proliferation of 

the psycho plastic ridiculous.

So when we see the features 

of these tubular aggregates,

you can say that with the 

mitochondrial collections sub cycle 

um a collection of mitochondria they have in common 

that they stay in bright red with the modified tri 

gram stain.

And both of them have no activity 

of minors in a TPS.

But the big difference is the tuba aggregates 

are only situated in Type two fibers 

while the mitochondrial 

accumulations are often seen in 

Type one fibers.

Although they can be found also 

in Type two fibers.

And then of course mitochondrial 

AGRA grades have a high 

activity for these enzymes as 

well.

Now I come to seven patients we saw 

recently,

Men and women and you can see 

that this is a disease with a very 

long duration 25 years or 

13 years.

And these people suffered from a 

very slowly progressive a 

proximal myopathy limb girdle type of 

myopathy without any special 

features.

These little white stars means there is a 

slight elevation of the CPK level in the 

serum.

But you see that this man,

for instance has the disease for 25 years.

And this man has also for 25 

years but his CPK is 

normal and this is just slightly elevated.

So we had the hope that we could 

diagnose these cases by means of 

missile biopsy and I will now show you the 

missile biopsy of a few of these 

cases.

And first of all you see here and transfer 

section of a perfect slide 

state stained with H.

And E.

And there's nothing much to 

see.

There's a normal diameter of most of the 

fibers.

There's no increase of fat tissue or 

increase of connective tissue.

There are no cellular infiltrates.

But yet you can see in this fiber 

very tiny little factual.

And you see here in this fiber three 

factual as well.

Another biopsy of another patient shows 

more of these vegetables.

For instance here in many of the fibers 

are very large 

Victuals and some of the fibers.

Another possibility.

This is a crisis state section state with H.

And T.

Is that most of the fibers are normal and 

just one single fiber is involved.

And then you see these very very many 

of these very tiny 

vegetables.

Uh The solution is that 

when you see a child with the same 

uh kind of disease 

then it's called uh 

gino sis.

This is pompous disease.

And of course then there are no difficulties 

and recognizes in recognizing 

these particular cases.

And when you do a P.

A.

S.

Staining then of course you see the 

accumulation of P.

A.

S.

Positive material.

And all these patients 

showed seven patients were suffering 

from type two sm smell test 

deficiency.

Type two uh 

glycogen storage disease.

And in Children this is called pompous 

disease.

You see that there are eight types 

and in many of these types.

The missiles are involved as well.

Andersons disease is very rare 

and forceful frank 

tokens deficiency also 

is very rare in the built patients.

In most of these 

cases you can 

diagnose the enzyme deficiency 

by biochemical as say.

And as a matter of fact,

the seven patients I have shown the 

muscle tissue and leukocyte 

uh did not contain 

the asset melters 

enzyme.

So in this particular group of 

diseases,

glycogen storage diseases or glycogen Gnosis,

biochemistry is the main thing 

for a correct diagnosis.

Pathology may give you a 

clue when you see as is in 

the case in melted deficiency.

When you see these Victuals.

And by the way,

these Victuals show a very high 

activity of a license thermal 

enzyme that is 

acid phosphate.

Sometimes just the 

histone pathology may give you the 

correct diagnosis.

For instance,

as seen here in central 

core disease,

the central cost and blue 

but it is very difficult to recognize them in an 

H and E stained section.

And this is a long funeral section and again,

you see easily these blue stained 

cause and it's very difficult to recognize them 

here in the H and E.

This happened to be our first case of 

central core disease.

And again you see the cars 

running along the longitudinal 

section of these particular 

fibers and all the cores are staying 

blue 

when you do cry state sections in these cases 

you see that the courts are found only in 

type one fibers.

The light fibers here in the Maya february https 

staying are type one.

And here the dark fibers are of type one.

So you see many 

uh type one fibers 

containing these costs 

and this is another patient.

And then you see that almost all type one 

fibers contain one or several 

cost and none of the type 

two fibers show any course at all.

This is a higher magnification of a core 

region showing you that this region 

is devoid of any enzyme activity and that's 

because there are no mitochondria 

mitochondria in this particular area of 

the muscle fiber.

And this is a transfer section showing 

again that the oxidative enzyme 

activity is present at the 

peripheral rim with this core 

region is almost devoid of enzyme 

activity.

Another morphological feature 

readily seen is the 

formation of rods and this is a case of 

congenital name allene myopathy.

And here is a transfer 

section of another case.

And then it's very difficult to recognize the 

fiber not containing any roads.

Most of the fibers contained rods 

and as you will see here,

most of the roads have a sub 

cycle level position.

But of course sometimes you see them in the 

middle of the fibers as well.

And this is in direct microscopic 

picture showing you the sub cycle 

collections of these rods 

and the next one shows 

you that also in the interior 

of the fiber rods are 

present.

And as you know,

these rods derived from the C.

Disk as seen here,

another feature morphological feature of 

mammalian myopathy is a type 

one fiber predominance or as 

you can call it also type two fiber 

positive.

And this is an 

example of a patient suffering from 

mammalian myopathy and it's obvious 

that this is an auto Zamel dominantly 

inherited disease.

However,

this is another case of typical mammalian 

myopathy and this 

patient has a healthy mother and 

unhealthy father.

So 

uh you can say that is 

a AutoZone dominantly inherited 

disease called family myopathy.

And maybe there is another disease 

that is a recessive inherited 

kind of Nummelin myopathy.

So far there are seven 

publications of 

authors who have examined in cases 

of normally myopathy,

the mother and the father as well.

And then you see that in four of these 

cases the murder was suffering from muscular 

weakness and in two of these cases 

the mother was showing rods in her 

muscle biopsy as well.

So apparently these are examples 

of autism,

all dominantly inherited kind of 

type of Nummelin myopathy.

But on the other hand,

there are many patients with completely 

healthy fathers and mothers 

and non no 

roads in the biopsies 

dr arts.

In our laboratory had the opportunity to examine 

six patients suffering from 

lean myopathy.

And in all these patients the father and the murders 

were examined and then you see there's only one murder 

showing muscular weakness and in all the other 

cases no muscular weakness was was 

present.

Yet in two parents,

two pair of parents.

There were rots in there 

In the biopsy and this was 

confirmed in three cases by electron 

microscopy.

So coming back to that particular 

patient patient I showed you 

this patient is suffering from muscular weakness 

and he is showing rods in his biopsy.

His pants are completely normal,

but in the biopsy they 

also show rods.

And that means that this is a auto so more 

recessive mode of transmission 

when you see rods in the missile biopsy.

That by no means means that you 

have to do with a rod 

myopathy.

Because ever since a 50 

in 1965 found rods 

so called secondary roads in central core 

disease.

Almost every year year there has been 

somebody who found rods 

in all these kinds of different 

missile diseases.

And this is an example of 

central Curtis's.

This is the core showing 

like microscopically Rod's collection of 

sub cycle lemon rods and this is the E.

M.

Of the same patient.

Another kind of morphological 

uh change in the 

missile fiber is the so called focal loss 

of cross stations.

This is in trans first section.

And first of all,

you see the white variation of the 

diameter of the missile fibers.

And moreover,

you see the increase of internal nuclei 

trans in longitudinal sections 

stained with P.

T.

H.

You will see that all of a sudden there is a loss 

of cross striations in these particular parts of the 

muscle fibers.

And moreover,

you will see see that in these particular 

regions there are many 

nuclei,

this particular nuclear line.

And again this is showing you a case 

of so called focal loss of cross 

creation.

And here again you can see there 

are no cross striations in these particular 

areas.

And again there is an increase of particular 

nuclei and you can see that the 

transition between normal and 

abnormal is very sharp.

And here again is a chris state 

section stained for oxford enzyme 

activity.

And in these zones where 

the loss of cross striations is 

present,

there is no activity.

And that is because there are no 

mitochondria as shown here in the 

E.

M.

Picture.

This is the normal part of the missile showing 

many mitochondria and all of a sudden there's a 

very sharp transitional zone 

between normal and abnormal.

This is the focal loss of cross creations 

zone and there is a streaming of the Z.

Discs and there is no mitochondria.

And again like in other types of 

so called congenital myopathy.

You will see there is a type two 

positively or Type one predominance 

more often in these cases of 

uh focal loss of cross 

striations,

there is not only a Type one predominance 

but the type one fibers are 

too small.

So there is a type one fiber hypertrophy 

according to Brooke and angle the 

normal diameter of this boy 

whose age is six years 

is 30 to 40 

microns.

And you can see that his 

mean diameter is much 

smaller.

So in focal loss of cross 

striations.

Central core disease.

Normally myopathy 

Pathology is # one.

It's very important to know 

that when you see things 

like for instance a core 

or a rod,

then you cannot diagnose this case 

without a muscle biopsy.

On the other hand,

I think it's you're not justified to 

say that a disease 

is rot myopathy 

because you see rods and I will give 

you an example of this 

particular difficulty we 

can encounter.

This is a pedigree showing you a 

boy suffering from a congenital 

progressive myopathy.

He has five completely 

normal healthy sisters and his 

mother and his father both are very,

very healthy.

Now I show you first of all the 

muscle tissue of this boy.

And first of all you see that there is again 

a Type one predominance.

All these type all these fibers are of 

type one.

And then you see that he 

also has focal loss of cross 

striations here and there are no 

cross striations scene.

And moreover,

he has the typical collections of 

these particular nuclei.

But in another part of his 

biopsy we found the 

collection of rods and this by the 

way was confirmed by electron 

microscopy.

Then we did a biopsy in the deltoid 

missile of his completely normal father 

without any signs or symptoms of 

neuro muscular disease.

And then you see this father 

also shows a predominance 

of Type one fibers or a positive of type 

two fibers.

And moreover,

These fibers,

type two fibers angular dated and 

small.

And this healthy man also 

showed collections of rods 

in the cryo states section stand 

for with a 

modified try growing state.

Now I will show you The missile 

biopsy of the murder and she has a 

beautiful normal mosaic 

pattern of type one and type two 

fibers.

But this lady again 

showed collections of roads 

and the modified tri 

gram stain.

So when we look at the 

pathology in these cases,

you can say that these 

people had rods 

and their son had rods and focal 

loss of cross striations.

And you compare 

pathology with muscular 

weakness.

Then you can say this 

apparently is an auto so more recessive 

disease.

But that's all you can say.

You are not allowed to say that this boy is suffering from 

Hamelin myopathy with some 

focal loss of crustaceans.

And you are not allowed to say that he is suffering from 

focal loss of crustaceans with the formation of 

some rods.

The name of this disease as yet 

is not known.

And the same problem we had with the 

other family in which the 

disease apparently was autism,

A dominantly dominant inherited.

And here you see the grand matter,

Her son and a little girl 8 

7.

When we saw her,

I first will show you a few slides 

of the grand murder.

And here again you see the 

cycle sub cycle Imo collections of 

roads.

Beautiful roads are seen here and there is an 

increase of vesicular nuclei.

And another picture of her 

biopsy shows again the sub cycle M.

O.

Collections of these rods 

everywhere.

And I must say that seven years 

ago I diagnosed this case as a 

case of normal in myopathy.

Now I will show you a picture 

of a vessel biopsy of her sin,

the father of this little girl.

And then you see that this 

man shows focal 

loss of cross striations.

Typical picture of focal loss of cross striations.

And here is in a state section 

showing you the loss of enzyme 

activity in these regions because I know 

mitochondria and this 

is again a very sharp 

demarcation between normal and 

abnormal.

But moreover,

you see a collection of rods here 

and a collection of rods there and this again 

was confirmed by 

electron microscopic investigations.

And now I'll show you the biopsy of 

this seven years old girl.

And she again 

showed a typical picture morphological 

picture of focal loss of cross station.

Here is a beautiful 

zone.

All the cross stations are 

lost.

And here is the 

collection of physical er 

nuclei.

And again this 

lady showed 

a collection of rods seen at the ultra 

structure level.

So when we compare 

pathology with clinical 

features,

then you see that the grandmother 

had normally myopathy 

because he had so many name a leans.

But after re examination of 

her biopsy I found two fibers,

just two fibers showing focal loss of cross 

station.

And this man showed both of them.

And this little girl showed 

mainly focal loss of crustaceans with a 

few uh rods 

seen at the ultra structure level.

And when we compare these two 

muscular weakness and the pathology again,

the only thing you can say is that there is 

a lot a zonal dominantly 

inherited myopathy.

And you cannot say that 

this girl is suffering from mammalian myopathy 

with rods with 

uh focal loss of crustacean or her 

grandmother from focal loss of crustaceans with 

rods.

Of course all these people are suffering 

from the same disease.

And this last picture gives you 

a symbolic 

impression of what I like to say.

This is a painting 

of the well known dutch artist Asher 

for this reason for this occasion stained with 

a and then you 

see that there are people who have 

caused in their biopsy 

and there are people who have focal loss and there are 

people with formation of roads.

But in some biopsies you can 

find cause and roads or you can 

find focal loss and roads.

And so far,

I've never came across a biopsy in 

which you see cause and focal loss together.

So I hope that I have given 

you at least an impression of some of the 

pathological reactions of muscle 

tissue.

In conclusion we can say that muscle 

pathology can be the answer too many 

questions and in some cases may even be 

the very last answer.

MR pathology often shows a lot of 

non specific reactions and in these 

cases gives no answer at all.

Mr pathology may be dangerous 

because it can tempt people to name a 

disease after only one pathological 

feature seen under the microscope.

Both all,

however,

we must be aware that MR pathology is 

just one of the many ways that can lead to 

a correct diagnosis.

Thank you.