U.S. patent application number 09/841546 was filed with the patent office on 2002-12-12 for method of diagnosis and treatment and related compositions and apparatus.
Invention is credited to Hammesfahr, William M..
Application Number | 20020188202 09/841546 |
Document ID | / |
Family ID | 22287251 |
Filed Date | 2002-12-12 |
United States Patent
Application |
20020188202 |
Kind Code |
A1 |
Hammesfahr, William M. |
December 12, 2002 |
Method of diagnosis and treatment and related compositions and
apparatus
Abstract
A method for treatment of a disease comprising vasospasm or
other symptom alleviable by smooth muscle relaxation and a
vasodilator delivery system. The figure is a TCD of MCA post
nitroglycerine spray obtained during continuous monitoring.
Inventors: |
Hammesfahr, William M.;
(Clearwater, FL) |
Correspondence
Address: |
RICHARD COALE WILLSON JR
3205 HARVEST MOON DR
STE 200
PALM HARBOR
FL
34683-2127
US
|
Family ID: |
22287251 |
Appl. No.: |
09/841546 |
Filed: |
April 23, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09841546 |
Apr 23, 2001 |
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09101934 |
Jul 13, 1998 |
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6258032 |
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60010881 |
Jan 31, 1996 |
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Current U.S.
Class: |
600/454 ;
600/504 |
Current CPC
Class: |
A61B 5/4094 20130101;
A61K 31/15 20130101; A61K 31/4168 20130101; A61K 49/0004 20130101;
A61B 5/369 20210101; A61K 31/4422 20130101; A61K 31/21 20130101;
A61K 31/4439 20130101; A61B 8/06 20130101 |
Class at
Publication: |
600/454 ;
600/504 |
International
Class: |
A61B 008/06 |
Claims
What is claimed is:
1. A method for the treatment of diseases comprising vasospasm or
other symptom allevietable by smooth muscle relaxation, comprising
in combination: a) measuring blood flow in at least one area; b)
administering a first dosage of a vasodilator; c) remeasuring blood
flow, and; d) administering a further dosage of a vasodilator, said
further dosage being adjusted in response to the remeasured blood
flow; e) continuing said treatment over a period of days while
titrating said dosage according to still further measurements of
blood flow to maintain optimal blood flow velocity.
2. A method according to claim 1 wherein the symptoms comprise
cerebral vasospasm.
3. A method according to claim 1 wherein the measuring comprises a
technique selected from the group consisting of Transcranial
Doppler (TCD), quantitative electroencephalogram and determining
relative vessel diameter.
4. A method according to claim 1 wherein the blood flow is measured
as Mean Fluid Velocity (MFV) in at least one intracranial
vessel.
5. A method according to claim 4 wherein the MFV rises above about
0.4 meters/minute during vasospasms.
6. A method according to claim 1 wherein the treatment is continued
for from about 5 to 250 weeks.
7. A method according to claim 1 wherein the vasodilator is
selected from the group consisting of Nitroglycerin in pill, patch,
ointment, cream, inhaler, spray and other forms, Nitroglycerin
equivalents and substitutes, such as p.o. clonidine, Dynacirc
(isradipine), hydrazine, nifedipine, and medicines from the
empirical group of medications which have the common characteristic
of causing smooth muscle relaxation and which systemically reduce
pulmonary capillary wedge pressure, and combinations of the
foregoing.
8. A method according to claim 1 wherein the disease is selected
from the group consisting of whiplash, closed head injury with
vasospasm, attention deficit disorder with vasospasm, migraine with
inter-octal evidence of vasospasm, syncope or blackout spells of
unknown aetiology with evidence of vasospasm, seizure with evidence
of vasospasm, and dementia with evidence of vasospasm, concussion
and post-concussion syndrome with evidence of vasospasm, migraine,
sympathetic vasospasm associated with breast implants, and cerebral
vasospasm.
9. A method according to claim 1 wherein the disease is selected
from the group consisting of dyslexia, memory disturbances,
depression, psychosis, reflex sympathetic dystrophy, mood disorders
and sensory motor disorders; transient ischemic attack (TIA),
pseudoseizure, hemibalism, and stroke; tremor, Parkinson's disease,
torticollis, electrical shock trauma, attention deficit disorder,
concussion and post concussion syndrome, in which vasospasm can be
detected.
10. A method of claim 1 wherein the patient treated initially
presents with transient or continuous TCD Mean Flow Velocities
(MFV) of greater than 0.1 meter per second.
11. A method of treatment of intracranial vasospasms comprising
intermittent application of a vasodilator and reducing dosage as
the vasospasms reduce in frequency and/or severity.
12. A method of claim 1 wherein the treatment is applied to a
patient who initially presents with transient or continuous TCD
Mean Flow Velocities (MFV) of greater than 0.3 meters per
second.
13. Vasodilator delivery systems specially adapted to deliver about
5 to 25% of conventional dosage of vasodilators and marked with the
appropriate DRG and/or ICD 9th. codes and/or instructions for
titrating or tapering their use, to facilitate their proper
application for treatment of diseases involving vasospasms.
14. A delivery system according to claim 13 adapted for transdermal
delivery.
15. A delivery system according to claim 13 adapted for delivery of
about 0.02 to 20 milligrams per day (Nitroglycerine equivalent) of
vasodilator.
16. A delivery system according to claim 13 adapted for delivery of
a vasodilator selected from the group comprising Nitroglycerin in
pill, patch, ointment, cream, inhaler, spray and other forms,
Nitroglycerin equivalents and substitutes, comprising p.o.
clonidine, Dynacirc (isradipine), hydrazine, nifedipine, and/or
other medicines selected from the empirical group of medications
which have the common characteristic of causing smooth muscle
relaxation and/or which systemically reduce pulmonary capillary
wedge pressure, and combinations of the foregoing.
17. A method according to claim 1 wherein the disease is selected
from the group consisting of fibromyalgia, cardiac disease, gastric
disorders and other systemic disorders, psychosis, other
psychiatric disease, attention deficit disorder, comprising
vasospasm as a component.
18. A method according to claim 1 wherein the disease is selected
from the group consisting of systemic disorders comprising
vasospasm as a component.
19. A method for diagnosing and treating a disease caused at least
partially by insufficient cerebral perfusion, comprising in
combination: testing for presence of a continued diastolic flow
beyond end diastolic velocity as an indication of vasospasm,
administering a vasospasm-reducing dosage of a medicine selected
from the empirical group of medications which have the common
characteristic of causing smooth muscle relaxation and/or which
reduce pulmonary capillary wedge pressure, repeating said testing
over time and titrating said dosage to minimize occurrence and
severity of said vasospasms.
20. Each invention substantially as described herein.
Description
[0001] This application is a Divisional of U.S. Ser. No. 101,934
filed Jul. 13, 1998, now U.S. Pat. No. 6,258,032 classified in U.S.
Class 600/454 and International Class A61B 008/06; and claims
priority of provisional patent application 60/010,881 filed Jan.
31, 1996 and of PCT/US97/01576 filed Jan. 29, 1997.
BACKGROUND OF THE INVENTION
[0002] I. Field of the Invention
[0003] This invention deals with medicine and the diagnosis and
treatment of certain types of blood vessel diseases and a variety
of disorders which all have been discovered to have in common a
condition called "Vasospasm" or "Narrowing of the Blood
Vessels."
[0004] II. Description of Prior Art
[0005] The most relevant prior art appears to be:
[0006] 1. Roger P. Woods, Marco Iacoboni, M.D., Ph.D., and John C.
Mazziotta, M.D., Ph.D.; Brief Report: Bilateral Spreading Cerebral
Hypoperfusion during Spontaneous Migraine Headache. N Engl J Med
1994; 331; 1689-92.
[0007] 2. M. Hennerici M.D., W. Rautenberg, M.D., G. Sitzer, M.D.,
and A. Schwartz, M.D.; Transcranial Doppler Ultrasound for the
Assessment of Intracranial Arterial Flow Velocity--Part 1,
Examination Technique and Normal Values; Surg Neurol 1987; 27;
439-48.
[0008] 3. U.S. Pat. No. 5,309,923 to Leuchter and Cook, U.S. Pat.
No. 5,307,807 to Sosa et al, U.S. Pat. No. 5,287,859 to Erwin
describe "qEEG" devices and techniques useful with the
invention.
[0009] 4. U.S. Pat. No. 5,163,444 to Braverman discusses the P300
brain waves mentioned below.
[0010] III. Problems Presented by Prior Art
[0011] Prior treatment regimens have generally focused on the acute
disease while the present invention embodies the discovery that the
vasospasms and vascular narrowings are commonly chronic in nature.
Further, past dosages have often been excessive and such
over-dosages are found by applicant's investigations to actually be
harmful in patients at some stages, because such dosages can
themselves subtlety promote vasospasms.
SUMMARY OF THE INVENTION
[0012] I. General Statement of the Invention
[0013] It is an object of this invention to treat vascular spasm as
identified primarily from ultrasound, but which may be suspected on
the clinical grounds, with the use of vasodilators in a progressive
step-wise fashion, preferably titrated against continuing testing.
The introduction usage of the medications and tapering of the
medications must be done in a specific fashion in order to result
in a clinical improvement of the patient in a variety of conditions
which all have in common the presence of vascular spasm. Certain of
these conditions have not previously been identified as having
vascular spasm as a component of their disorder, and these
conditions have been identified in applicant's clinical practice
and thus will be named further under the section that deals with
claims. It has been recognized that patients with vascular spasm
have a typical clinical presentation of symptoms, and that these
symptoms follow a progression in substantially direct correlation
to the vascular spasm identified on Transcranial Doppler (TCD), a
technique using ultrasound imaging of the brain for evaluation of
vascular size. It is further recognized clinically that vascular
dilation medications may have paradoxical responses depending upon
dose. In essence, there is a therapeutic window, a dose which is
the proper dose for treatment of the condition which changes over
time. Initially under dosing the patient will result in no change
of their symptoms, as well as overdosing the patient will result in
the exact same symptoms as under dosing the patient or giving the
patient no medication at all. Thus vascular dilation medications
tend to have a paradoxical response with overdose. The proper
dosage for a patient is based upon clinical response in association
with objective data as may be identified from Transcranial Doppler
ultrasound as well as other imaging modalities.
[0014] Essentially the preferred methodology is to obtain an image
or measurement of the intracranial blood vessels in the diseased
conditions to be noted under claims, and then introduce low dose
vasodilation medications. Repeat ultrasounds or other imaging
modalities are used to titrate the patient's medical response. As
vascular dilatation occurs, medications hen become altered in a
stepwise tapering fashion, using ultrasound or other imaging
modalities to identify the redevelopment of vasospasm and the
appropriate dosage of medication. It is recognized that patients'
metabolism may vary across the course of the time that they are on
these medications, and it is further recognized that patients'
clinical symptoms may not be a useful guide to their response to
medication. Accordingly, repeat evaluations with the use of imaging
modalities are used to assess pharmacological response.
[0015] The invention comprises a method of treating a patient
presenting with symptoms suggestive of a stroke or multiple
sclerosis (MS) and/or reporting trauma to the neck and/or head e.g.
whiplash or concussion from a fall or any other disease discovered
to be alleviatable by relaxation of smooth muscle or to comprise
vasospasm, preferably intracranial vasospasm as a symptom;
comprising in combination:
[0016] a) testing by determining rate of blood flow, preferably
intercranially or in the arteries of the neck and or upper back,
and/or determining relative diameter of those vessels e.g. by
magnetic resonance imaging (NMRI) and/or determining evoked
potential;
[0017] b) treating the patient with an effective dosage of a
vasodilator, preferably nitroglycerin administered by patch,
preferably at a rate less than about 0.8 mg/hr;
[0018] c) re-determining said rate or diameter or potential
(collectively "blood flow") after said treatment, to evaluate
recurrence of vasospasm;
[0019] d) adjusting the dosage in response to the results of the
re-determining;
[0020] whereby symptoms comprising headache, burning sensation or
pain in the head dizziness, or fainting, etc., or other symptoms of
the disease treated, are alleviated.
[0021] Disease:
[0022] The technique and associated compositions are valuable in
the treatment of any condition in which vasospasms, preferably
cerebral vasospasms are detected as a component, including without
limitation, those conditions listed under Utility of the
Invention.
[0023] Symptoms:
[0024] The common symptom to all these conditions is the vasospasm,
particularly cerebral vasospasm.
[0025] Testing:
[0026] Transcranial Doppler is the most preferred test, both for
diagnosis and also for titrating dosage of the vasodilators
preferred for treatment. Other tests will preferably be used as
discussed under Methodology. Generally intracranial blood
velocities greater than 0.6 meters/second, are indicative of
vasospasm. Generalized cerebral vasospasm is identified by TCD Mean
Flow Velocities (MFV) of greater than 0.1, more preferably than 0.3
and particularly greater than 0.4 meters/second in intracranial
vessels (about 0.07, 0.2 and 0.4 meters/second, respectively, for
vertebrobasilar system) and prolonged diastolic flow component in
which continued elevation of diastolic flow beyond end diastolic
velocity occurs throughout substantially the entire course of
diastole. This prolonged diastole is the most preferred indicator
of vasospasm. Other presently available tests which are valuable
for vasospasm detection and dosage titration comprise SPECT nuclear
medicine testing, angiograms, EEG, qEEG, P300, and other
neuropsycological, psychological and electrophysiological tests
which can monitor mental impairment due to vasospasm.
[0027] Vasodilator:
[0028] Nitroglycerine is the most preferred vasodilator for the
treatment of the invention, both because of its ready availability
in a variety of forms; pill, patch, ointment, cream, spray,
inhaler, etc., and because its pharmacology is so well known. The
many Nitroglycerine equivalents and substitutes, such as p.o.
clonidine, Dynacirc (isradipine), hydrazine, or long acting
nifedipine and others known to the art, can be used to replace or
to supplement Nitroglycerine. For patients exhibiting
Nitroglycerine intolerance, a combination of Nitroglycerine (spray
or patch) with Nifedipine is particularly preferred.
[0029] Alpha blockers have been tried. Hytrin (Terazosin) has not
been found to be effective. Catapress (Clonidine) has been
extremely effective. Minipress (Prazosin) has been significantly
effective and frequently better tolerated in the long run than
Clonidine, although in Applicant's patients, it seems to treat the
problem successfully enough to prevent the symptoms, but not enough
to allow complete resolution of the vasospasm. Cardura (Doxazosin)
has been a relatively mild medication. Aldomet (Methyldopa) has
been useful in some patients. Reserpine has been an extremely
effective medication. In the short term, it is helpful due to the
parasympathomimetic effect, which tends to decrease the activity of
the Sumpathetic nervous system. Later, its direct sympatholytic
action is very effective. Frequently, a dose needs to be adjusted
downward approximately 6-10 weeks after institution of therapy. It
has even been useful in treating migraine induced depression due to
chronic vasospasm with or without headache in those patients who
could not tolerate other vasodilators. Clonidine has also been
useful in these depressed patients who could not respond to other
vasodilating medications.
[0030] ACE inhibitors are effective. With use of ACE inhibitors and
concomitant administration of low dose Nitroglycerin, {fraction
(1/10)}th inch once a day to several times a day, most patients may
be eventually weaned from the use of oral medications, although
Applicant does tend to maintain them on low dose Nitroglycerin in
perpetuity. Other Angiotensin Converting Enzyme Inhibitors,
including Capoten (Captopril), Altace (Ramipril), Lotensin
(Benazepril), Monopril (Fosinopril), Prinivil (Lisinopril),
Vasotech (Enalapril), and an ACE inhibitor have also been tried.
Applicant suspects that ACE inhibitors work the best due to their
activity on the Nitric Oxide pathway. They are most effective at
reversing the vasospasm when used in conjunction with low dose
nitrates.
[0031] Calcium channel blockers are effective. The most effective
has been Dynacirc (Isradapine). Much less effective have been, in
descending order of effectiveness, Nifedipine, Nimodopine, Plendil
(Felodipine), Dilacor (Diltiazem), Cardene (Nicardipine) and,
Norvasc (Amlodopine) and finally, Verapamil.
[0032] Other agents that deserve special mention include Toradol IM
in doses of 90-120 mg. In lower doses, this is not so effective.
Unfortunately, due to the new FDA guidelines, Applicant no longer
uses this medication in these doses. Hydralazine is effective, but
tends to cause significant blood pressure changes in these
patients. Interestingly though, Hydralazine tends to improve the
morphology of the diastolic flow component dramatically, which in
view of Hydralazine's effect on arterioles, bolsters the
perspective that the diastolic phase of the Transcranial Doppler is
a good indicator of downstream runoff.
[0033] Psychiatric agents frequently have vasoactive effects.
Prozac, and other non-vasoconstricting medications are helpful.
[0034] As examples of the many drugs available: Clonidine has been
extremely effective. Hytrin (Terazosin), Ismelin (Guanethidine),
Minipress (Prazosin), have been all tried, with less successful
results. Cardura (Doxazosin) is still being tried, but initial
results are just now coming available. Dibenzyline
(Phenoxybenzamine) beta blockers, Inderal (Propranolol), Tenormin
(Atenolol), Normodyne (Labetolol), Lopressor (Metoprolol) Imitrex
(Sumatriptan), IM Toradol (Ketoralac) Channel Blocker, and an ACE
inhibitor along with low dose Nitroglycerine and a Clonidine patch,
as well as magnesium, Brethine, etc.
[0035] Accupril (Quinapril), Altace (Ramipril), Capoten(Captopril),
Lotensin (Benazepril), Monopril (Fosinopril), Prinivil
(Lisinopril), Zestril (Lisinopril timed released), Univasc
(Moexipril), Vasotec (Elalapril), Cozaar (Losartan). Accupril
(Quinapril) has Inderal (Propranolol), Tenormin (Atenolol),
Normodyne (Labetolol), Lopressor (Metoprolol) Angiotensin
Converting Enzyme Inhibitors (ACE) inhibitors have been tried
including Accupril (Quinapril), Altace (Ramipril),
Capoten(Captopril), Lotensin (Benazepril), Monopril (Fosinopril),
Prinivil (Lisinopril), Zestril (Lisinopril timed released), Univasc
(Moexipril), Vasotec (Elalapril), Cozaar (Losartan). Accupril
(Quinapril) has consistently been the most effective. p.o.
clonidine, Dynacirc (isradipine), hydrazine, Adalat (Nifedipine) in
standard doses and timed release dosages has been helpful but as a
second line drug. Careen (Nicardipine), Nimotop (Nimodopine),
Cardizem (Diltiazem), Norvasc (AmlodipineMellaril (Thioridizine)
has not been effective. Thorazine Chlorpromazine) has been
moderately effective. Navane (Thiothixene) has been extremely
effective.
[0036] All of the effective medications have the common
characteristic of causing smooth muscle relaxation and reduce
pulmonary capillary wedge pressure in most cases, which empirically
defines a class of useful medications which also includes many
other medications, some of which are setforth in Appendix A, filed
with this application.
[0037] Dosage:
[0038] It is an important feature of the invention that the
vasodilator dosage is substantially lower than dosage usually
prescribed for treatment of coronary disease, preferably about 1 to
40%, more preferably 5 to 30, and most preferably 10 to 25% of such
conventional dosage. Based on a 70 kilogram patient, on a
Nitroglycerine-equivalent basis, about 0.001 to 5000, more
preferably about 0.01 to 1000 and most preferably 0.01 to 20
milligrams per day of vasodilator will be optimal in most cases.
Still lower rates will be employed on pediatric, and lower body
weight adult, patients. Stated differently, from about 10 minutes
to 20 hours or even more per day of application of a commercial
Nitroglycerine patch can be administered during initial treatment.
Further, this dosage will be optimized by reducing or increasing
the dosage in response to continuing test results, particularly TCD
and qEEG, showing reduction in frequency and/or severity of the
patient's vasospasms. In most cases, just sufficient vasodilator
will be administered to achieve optimum reduction in vasospasms
preferably measured as optimal TCD Mean Flow Velocity (MFV) at the
respective stage of treatment. It will be recognized that these
dosages are mainly far lower than the vasodilator dosages commonly
employed to treat cardiac disease and this is because the treatment
of vasospasm needs much lower dosage, and that vasospasm may even
be induced by the vascular reaction to high dosages of vasodilator.
Without being bound to any theory, it appears that the number of
receptors increases during treatment, so that some patients are
able to tolerate only lower dosages as treatment continues. Thus,
the "titration" of dosage from time to time on the basis of test
results is stressed in the present application.
[0039] Duration:
[0040] Because of the discovery that the vasospasms are not merely
acute, but are chronic, treatment duration will be prolonged in
most cases, extending over months and even years in some cases.
Typically treatments will extend over about 5 to 250 weeks, more
preferably 8 to 100, and most preferably 12 to 60 weeks, though
treatment duration will be controlled by the patient's response as
indicated by the continuing testing.
[0041] Titration:
[0042] Frequent testing, as much as even several TCDs in a single
day during initial treatment, will be used to titrate dosage so as
to avoid overdose (which can itself trigger vasospasms) as the
patient's condition improves.
[0043] Delivery Systems:
[0044] The average dosage on a typical patient will be in the range
of roughly one milligram per day. It is desirable to have delivery
systems, sprays, ointments, creams, inhalers, and preferably
patches of reduced delivery as compared to the conventional systems
now available commercially. Such reduced delivery systems are
particularly desirable for patients who tend to be too
noncompliant, e.g. mentally impaired, to follow reliably a
treatment regimen of intermittently applying and removing
conventional patches to reduce dosage. Such vasodilator delivery
systems will preferably be marked (or packed) with the appropriate
DRG and/or ICD 9th. codes and/or instructions for titrating and
tapering their use, to facilitate their proper application.
[0045] 1. Utility of the Invention
[0046] This technique is useful in treating a variety of conditions
including closed head injury with vasospasm, attention deficit
disorder with vasospasm, migraine with inter-ictal evidence of
vasospasm, syncope or blackout spells of unknown aetiology with
evidence of vasospasm, seizure with evidence of vasospasm, and
dementia with evidence of vasospasm, and post-concussion syndrome
with evidence of vasospasm, migraine, post-concussion syndrome,
sympathetic vasospasm associated with breast implants, and cerebral
vasospasm. The invention embodies the discovery that such
vasospasms are a component symptom of many whiplash injuries.
[0047] While less studied at present, the invention can be used to
diagnose and treat the following other diseases which have now been
found to frequently involve vasospasms: neurocognative disorders
such as, dyslexia, memory disturbances, depression, psychosis,
reflex sympathetic dystrophy, mood disorders and sensory motor
disorders; transient ischemic attack (TIA), pseudoseizure,
hemibalism, and stroke; tremor, Parkinson's disease, torticollis,
electrical shock trauma, as well as any other disease in which
vasospasm can be detected as a component of symptoms. Even cases of
Benign Prostate Hypertrophy (BPH) can be treated with the
vasodilators of the invention to relax the smooth muscle of the
sphincter (where the vasodilator relaxes the muscle even where
vasospasm is not a symptom) allowing better emptying of the
bladder. Further clinical testing has also established the
usefulness in some cases, of additional diseases which have now
been found unexpectedly to involve a substantial degree of
vasospasm, comprising; vertigo, autism, depression, psychosis,
transient global amnesia, memory disabilities, balance
disabilities, Tourette's Syndrome, Tinnnitis, Multiple Sclerosis
and Multiple Sclerosis-like syndrome, hyperactivity and Attention
Deficit Disorder, deficits resulting from strokes of various
causes, migraine, seizures, balance disorders, concussion,
post-concussion syndrome sometimes including temporal mandible
joint pain (TMJ) or facial pain, cerebral ischemia and other
vascular components discovered to be associated symptoms in some
cases of psychiatric disorders such as chronic depression and some
psychosis, as well as vascular dysfunction from any cause such as
kidney disease and peripheral vascular disease e.g. from diabetes,
cholesterol, infection or other cause. A basic factor is that
neurological diseases are really symptom diagnoses for the most
part. Thus depression is the diagnosis for a specific type of
behavioral abnormality, not the underlying pathological or
anatomical diagnosis. This is also true for stroke, multiple
sclerosis, vertigo, balance disorders, and many other diseases may
be directly caused by ischemia, or have a component of their
problem caused by ischemia, or have associated problems caused by
vasospasm arising from their associated problems.
BRIEF DESCRIPTION OF THE DRAWINGS
[0048] FIG. 1 is a Transcranial Doppler (TCD) of MCA immediately
prior to treatment by Nitroglycerine spray.
[0049] FIG. 2 is a TCD of MCA post Nitroglycerine spray obtained
during continuous monitoring.
[0050] FIG. 3 is a related raw EEG scan.
[0051] FIG. 4 is a brainmap showing a spatial distribution of alpha
frequency mu rhythm.
[0052] FIG. 5 is a brainmap showing a spatial distribution of beta
frequency mu rhythm
DESCRIPTION OF THE PREFERRED EMBODIMENTS
EXAMPLES
Whiplash, MS, Migraine
[0053] A clinical review and correlation among 38 whiplash
patients, 19 patients with MS-like syndrome, one with MS associated
with breast implants, as well as 5 migraine patients is presented.
All patients have similar clinical complaints, EEG abnormalities,
and cerebral vasospasm identified on Transcranial Doppler testing.
All have similar clinical responses to medication that resulted in
clinical improvement paralleling the course of clinical resolution
of the cerebral vasospasm.
[0054] Methodology:
[0055] All patients are evaluated with a complete history, physical
exam, and neurological exam by a Board Certified Neurologist. All
patients have blood work consisting of a CBC with differential
count and platelets as well as an SMA-30 obtained. All whiplash
related patients underwent a CT or MRI of the brain, EEG and qEEG,
B-mode and spectral analysis ultrasound of the subclavian, carotid,
and vertebral circulation, and Transcranial Doppler (TCD)
examination of the intracranial circulation. In some situations,
repetitive Transcranial Doppler examinations are performed on the
same patient in the same day. Initially, these tests are performed
by maintaining the probe on the patient's head through the course
of several hours, but later the technique involves using the same
probe, patient position, technician, depth, and cranial window with
serial but interrupted exams across the course of the day. In all
cases, the highest spectral frequencies are recorded, as well as
repeat exams at the same depth and window as the baseline
pre-medication windows were obtained. Immediately prior to initial
TCD exams, a neurological exam is carried out. At the time of
initiation of treatment for the cerebral vasospasm, at which time
vasoactive medications are administered after the baseline TCD and
neuro exam are obtained, repeat TCD exams are carried out and when
medication effects on the intracranial circulation were identified,
repeat neurological exams are obtained. In 5 patients, P300 are
obtained prior to initiation of treatment and, again, several
months later. The same methodology is used in those patients
referred for evaluation of possible MS-like syndrome as recognized
in the recent global settlement. With these patients, triple evoked
potentials, EEG and qEEG, and a vascular evaluation as outlined
above is carried out in all patients, and in 11 who decided to
attempt treatment with vasoactive drugs, the methodology outlined
above for initiation of as in the MVA-related post-concussion
syndrome are used. 10 of the 19 MS-like syndrome patients
additionally had brain MRI tests performed. In 3 of the MS-like
syndrome patients, P300 tests are obtained and serial studies after
1-2 months of treatment in all 3 were also obtained. The same
methodology are also used with respect to the patients with a
history of migraine, although only two of these had MRI or head CT
exams performed at time of initiation of treatment. All 5 had
carried a diagnosis of migraine headache for at least 10 years
prior to evaluation.
[0056] All patients noted that these symptoms are intermittent in
occurrence, and at times some symptoms would coexist with other
symptoms, and at other times these symptoms would be dissociated
each from the other. All noted that the symptoms could be
aggravated by stress. All patients had tried over the counter and
prescription anti-inflammatories and muscle relaxants prior to and
during the initial stages of evaluation without significant relief.
All had been tried on Fioricet or Fiorinal, Midrin (isometheptene
mucate), and aspirin. 22 of the 38 patients had also been tried on
calcium channel blockers, beta blockers, Imitrex (sumatriptan
succinate), and p.o. Toradol (ketorolac tromethamine). 21 of the 38
used narcotics for pain control. Neurological exam on these
patients are remarkable, during exacerbation, for lower extremity
hyperreflexia, abnormal tandem gait, and abnormal Rhomberg exam.
All patients' examinations could be aggravated by inducing
psychological stress in the patients or performing actions that
increased their pain, as would occur by doing activities that would
aggravate their neck discomfort. All patients had normal MRI or CT
examination of the brain EEG and qEEG exams are performed on each
of these patients, with the following findings. All patients had a
low voltage 5-20 microvolt polymorphic delta and theta pattern
identified in the frontal and temporal areas. Those who complained
of ataxia and balance disturbance had the same abnormalities
identified in the occipital lobe. All had a superimposed mu rhythm
in the frontal and temporal areas better identified on qEEG than on
bipolar montages as this rhythm appeared as a subharmonic
superimposed over the posterior occipital alpha rhythm on the
bipolar montage. The qEEG, a 16 channel average referential
montage, allowed improved definition of wave form analysis and
spatial distributions and confirmed the underlying EEG evaluations.
TCD exams in all patients showed evidence of generalized cerebral
vasospasm as identified by Mean Flow Velocities (MFV) of greater
than 0.1, more preferably 0.2 and most preferably 0.4 meters/second
in intracranial vessels (about 0.06, preferably 0.2 and most
preferably 0.3 meters/second for vertebrobasilar system) and
prolonged diastolic flow component in which continued elevation of
diastolic flow beyond end diastolic velocity occurs throughout the
entire course of diastole. In all cases, the EEG and qEEG
abnormalities mirrored the distribution of vascular abnormalities
identified on Transcranial Doppler.
[0057] Results:
[0058] 38 patients referred with post-concussion syndrome after
whiplash due to fall, motor vehicle accident (MVA), or beating are
evaluated. On initial evaluation, their clinical complaints
included intermittent headache, photophobia, visual blurring or
transient scotomas, hyperacusis, word finding or word substitution
problems, ataxia or balance disturbance, memory and concentration
lapses, and, in some cases, black out spells associated with
syncope. A baseline blood pressure, neurological exam and TCD are
then obtained at the time of initiation of treatment, and treatment
are initiated with nitroglycerin sublingual spray. Initially,
continuous TCD monitoring was performed for out to two hours from
administering the spray. Continuous monitoring was performed of
that vessel previously identified to be in the most severe spasm.
Ongoing monitoring of blood pressure and pulse with an electronic
monitor was also performed. When pharmacological relaxation had
peaked, repeat neurological exams are performed as well as
patient's clinical perspectives on their symptoms are sought.
[0059] All patients showed improvement in Mean Flow Velocities at
15 minutes who are continuously monitored, and the peak degree of
relaxation was seen at 1 hour with continued relaxation of the
intracranial spasm identified out to two hours. At the time of peak
relaxation, approximately 1-2 hours out from administration of the
nitroglycerin or other vasoactive drugs, a full TCD and
neurological exam was carried out. No blood pressure changes,
including orthostatic changes, of significance are noted as defined
as changes in systolic or diastolic readings of 10 points or
greater and changes in pulse of 10 points or greater. Generally no
changes in pulse or blood pressure are noted beyond changes of less
than 5 points in any of the readings. Continuous TCD monitoring was
performed in 9 patients. Serial TCD monitoring was performed in 25
patients, usually at 45-60 minutes post administration. All
patients showed clinical improvement, however 3 patients did not
show significant TCD improvement. These patients are subsequently
identified as unable to tolerate Nitroglycerine and are nitrite
sensitive. In those patients who are continuing to be monitored,
they redeveloped their subjective symptoms and objective exam
abnormalities as the vasospasm returned as documented on TCD.
[0060] The TCD exam became vital for individualizing treatment. It
was found that the therapeutic window for Nitroglycerine changed
over the first 3 months of treatment and patients frequently
redeveloped their symptoms or developed migraine headaches. Here
the TCD was vital for modifying treatment. In these patients, while
on Nitroglycerine, a repeat TCD is obtained and then a therapeutic
challenge is administered by spray. Repeat TCD is obtained at 15
minute and 1 hour intervals. Those patients who had developed a
Nitroglycerine-induced migraine or migraine equivalent mirroring or
superimposed on their original problem developed worsening of the
TCD at the 15 minute or the 1 hour interval. Those who required
increases in their dose, showed improvement of Mean Flow Velocity
on TCD. 1 patient who had previously failed Nitroglycerine spray or
patch alone due to a nitrite sensitivity, and failed Nifedipine
alone, is able to tolerate the two in a combined dose with virtual
complete resolution of clinical symptoms as confirmed by history,
exam, and TCD findings. With removal of the Nitroglycerine, while
any degree of abnormalities are still seen on TCD, applicant's
patients' problems recur. However, with continuing treatment until
Mean flow Velocity has returned to normal and is documented as
normal during Nitroglycerine free intervals during the day, the
patients could then use the Nitroglycerine spray or patch on a PRN
basis for treatment of any of the above mentioned complaints with
great success rather than continuing to require scheduled daily
doses of medication.
[0061] While most patients eventually reached a peak daily dosage
of 4-6 hours in two to three divided doses on a nitroglycerin patch
during treatment, dosage requirements varied from 10 minutes a day
in two adolescent girls, and one 30 year old male, up to a total of
24 hours a day for one 34 year old woman whose initial complaints
prior to starting the Nitrodur (nitroglycerin) patch included
severe ataxia, confusion and intermittent syncope or episodes of
hemiparesis in addition to the visual blurring, headaches and
concentration and memory changes seen in the other patients.
[0062] Most patients are on this dose for 1-2 months, and then
tapered. No patients who are able to tolerate Nitroglycerine
treatment continued to require narcotics, and only two of the above
patients in this series remained on narcotics where 21 of the 38
who started treatment are on narcotics for pain control. Of great
significance is that 2 patients with intermittent syncope also have
episodic hemiplegic migraines. They showed complete resolution of
both of these problems shortly into therapy. There are only 3
failures to treatment. 1 patient with post-traumatic syncope of
unknown aetiology who is nitrite sensitive continued with these
episodes, and one such episode is brought on by 3 minutes of a
Nitrodur patch being applied. She eventually responds to
maintenance treatment with p.o. hydralazine in doses high enough to
treat the vasospasm. The second patient is unable to tolerate
Nitroglycerine or short-acting nifedipine, which caused angina, but
did respond to Adalat, a long acting nifedipine preparation. The
third continued on narcotics at low doses but unchanged from the
dose she presented on.
[0063] Applicant's patients range in age from 15-76, consisting of
12 men and 26 women. In four patients with post-traumatic
fibromyalgia and fibromyositis, the symptoms of fibromyalgia and
fibromyositis completely resolve while on Nitroglycerine. They are
in the tapering phase, and the symptoms are not recurring of these
fibromyositic and fibromyalgic conditions. The P300 in the 5
patients evaluated also shows improvement during the course of
treatment. In 3 of these patients, this improvement is
independently confirmed by the neuropsychologists treating the
patient. The other patients do not have ongoing neuropsychological
follow-up. FIGS. 1 and 2 represent examples of the baseline TCD
while patient is symptomatic, and a follow-up TCD with resolution
of patient's complaints after a Nitroglycerine sublingual spray.
FIGS. 3, 4 & 5 represent examples of raw EEG tracing obtained
on an average referential montage and two accompanying qEEG epochs.
The first brainmap, FIG. 4, shows examples of the distribution of
the alpha frequency mu rhythm, frontally, temporally, and
occipitally; and the second, FIG. 5, is similar but shows that
these mu rhythm frequencies are frequently in the beta range. On
these maps, the frontal lobe is to the top, and the occipital lobe
is inferior.
[0064] In 19 patients with MS-like syndrome and 1 with MS
associated with breast implants, a similar pattern of complaints,
Electro-encephalographi- c and TCD findings is seen. Our patients
range in age from 23-61. The pattern of complaints is the sane as
the whiplash patients. Headache, concentration and memory
disturbances, visual blurring, intermittent focusing abnormalities,
balance disturbances, ataxia, photophobia, and hyperacusis are
complained of in all patients. The severity of the complaints,
however, tends to be less than that of the whiplash patients,
however, their complaints of memory and cognitive dysfunction and
mood swings tend to be considered by the patient to be their most
severe problem in all but the one case who is felt to have MS. Of
the 10 patients who had MRI's performed, 2 had a few scattered
UBO's consistent with small white matter infarcts, and one had
large plaques consistent with MS on MRI and brain biopsy. All
patients had fibromyalgia and fibromyositis.
[0065] All but one of the patients had MRI or surgical confirmation
of implant rupture and in that one patient, it is clinically
suspected due to patient's symptoms, their progression, and length
of time of implant (20 years). All patients had the same
constellation of EEG and qEEG abnormalities, TCD abnormalities that
paralleled the vascular distribution of the EEG changes in a
fashion identical to that seen in the whiplash patients and that
followed clinical distributions subserved by vasculature.
[0066] 11 patients decided to start treatment with vasoactive
medications. 10 started initially with IM Toradol, followed by
maintenance dosing of Toradol given by mouth is seen to give
consistent improvement clinically and with respect to the TCD.
Unfortunately, gastritis developed in all cases and the patients
are switched to Nitroglycerine by spray and patch, and is joined by
the 11th patient, who initiated treatment with Nitroglycerine.
Again, using the method outlined for initiating treatment with the
MVA patients, baseline blood pressures, neuro exams, and TCD exams
are performed with serial examinations on the first day also
carried out as previously discussed. Results are identical. All
patients have dramatic clinical improvement in exam and clinical
symptoms with resolution of vasospasm as documented on TCD. All
patients relapse as the initial dose of medication wears off as
again documented by TCD. Although no patients are found to be
nitrite sensitive in this group of patients, the TCD again became
invaluable in monitoring and modifying dosage regimens.
Interestingly, unlike the whiplash related patients, most of whom
are able to taper their use of the nitroglycerin use within
three-four months of treatment initiation without requiring the use
of other medications, none of the breast implant cases have been
able to dramatically reduce their need for the medication below a
Nitrodur 0.1 mg patch for 4 hours a day. Again, the therapeutic
window for Nitroglycerine modified in these patients over time, the
TCD became again invaluable for individualizing the dose necessary
for treatment. In all patients who started the Nitroglycerine
treatment, the symptoms of fibromyalgia and fibromyositis resolved
while on therapy and returned if they stopped therapy.
[0067] Five patients had a history of intermittent migraine
headache, with only one patient noticing intermittently a history
of scintillating scotoma as a prodrome to the headache. Later,
after treatment had been initiated, all reported that they could
start to recognize prodromes that they previously did not consider
as prodromes. These included mild balance disturbance, feeling of a
mildly clouded sensorium, or abrupt sensation of severe fatigue of
acute onset. All 5 patients are men, ages 37-58. All showed
evidence of vasospasm on TCD and the headache resolved with
Nitroglycerine patches applied for 10 minutes to 1 hour. Follow-up
TCD at the end of application of the patch are obtained in 3
patients which confirmed reduction of the vasospasm. At the time of
symptomatic treatment, all patients had minimal lower extremity
hyper-reflexia, and a minimally abnormal test on Rhomberg exam and
tandem gait testing. These abnormalities all resolved with the
nitroglycerin.
[0068] Discussion:
[0069] In applicant's practice, the association of cerebral
vasospasm is consistently found to be associated with a typical
clinical complex. This complex includes complaints of balance and
memory problems, intermittent visual blurring, scotomas, or
difficulty focusing, intermittent photophobia, and/or hyperacusis,
memory and concentration lapses, word finding difficulties,
dysaphasias; and, in more severe cases, headache which sometimes
progresses to hemiplegic migraine with documentable weakness,
asymmetric reflexic changes or fanning of toes or further
progression to headache associated syncope or syncope with
tonic/clonic activity and post-ictal confusion. Neurological exam
most consistently shows a positive Rhomberg exam, abnormal tandem
gait, and in more severe cases showed fanning of toes or
intermittent Babinski's and reflex changes. The symptoms and
neurological exam wax and wane in severity of abnormalities. In
whiplash patients, the exam worsens with psychological stress or
pain, and, in the breast implant patients, psychological stress
would precipitate a worsening of the exam. The patients often
appeared to be photophobic or would startle easily to sound. EEG
and qEEG's, even those with syncope or syncope and secondary,
observed, tonic/clonic activity, would be minimally abnormal.
However, the pattern of EEG abnormalities, as well as the
subjective complaints and neurological exam findings, mirrored the
vascular distribution of the abnormalities seen on TCD.
Interestingly, this syndrome in the whiplash patient and the breast
implant patient has now been found to only rarely develop
immediately with the causative trauma, but instead to develop over
a time course of weeks to many months after the initiating
irritant.
[0070] In the early stages of treatment of these patients,
applicant monitors specific vessels continuously while giving
patients test doses of medication. applicant did this in order to
more quickly evaluate which medications are most effective for each
patient and to individualize doses. It became clear that such
extensive and time-consuming studies are not necessary, as this
condition of cerebral vasospasm in these patents is a generalized
phenomenon to the cerebral circulation. The problem is probably
systematically generalized as common associated complaints during
times of these previously mentioned complaints include prinz-metal
type angina, intermittent coolness of the extremities to the touch,
and menstrual cycle irregularities in some women. All of these
symptoms, except for the menstrual cycle irregularities would be
aggravated by stress and are improved by treatment with the
vasoactive drugs. BAER studies are initially performed on many
patients as part of the evaluation of the ataxia, but are not
helpful as they frequently are abnormal if vertebral artery spasm
is seen on TCD. The BAER abnormalities resolved with resolution of
the TCD spasms in those where applicant has had the opportunity to
repeat the study. Significantly, though, those with abnormal BAER's
at institution of therapy, had more severe reactions to the initial
stages of treatment with Nitroglycerine and reported more severe
reactions then they had previously been treated with
vaso-constrictive medications for headache control. It has now been
found that Nitroglycerine, in the early stages of administration,
can give transient severe vasoconstrictive episodes, apparently due
to a hypersensitivity reaction in which, during early
administration of the drug, some individuals develop transient
worsening of the vasospasm which may result clinically in migraine
headache, seizure, or syncope. In some cases, such episodes can be
mistaken for stroke.
[0071] Thus, great care must be used in administering this drug to
someone in the midst of an exacerbation. In applicant's practice,
the first dose of Nitroglycerine is always given under direct
physician observation, immediately after obtaining a baseline TCD.
This is done as those patients with the most severe reactions to
Nitroglycerine generally, but not invariably, had the most severe
abnormalities on TCD, or are patients severely symptomatic for a
long time, or are less than the age of 20. This transient
supersensitivity may be witnessed on TCD but did not occur with any
of the other vasodilating medications applicant has tried,
specifically, p.o. clonidine, Dynacirc (isradipine), hydralazine,
or long acting nifedipine. It, clinically, probably does occur in
some patients after administration of the short acting form of
nifedipine but applicant has not personally witnessed the TCD
reactions for this drug as applicant has with the other mentioned
drugs.
[0072] Multiple other vasoactive medications are tried on these
patients prior to attempting nitroglycerin. Those medications that
caused vasoconstriction on the TCD, such as Stadol (butorphanol
tartrate), DHE, and Imitrex, in every case worsened the patient's
neurological exam and mentation but improved their headache.
However, in applicant's patients, the more serious neurological
events such as syncope, TIA, or seizures, are usually preceded by a
headache. Due to applicant's concern that headaches may be a
significant warning sign of impending serious neurological events,
the cerebral equivalent of angina, applicant attempted vasodilator
to reduce the vasospasm. Those that resulted in vascular
dilatation, such as Toradol, Nitroglycerine, clonidine,
hydralazine, Dynacirc, and long acting forms of nifedipine, all
resulted in clinical and neurological exam improvement mirroring
the TCD exam's improvement. These medications also alleviated or
treated the headache. All medications in this and generally reduce
pulmonary capillary wedge pressure, which empirically defines a
class of useful medications.
[0073] Common clinical symptoms of headache, intermittent visual
abnormalities, ataxia or balance troubles in patients with usually
normal brain CT or MRI scans but abnormal EEG and TCD findings
suggestive of cerebral vasospasm are presented. These patients are
found to have a clinical aggravation of their symptoms directly
related to the degree of vasospasm seen on TCD. Techniques which
modified this vasospasm could cause clinical improvement or
worsening paralleling the degree of severity seen on TCD. This
application is not meant as a final recipe for the treatment of
cerebral vasospasm on the outpatient basis, but instead is meant to
provide basis for further study into the mechanism of these
findings in disparate conditions and possibilities for
treatment.
[0074] Applicant believes he is the first to identify vasospasm in
patients with the condition whiplash. Half of these patients are
also identified as having either closed head injury symptoms or
post-concussion syndrome symptoms. These patients have
neuropsychological testings which for the most part confirmed the
findings of closed head injury in the previously mentioned half of
the group.
[0075] In treatment of patients with migraine headache, the present
state of the art is to treat patients with migraine with
vasoconstricting medications as opposed to vasodilation
medications, and in fact the present state of treatment of these
conditions with the vasodilating medications mentioned is
considered that the vasodilator may cause migraine headaches.
Additionally, applicant has four patients with attention deficit
disorder and four patients with seizure, all with vasospasm and all
of which have responded well seen from both neuropsychological
testing or seizure control with the use of vasodilator as described
herein. In summary, vasospasm has been discovered to be a
clinically common and treatable entity.
[0076] In FDA attachments for medications in which migraine
headache is identified as a side effect, no indications for the
previously mentioned treatments are identified.
[0077] Additionally, good results are obtained in a number or
patients presenting with systemic disorders, including cases of
fibromyalgia, cardiac disease and even gastric disorders, by
testing and treatment to reduce or eliminate vasospasms according
to the techniques described above. Still further study after the
fling of the provisional application shows good results in the
treatment of additional diseases which have now been found
unexpectedly to involve a substantial degree of vasospasm,
comprising hyperactivity and Attention Deficit Disorder, deficits
resulting from strokes of various causes, migraine, seizures,
balance disorders, concussion, post-concussion syndrome sometimes
including temporal mandible joint pain (TMJ) or facial pain,
cerebral ischemia and other vascular components discovered to be
associated symptoms in some cases of psychiatric disorders such as
chronic depression and some psychosis. For brevity Appendix A
(based on papers to be published) gives clinical details and the
following Examples summarize the clinical treatment and
results.
[0078] While the diseases to which the new techniques have been
found applicable seem to be disparate and unconnected, the modality
bridging all of them appears to be the relaxation of smooth muscle
tissue by treatment with low dosage of vasodilator and the
titration of this dosage over time to avoid overdosage as the
patient's response to the medication changes. Thus, relaxation of
smooth muscles underlying the vascular system alleviates vasospasm,
the relaxation of spincter muscles alleviates BPH, and the
relaxation of downstream arteries alleviates the effect even of
physical buildup of cholesterol.
EXAMPLE
Attention Deficit Disorder
[0079] Attention Deficit Disorder has been found to affect more
than 12 percent of the school age population. This disorder has now
been found to continue into adulthood and many ADD adults with a
mild condition had proceeded through life undetected. Limited blood
flow to the brain (cranial perfusion) has been postulated as a
cause for this condition. Two adults, siblings, were evaluated and
treated as taught herein,(a regimen was made up of a low dose
Calcium Channel Blocker, and an ACE inhibitor along with low dose
Nitroglycerine and a Clonidine patch), to increase blood flow to
the brain with results showing increased social and emotional
control of themselves and IQ improvement of approximately 30
points. Also they improved in achievement motivation and specific
goals for their lives.
EXAMPLE
Concussion or Post-Concussion Syndrome
[0080] It was discovered that most patients referred to a
neurologist's office for brain injury or concussion do not have a
brain injury. Rather, they have an injury to the control mechanism
that controls blood flow to the brain. This injury results in
causing blood flow to the brain to decrease. This drop off in blood
flow accounts for all or much of the clinical symptoms. It is
reversible. Of 22 patients randomly identified by computer with
presenting symptoms of brain injury and a diagnosis of concussion,
one third had no brain injury, but only a vascular disorder, and
the other two thirds identified that a significant portion, or all
of their symptoms were alleviated with she use of common
vasodilating medication. A further aspect was that 22 out of 22
patients referred for evaluation of closed head injury and
concussion complained, on careful questioning, of their symptoms
becoming worse as time went on. These symptoms that developed or
worsened progressively were reversed with vasodilating
medication.
EXAMPLE
Psychosis Caused by Cerebral Ischemia
[0081] In this Example, a patient who has an acute psychotic break
is presented. The patient is identified as having a history of
migraines and then developing acute schizophrenia. She is
hospitalized for an acute psychotic break. Due to difficulty in
controlling the thought disorder, the hospitalization is extended
for 3 weeks. She is then released and self-discontinued her
medications. Out-patient evaluation of her reveals that the blood
vessels leading into her brain are overly constricted, and she is
placed on medication to dilate these blood vessels. The patient's
thought disorder processes, memory disturbances and headaches
completely resolve. This represents a new approach to the diagnosis
and treatment of psychosis and underlying concerns.
EXAMPLE
Reversing Stroke Using Common Vasodilators
[0082] In this Example, three patients with strokes improved
dramatically in minutes to days after devastating strokes by using
the new therapy taught herein (e.g. Dynacirc 10 mg t.i.d. and
repetitive uses of Nitroglycerin.) The first patient developed a
large stroke, which caused her to be able to walk only with
assistance and a cane, and not to be able to speak her thoughts.
One month later, no major clinical changes had occurred. Within 45
minutes of instituting the present therapy, she can walk
unassisted, speak normally and had only minimal weakness. By the
next day, she can transfer from a dock to a boat unassisted. The
second patient has been paralyzed for one year on his left side.
Within one month, he has regained 80% of his strength throughout
most of his body. Within four months he can lift 300 pounds with
his paralyzed leg and 120 pounds with his previously paralyzed arm.
The third patient has severe weakness in his right arm and face for
four days. Within one hour of starting treatment, he has regained
most of the use of his arm. Nitroglycerin and other medications all
result in improvement in the patient's headache, but also resulted
in improvement of any other neurological abnormalities including
balance disorders, gait disorders, hemiparesis, abnormal Babinski's
and abnormal reflexes.
Modifications
[0083] Specific compositions, methods, or embodiments discussed are
intended to be only illustrative of the invention disclosed by this
specification. Variation on these compositions, methods, or
embodiments are readily apparent to a person of skill in the art
based upon the teachings of this specification and are therefore
intended to be included as part of the inventions disclosed
herein.
[0084] For example, the vasodilators include many that are not
named here, the tests for vasospasm are constantly improving and it
will be evident that new tests for blood flow and others not named
here will be useful in the step of testing for vasospasm described
in this application and that the treatable diseases will expand as
vasospasm is found to be a component of additional diseases.
Reference to documents made in the specification is intended to
result in such patents or literature being expressly incorporated
herein by reference.
[0085] Appendix A
EXAMPLE
[0086] ADD Method:
[0087] Two individuals were referred for Career Evaluations by
their Mother because they lacked ambition and success in work. They
were a 27 year old female and her 25 year old brother. They shared
the same biological parents, both professionals, and shared similar
behavior characteristics of:
[0088] Completing Junior College in 4+ years.
[0089] No record of full time employment for 4 months or
longer.
[0090] Limited friendships.
[0091] No specific career plans.
[0092] Enthusiastic beginnings but poor or incomplete endings.
[0093] Underachievement in relation to ability.
[0094] Both were administered a battery of tests which measured
neuropsychological functioning and personality variables. The
similarities continued with both scoring in the superior range on a
non-verbal abstract thinking intelligence test; average on the
Vocabulary subtest of the Wechsler Adult Intelligence
Scale-Revised: average in fine motor coordination and
organization.
[0095] Both scored low on achievement motivation, affiliation and
the ability to ask for assistance when they had no solution to a
problems. They were high on aggression and needed control.
[0096] On referral for neurological evaluation, mild physical and
significant objective testing abnormalities were found. Both
patients exhibited very mild balance difficulties only identified
on careful neurological testing. The patients had a mild tendency
to sway when standing at attention with their eyes closed (abnormal
Rhomberg testing). Both, further, had difficulty performing a
Tandem Gait with complete ease. The physical exam was otherwise
normal. An EEG and computerized EEG were performed and were
abnormal. These tests showed a frontal and temporal spatially
distributed alpha rhythm on an average referential montage.
Transcranial Doppler ultrasound showed middle cerebral artery
velocities of greater than 0.8 meters/second bilaterally in the
female, and 0.73 meters/second in the right MCA of the male, with a
normal 0.26 meters/second in the left MCA. Interestingly, on a
separate day, the male was retested and found to have elevated MCA
flow velocities of 0.86 meters/second on the right, and 0.92
meters/second on the left.
EXAMPLE ADD
[0097] Treatment:
[0098] Both individuals were treated with vasodilating medications
for 10 months and received psychotherapy and vocational counseling.
Relaxation and hypnotherapy were also used to develop visualization
skills for both recall of successful social and work experiences
and to visualize successful outcomes of activities to do.
[0099] In serial testing, the male underwent TCD's on three
separate occasions on the same day. After repetitive applications
of Nitroglycerin, the patient was re-examined and underwent
self-assessment, and had repeat Transcranial Dopplers performed. As
the right MCA mean flow velocity decreased from 0.86 meters/second
to 0.79 meters/second, to 0.72 meters/second, and the left MCA mean
flow velocity decreased from a baseline of 0.92 meters/second, to
0.84 meters/second, to 0.79 meters/second, the patient's exam
progressively normalized with eventual development of completely
normal balance testing. The patient also identified significant
improvement in concentration. By the end of the day, he identified
that he could read, understand and retain news articles and
magazine articles. He could also follow a television show
throughout. He could do neither at the beginning of the day.
Observers also felt his comprehension had significantly
changed.
[0100] On the basis of the objective disorders of flow and the
patient's reported and observed improvement during the trial
episode of administering medications to decrease the observed
vasospasm, we started the brother on vasodilators. After the
patient had been on medication for approximately 3 months, the
sister's observations of significant improvement in her brother's
functioning resulted in her self-referring for evaluation and
treatment. We initially used Nitroglycerin and later added a
variety of Angiotensin Converting Enzyme inhibitors, Calcium
Channel blockers, and Clopidine until the regimen that the patient
best tolerated was found. This regimen was made up of a low dose
Calcium Channel Blocker, and an ACE inhibitor along with low dose
Nitroglycerine and a Clonidine patch.
[0101] Over the next 6 months, both sibling's neurological exams
normalize. The Transcranial Doppler results showed marginal
improvement from office visit to office visit. However, the
patients have identified significant functional improvement which
wears off in direct relationship to the vascular pharmacokinetics
of the specific medication used.
EXAMPLE ADD
[0102] Results:
[0103] Both the male and female subjects experienced social,
emotional, physical and intellectual gains through these
treatments. Their Verbal IQ scores increased from scores of 110 and
119 to 143 and 146 respectively. On the Bender Gestalt Test they
eliminated all errors and their drawings were better organized with
improved fine-motor coordination. Both have been planning a
continuation of their college education with specific goals in
mind. The young man had played tennis in high school and has
maintained playing recreationally. He had noted specific
improvements in anticipating moves of his opponents and had
improved his game significantly. This was also noted by his
opponents and fellow tennis teacher.
[0104] Their personalities changed significantly. The female became
less fearful and argumentative and was self assured. The male as
stated "I can relate to friends and I am not the last to get the
joke. I am less the point of jokes and teasing." These were
significant personality and social changes for these
individuals.
EXAMPLE ADD
[0105] Discussion of Possible Theory:
[0106] This study utilized siblings who had been considered OK in
life, but themselves were frustrated and had self thoughts of
failure. Based on Career Neuropsychological testing, they were
found to be Adult-ADD. After 10 months of treatment with
vasodilating medications and psychotherapy. they have improved
their cognitive, social and emotional functioning. Their gains have
been significant and have stabilized. These have remained
consistent for over 11 months and indicate a permanent
solution.
[0107] From a neurological viewpoint, serial monitoring identified
close relationship between functional abilities and a degree of
vasospasm or constriction of the arteries. These patients' long
term TCD's do not reflect major improvements in the resolution of
the degree of spasm. The lack of complete resolution of the
vasospasm probably relates to, in these two specific patients,
their inability to tolerate even moderate levels of vasodilators
without developing symptomatic hypotension. These two patients
share in common with all Applicant's patients referred for
idiopathic Attention Deficit Disorder that we can seldom completely
resolve the vasospasm identified on ultrasound, but that any
improvement in the arterial constriction parallels functional
improvement. Patients with secondary Attention Deficit
Disorder-like syndromes, such as are seen after trauma, closed head
injury, neck injury, Reflex Sympathetic Dystrophy, cerebrovascular
accident, silicon implant disease and other toxic vasculopathies,
and so on, generally have profound vascular relaxation with the
commonly used vasodilators after approximately 6-10 months of
treatment. Nonetheless, our therapy in these two patients has
probably been successful by causing vasodilation of the small
arterioles and other blood vessels in the brain. Such vasodilation
would decrease the ischemia of the brain tissue and improve
performance. On a day when serial testing was performed when
repetitive vasodilation medication doses were used to decrease the
vasospasm, the patient showed significant improvement. This argues
that improved control of the vasospasm may be expected to cause
further functional improvement. Equally, it is strongly recommended
that psychological counseling and biofeedback be utilized in the
long term treatment of these patients, as such treatment, by
decreasing autonomic nervous tone, also enhances vasodilation.
EXAMPLE ADD
Literature
[0108] Learning disabilities (LD) and attention deficit
hyperactivity disorder (ADD) represent almost 25% of school age
learning--conduct problems. Despite their prevalence, much
confusion exists over the differentiation between LD and ADD. This
confusion emanates from the fact that some individuals suffer from
both disorders and school systems tend to group both disorders in
the same classroom or diagnostic category. The major confusion
results from the failure to appreciate the considerable progress
that has been made in recent years in defining and classifying each
of these common neurocognitive and neurobehavioral problems
(Shaywitz, et.al., 1995, p.s50).
[0109] Hallowell & Ratey. 1994 have found that a large number
of adult patients viewed as depressed, anxious,
obsessivecompulsive, personality disordered, dissociative or prone
to substance abuse were ADD. Until recently mental health
professionals have not paid much attention to this disorder in
adults, despite the fact that attentional disorders have major
ramifications for intellectual cognitive and emotional experience.
Miller, in a Wall Street Journal article in 1993. identified the
following as symptoms of ADD in adults:
[0110] A short attention span, especially for low-interest
activities.
[0111] Enthusiastic beginnings but poor endings.
[0112] Low frustration tolerance.
[0113] Difficulty listening.
[0114] Argumentative.
[0115] Frequent job changes.
[0116] Underachievement in relation to ability.
[0117] Frequent and unpredictable mood swings.
[0118] Avoids group activities; a loner.
[0119] Spends excessive time at work because of inefficiency.
EXAMPLE ADD
[0120] Bibliography
[0121] Hallowell, Edward M. and Ratey, John J. Answers to
Distraction, Pantheon Books, New York. 1994. p. 207-211.
[0122] Shaywitz, Bennett A., Fletcher, Jack M. and Shaywitz, Sally
E., "Defining and Classifying Learning Disabilities and
Attention-Deficit/Hyperactivity Disorder.", Journal of Child
Neurology, Vol. 10 Supplement Number 1, January 1995.
[0123] Concussion or Post-Concussion Syndrome
[0124] Professional Abstract
[0125] This article represents the first discussion that concussion
and post-concussion symptoms as well as progressive deterioration
after an accident may be vascularly mediated. Progressive
deterioration of patients, as well as patients complaining of
concussion or post-concussion syndrome or closed head injury,
should include vascular ultrasound screening of the brain.
[0126] This paper represents a complete evaluation of twenty-two
patients referred for evaluation of concussion and post-concussion
syndrome. All patients on referral from their primary treating
physician or psychologist also carried the diagnosis of concussion.
All patients complained of progressive deterioration starting some
time after an accident.
[0127] Six of 22 patients had a loss of consciousness, 7 of 22
patients had altered mental status at the time of the accident
which cleared completely, and 9 of 22 patients had no concussion or
mental symptoms, only spinal symptoms (2 of these 9 did have a
headache). It is assumed that one third of the patients did not
have a brain injury at the time of impact. An additional one third
had complete resolution of all symptoms after the trauma. However,
by the time of presentation, all had an abnormal neurological exam
and symptoms of concussion, closed head injury and post-concussion
syndrome.
[0128] All patients were found to have vascular flow abnormalities
by the Transcranial Doppler (TCD) showing evidence of abnormal
constriction of the arteries intracranially. Other imaging
modalities of these patients included CT and/or MRI scan in all
patients, EEG and computerized EEG in all patients: SPECT scan and
neuropsychological testing were additionally added in many
patients. The comparison of these various imaging and diagnostic
modalities is made.
EXAMPLE
Concussion or Post-Concussion Syndrome
Comparative Analysis and Evaluation
[0129] Twenty-four patients having been computer coded as
concussion syndrome were chosen at random per data from the office
computer; the patients were seen in this office between Feb. 23,
1995 through January 1996. Two of the patients were miscoded and
were dropped from this study. All patients were referred by their
primary physician or psychologist with the diagnosis of concussion.
injuries of twenty patients were sustained by motor vehicle
accidents and two patients' injuries were a result of falling. Each
patient was given a neurological examination by a board certified
neurologist, Transcranial Dopplers, standard and quantitative EEGs,
and most were given either/or MRIs or CT scans of the brain,
neuropsychological testing, and three patients had SPECT Scans of
the brain.
EXAMPLE
Concussion or Post-Concussion Syndrome
Clinical Presenting Symptoms
[0130] Loss of consciousness varied with patients having very brief
black-outs of seconds to twenty-five minutes. Six patients had a
loss of consciousness at the time of the accident with four
patients unconscious for brief seconds, one patient for five
minutes and one patient about twenty four hours. (Ref.Table IA.
Period of Total Unconsciousness at Scene of Accident with Other
Related Symptoms)
[0131] There were seven patients that denied loss of consciousness
but had less severe altered mental status such as amnesia, mental
confusion, dazed, dizziness, vertiginous and/or ataxia. (Ref.Table
IB. Altered Mental Status With No Unconsciousness and Related
Symptoms)
[0132] A third class of patients consisted of nine patients who had
no altered mental status but experienced a combination of a variety
of symptoms such as neck and back pain (two of them also had a
headache). One patient had no symptoms at all at the time of the
accident but developed severe back pain later at night following
the accident. (Ref. Table IC. Physical Symptoms With No Altered
Mental Status.)
[0133] Table IA Period of Unconsciousness at Scene of Accident and
Other Related Symptoms #of Patients Period of Total Unconsciousness
& Related Symptoms
[0134] 4 Brief loss of consciousness with neck and back pain of
seconds to less than 5 minutes
[0135] 1 Loss of consciousness for 5 minutes, dazed, confused with
neck and back pain
[0136] 1 Loss of consciousness for about 24 hours & awoke with
neck and back pain
[0137] Table IB. Altered Mental Status with Related Symptoms but No
Total Unconsciousness
[0138] 3 Immediate severe headaches, confusion, neck and back
pain
[0139] 1 Neck and back pain, vertiginous and nausea
[0140] 3 Amnesic for accident, confusion, back and neck pain
[0141] Table IC: Physical Symptoms with No Alter Mental Status
[0142] 2 TMJ and neck pain
[0143] 1 Neck pain only
[0144] 3 Neck and back pain
[0145] 2 Headaches and severe neck pain
[0146] 1 No symptoms at all at time of accident but later that
night developed back pain.
EXAMPLE
Concussion or Post-Concussion Syndrome
Additional Physical Symptoms
[0147] Temporomandibular Joint Injury
[0148] An associated finding in this study was TMJ and facial pain.
Of the twenty-two patients studied fifteen patients had pain in the
temporal mandibular joints with ten of the patients diagnosed with
having TMJ and five patients with mild symptoms of popping of TMJ
was considered to be clinically insignificant. Onset of symptoms
varied from immediate discomfort to four months post the accident.
Some of patients that were later diagnosed as having TMJ related
that in the beginning, they had so much head and facial pain that
they were not able to determine where the pain was coming from
until they have had a chance for some of the injuries to heal (Ref.
Table ID. Time of Onset of TMJ Symptoms Following Accident)
[0149] Table 1D. Time of Onset of TMJ Symptoms Following
Accident
[0150] 5 patients don't know when pain was localized to TMJ
[0151] 2 patients had immediate pain in TMJ
[0152] 1 patient had pain about two hours later
[0153] 3 patients had pain not immediately but within twenty-four
hours of trauma
[0154] 1 patient with previous treated TMJ became worse within
twenty-four hours following new injury
[0155] 3 patients pain was localized to TMJ 2 months post
accident
EXAMPLE
Concussion or Post-Concussion Syndrome
Thoracic Outlet Syndrome
[0156] A common associated complaint was symptoms of upper
extremity intermittent paresthesias consistent with Thoracic Outlet
Syndrome. Only rarely debilitating, and not complained of by the
patient unless checked for during a Review of Systems of 22
patients. (Ref. Table 1E.).
[0157] Table 1E.
[0158] 19 had Thoracic Outlet Syndrome.
[0159] 3 had no symptoms of Thoracic Outlet Syndrome.
[0160] Interval Between Date of Injury and Presentation:
[0161] Time lapse between the date of injury and the patient's
initial office visit varied from two weeks post accident to years.
(Ref. Table II, Time Lapse from Date of Accident & Initial
Office Visit)
[0162] Table II, Time Lapse from Date of Accident & Initial
Office Visit # of Patients Lapse time injury and initial office
visit
[0163] 1 11 days post accident
[0164] 3 1 month
[0165] 2 2 months
[0166] 4 3 months
[0167] 1 4 months
[0168] 1 5 months
[0169] 3 6 months
[0170] 1 7 months
[0171] 1 8 months
[0172] 1 14 months
[0173] 1 16 months
[0174] 2 3 years 1 25 years
[0175] Previous History of Head Injury:
[0176] An interesting finding during this survey was that 50% of
the patients have had at least one previous accident.(Ref. Table
III. Previous History of Head injury. Two of these patients had
loss of consciousness, one for less than 24 hours and the other
patient, with a Glasgow Score of 4, was unconscious for three
months. (Ref. Table III, Previous History of Head Injury)
[0177] Table III. Previous History of Head Injury
[0178] 13 patients had never had a previous accident
[0179] 4 have had 1 previous accident
[0180] 2 have had 2 previous accidents
[0181] 3 have had 3 previous accidents
EXAMPLE
Concussion or Post-Concussion Syndrome
Clinical Presenting Symptoms Summary
[0182] All patients developed delayed and progressive symptoms
which consisted of as neck and shoulder spasms migraine headaches,
memory and concentration problems, easy distractibility in an
attention deficit-like disorder, and most complained of
intermittent upper and/or lower extremity paresthesias due to
associated spinal injuries. Most patients complained of
intermittent balance problems of varying, usually mind severity,
tinnitus and/or visual burring were also frequent complaints.
EXAMPLE
Concussion or Post-Concussion Syndrome
[0183] Testing Results:
[0184] The patients were evaluated using multi-modality
neuro-diagnostic and imaging techniques. vaso A discussion of MRI,
SPECT scan results, neuropsychological testing, Transcranial
Doppler, EEG and QEEG follows. All modalities proved to be of
value.
[0185] EEG and QEEG Results:
[0186] With respect to EEG's, correlation of the abnormalities seen
in the standard and quantitative EEGs are very close in some cases,
but in other cases abnormalities are seen in the standard EEG that
are not seen in the qualitative EEGs and vice versa. The most
common feature observed in the standard EEG being an alpha-like
rhythm occurring bilaterally in the frontal and temporal areas that
was disassociated from the posterior alpha band seen only on an
average referential montage. The quantitative EEG's most common
finding was an underlying-slowing in the theta and/or delta
frequency range located bilaterally in the frontal and temporal
areas and at times appearing in the posterior head regions.
Epileptogenic spike discharges obvious in both standard, and
quantitative but not in the averaged EEG. However, the QEEG aided
in localization of the discharges with further analysis. (Ref.
Table IV, Comparison of Findings of Standard and Qualitative
EEGs)
[0187] Table IV. Comparison of Findings of Standard and
Quantitative EEGs:
[0188] A. Summation of Standard and Quantitative EEG Findings:
[0189] 18 Patients had abnormal standard and quantitative EEGs
[0190] 4 Patients had normal standard and quantitative EEGs
[0191] 2 Patients had epileptogenic spike discharges obvious in
both standard and quantitative EEGs but not in the average EEG.
EXAMPLE
Psychosis Caused by Cerebral Ischemia
[0192] Professional Abstract;
[0193] A patient with a schizophrenic reaction after a long history
of migraines is presented. The patient was hospitalized for an
acute psychotic break. Due to difficulty with regulating the
thought disorder, the hospitalization was extended to 3 weeks. On
discharge, the patient self-discontinued her medications with a
return of headaches and thought disorders. Evaluation of her
including EEG and vascular evaluation of the brain showed
abnormalities. The patient was placed on medication to treat the
vascular constrictive disorder and the patient's thought processes
returned to normal and the patient became headache free.
[0194] Case Study
[0195] The patient presented with a long history of migraine
headaches which had progressed over the year prior to development
of her schizophrenic break. The headaches would become daily. The
patient noted at times, due to the headaches, she would have
intermittent degrees of confusion, disorientation or memory
disturbances. She had no history of seizures. Two months prior to
presentation she became increasingly distressed about personal
family issues with aggravation of the headaches. She treated
herself with over-the-counter medications and then became concerned
that her husband might be leaving her. She went down to meet him at
his place at work, but became confused about how to enter the
building, and decided he was probably trying to leave the state.
She stole a truck, drove along the road she thought would lead to
him. She was followed by police who identified her as having
disorientated thought processes. She was hospitalized for
psychological evaluation, was found to have a reactive psychosis
and schizophreniform disorder.
[0196] The patient continued to have hallucinations and delusions,
was placed on Haldol (Haloperidol) from which she did not respond.
Headache was not a significant complaint in the hospital. She was
eventually placed on a combination of Navanne (Thiothixene) and
Ativan (Lorazepam). She improved significantly. Blood work
including thyroid studies were normal. The patient was released and
continued to have severe headaches, concentration problems and
memory problems. She felt these problems were aggravated by
activity. Her neurological examination was normal A CT scan of the
brain was obtained which was normal. An EEG and a QEEG showed
intermittent left temporal spike discharges, as well as bifrontal
temporal slowing activity in the 5 mv range in the delta and theta
patterns. A frontal alpha frequency band was also identified on an
average referential montage as well as the computerized EEG.
Transcranial doppler Artery showed evidence of mean flow velocities
in the MCAs bilaterally of 0.65 to 0.75 meters per second, and the
basilar artery of 0.7 meters per second.
[0197] The patient was placed on Inderal (Propranolol) as well as
Depakote (Sodium Valproate) without change in her EEG and continued
flow abnormalities on Transcranial Doppler Artery. The patient was
then placed on Nitroglycerin with complete resolution of her daily
headaches and improvement in her middle cerebral artery flows to
the normal range.
[0198] While taking Nitroglycerin medication, the TCDs continued to
improve with MCAs approaching 0.37 meters per second to 0.5 meters
per second. The patient's headaches completely resolved as did
memory disturbances, concentration problems and emotional
lability.
[0199] Discussion
[0200] The patient has a long history of migraine and develolped
migraine and/or stress-induced schizophrenic reaction. She had poor
response to Haldol (Haloperidol), but good response to Navane
(Thiothixene). On presentation to the neurologist's office, the
patient was off Navanne and evidence of vasospasm and evidence
consistent with cerebral ischemia as well as the spike discharge
was identified on EEG. The patient did not respond to standard
antimigraine medication or seizure medication. The patient
responded promptly to low-dose Nitroglycerin for control and
management for migraines with no recurrent episodes of thought
process disorders, memory disorders or disorientation when taking
medication.
[0201] This suggests that some patients with vasospasm and
vasoconstriction with secondary ischemia of the brain may develop
neurocognitive changes including psychosis. Applicant has had
several other patients with diagnoses of chronic depression or of
steroid induced psychosis, in these cases headache was not a
complaint, who had similar vasospasm identified on Transcranial
Doppler and similar EEG changes as this patient. They also
responded with clearing of their psychiatric disorders with
vasodilators. It is thus our recommendation that, in the evaluation
of the psychotic or psychiatric patient, evaluation for vasospasm
and cerebral ischemia should be performed and treatment instituted
empirically to reverse any abnormalities found, as the psychiatric
disturbance may have a vascular component.
[0202] Migraine Forum (Whip-Lash/Breast Implants/Migraine)
[0203] Applicant has a baseline practice consisting of mainly
post-traumatic, closed-head injuries and post-traumatic migraine
disorders of which many have attention deficit disorders (ADD).
However, several years ago Applicant had a large number of patients
who presented with ADD of which the origin of their problems was
associated with silicon breast implants (silicon toxicity). What
became evident in evaluating of these patients was that the
neuropsychological tests, computerized EEG and Transcranial Artery
Doppler results were essentially identical. Another common
characteristic in these patients was the waxing and waning nature
of at least some of their complaints. Those patients with Attention
Deficit Disorder both post-traumatic and in particularly those
patients with silicon breast implant disease with MS-like syndrome
would have normal neurological examination one day and on another
day the exam would be normal. This finding substantiated the
patients' complaints of waxing and waning of symptoms and seemed to
be related to the degree of physiological or psychological stress
the patient experienced when being interviewed or tested. The
degree of abnormality of neurological exams would extend to the
point of normal or abnormal Romberg and Tandem Gaits, reflex
examinations and Babinski examinations in the same patient. Evoked
potential test results varied from normal to abnormal on different
days and the testing was performed by the same examiners.
[0204] In this same time frame, a series of new medications were
developed to treat migraine headaches. As headache was a major
complaint of many of Applicant's patients, we tried these
medications out including Imitrex (Sumatriptan), IM Toradol
(Ketoralac) and other medications under direct monitoring. As
Applicant's patients tend to be intractable, it was not expected
that any of these medications would have dramatic results. Rather,
it was expected that one or another set of medications might help
point the way into using specific classes of medications or
approaches. Accordingly, each of these patients. equivalent of a
large number of patients, were monitored continuously across the
day. The patients would come in and be hooked up with EEG's or
Brain Stem Auditory Evoked Responses, or VEP's, or Transcranial
Dopplers, and across the day would have many of the different
short-acting medications tried on them to see which would work and
which monitoring tool would be most effective in identifying the
improvement.
[0205] With respect to the different monitoring tools, some were
more helpful than others. It was found that the EEG was not very
sensitive. The Brain Stem Auditory Evoked Response and other evoked
potential tests were very insensitive tools for monitoring, because
of the length of time required to perform the test after
short-acting medications were given in IM or sublingual or nasal
spray administration route. The Transcranial Doppler consistently
appeared to give the best indication as to which medications would
work. If an ultrasound showed improvement, the patient invariably
also reported improvement in their clinical symptoms. These
symptoms included not only headache, but also sensations of
confusion, balance disorder, abnormal Romberg or Tandem Gait of
other neurological abnormalities. If the medications showed
evidence of increasing vasoconstriction on the doppler, the
patients who had a headache, frequently reported improvement in the
headache, but a worsening of their confusional state or a worsening
of other neurological symptoms. Those patients were identified as
having improvement on ultrasound with doppler also showed
resolution of their headache, but did not show the deterioration in
their neurological effects. This was completely unexpected. The
general approach towards migraine and headache has always been that
the headache represents a vasodilation and frequently a
hyperperfusion state. The aura, of course, represents a
vasoconstrictive phase. What our results seemed to suggest was that
the doppler, which looks at essentially the area of blood vessels
around the base of the brain, was showing vasoconstriction.
Vasoconstrictive medicines would relieve the headache presumably
through a similar mechanism, as a vasoconstrictive medication
probably relieved coronary artery disease. It would relieve it by
decreasing the vasodilation that occurs downstream from the area we
are able to directly insonate.
[0206] Unfortunately, if cerebral artery disease is anything like
coronary artery disease, that downstream dilation represents an
attempt by the body to compensate and maintain perfusion to thus
becoming ischemic.
[0207] In Applicant's patient population all medications which
resulted in vasoconstriction. relieved the headache, but caused
neurological deterioration. As the medication wore off, as
documented by the patient's clinical symptoms, sonography data, the
patient's neurological abnormalities improved. Similarly, those
medicines which resulted in direct vasodilation such as Hydralazine
(Apresoline), Nitroglycerin and other medications all resulted in
improvement in the patient's headache, but also resulted in
improvement of any other neurological abnormalities including
balance disorders, gait disorders, hemiparesis, abnormal Babinski's
and abnormal reflexes.
[0208] Observations Noted Concerning Transcranial Dopplers
[0209] A special word about Transcranial Doppler needs to be made.
We found that morphology of a Transcranial Doppler Artery
Ultrasound is as important as mean flow velocities. In our
patients, as they became more normal, and as their fixed deficits
and europsychological abnormalities resolved etc., the morphology
of the wave form would be similar to that of an internal carotid
artery tracing. We did not find that there would be elevation of
flow readings throughout diastole, as is more commonly published.
It is important to identity that the original normative data
obtained in 1979, used for "Normals" patients with post-traumatic
migraine disorders, "psychogenic seizures", and the interictal
migraine phase may not be appropriate. It is important to note that
other labs which have done less extensive studies of normal versus
non-normal, may have unknowingly used many patients with a history
of migraines or whiplash headaches. Some have not identified the
close relationship between degree of vasospasm and clinical
abnormalities. This may be due to less lengthy monitoring or
evaluations being carried out by those labs in comparison to our
own. Equally, the trend clinical correlation is a general one.
Remembering hemodynamics, it is important to note that if the blood
vessel is constricted, patients do have a limited ability to
compensate for the effects of that vasoconstriction by dilating
distally to the constricted area.
[0210] Patients will not be abnormal clinically during the early
stages of constriction of an artery. It is only once the downstream
area is no longer able to dilate to a degree enough to maintain a
significant pressure gradient across the vasoconstricted area that
the patient will develop symptoms. It is important to continue to
monitor and treat these patients until the sonographic studies
return to normal and beyond. Realizing that blood vessels constrict
across the day in response to sympathetic nervous system
variability, internal steroid release, physiological and
psychological stress, including the physiological stress of photic
stimulation, driving etc., and thus to obtain an ultrasound at one
moment, must be correlated with the patient's clinical symptoms and
any complaints of variability across the day.
[0211] We also found that over time, chronic, untreated patient
studies frequently falsely appear to normalize with a dropping of
mean flow velocities. This occurs as the body develops compensating
mechanisms to relieve the ischemia. Thus morphology becomes
extremely important in identifying those who have ongoing
vasoconstrictive disorder intracranially. The development of a
pattern a time goes on is to have a blunted upstroke in the
systolic portion of the ultrasound, but with an overall mean flow
velocity of less than 0.6 meters per second. That blunting, which
is also seen in disseminated vascular disease from any cause, is
highly suspicious for severe vasospastic disorder. A computerized
EEG or standard EEG consistent with brain dysfunction or ischemia,
and/or neuropsych testing consistent with variability of cognitive
injury (especially with fluctuating cognitive deficits across
several hours or days of testing) with ischemia is often helpful
corroborating study. These are patients who should not be treated
initially with Nitroglycerin or other potent medications, but
should first have other medications which are direct vasodilators
instituted at low doses and slowly advanced as the patient is able
to tolerate it. This institution with alternative vasodilators,
tends to decrease the incidence of a potentially dangerous nitric
oxide sensitivity reaction.
[0212] With respect to Nitroglycerin, what we have seen is several
time courses of the effect of Nitroglycerin. The first is an acute
effect which lasts between 15 and 45 minutes. The method of
administration being a patch, pill or sublingual spray determines
the rapidity of absorption and distribution. It seems to have a
lingering effect for approximately 2 to 3 hours. Nitroglycerin then
gets converted into a variety of subsidiary byproducts, all with
some vasodilating properties. Each of these medications themselves
can accumulate in patients to toxic doses, and can cause a reactive
cerebral vasoconstriction. Thus, it is easier to maintain patients
on intermittent low dose Nitroglycerin applications, then chronic
applications of medication, as the clinical data and clinical
response to the vasodilator challenge becomes confused. With
respect to Nitric Oxide sensitivity, those patients in Applicant's
clinical practice who have not been premedicated with a beta
blocker, an alpha blocker or a direct vasodilator such as a calcium
channel blocker or an ACE inhibitor, who are given their first dose
of Nitric Oxide and developed acute erythema of the nose or face,
are having a reactive vasoconstriction and distal vasodilation
occurring at the same time. Those patients on Transcranial Doppler
Artery Ultrasound will have acute spasm of the arteries and active
constrictions and dilations may frequently be seen. Those patients
may have a seizure or a stroke or a blackout spell. This problem
can be immediately reversed with IM Toradol (ketoralac). Toradol in
90 to 120 mg IM doses causes acute vasodilation on ultrasound in
most patients. In lower doses, the Transcranial Doppler Artery
ultrasounds generally do not show significant changes, but the
patient reports a symptomatic improvement. For most patients,
standard doses of nitrates in any form will aggravate the
vasospasm.
[0213] IV Toradol (Ketorolac) in 30 to 60 mg doses does not cause
any improvement on Transcranial Doppler Artery Ultrasound, and
patients generally report a sensation of vertebrogenic syndrome
with increase spaciness, confusion, worsening headache and
worsening spasm. Although Applicant has not identified this
directly, their clinical course is that of a development of a
vasoconstricted vertebral or basilar artery syndrome. This probably
relates to a carrier drug in the I.V. Toradol solution, as giving
the Toradol intramuscularly (I.M.) or in the alternative oral form
after oral or I.M. loading gives the expected vasodilation. Without
a change in formulation, Applicant would not recommend the I.V. use
of Toradol to reverse acute and life threatening vasospasm or
stroke. Multiple medications over the last several years have now
been tried for the vasodilators. Each of these classes and results
will be discussed in their specific following paragraphs.
[0214] With respect to betablockers, Inderal (Propranolol),
Tenormin (Atenolol), Normodyne (Labetolol), Lopressor (Metoprolol)
have all been tried. None of these have been significantly
effective at vasodilation. However, when using vasodilators,
patients will frequently notice waxing and waning of their
effectiveness. This is especially noticeable in patients who are
beginning to be tapered off their medications due to good
responses, and thus cannot tolerate higher doses of vasodilators
without developing symptomatic lethargy, hypotension, etc. from the
medications. In these patients Beta blockers have been extremely
effective in smoothing out the sympathetic nervous system
excitability and variability that may be seen. In Applicant's
patient population, Inderal (Propranolol) has been most effective.
The other medications have not been effective, although probably
are useful in blunting any acute response to Nitroglycerin
administration from a hypersensitive Nitric Oxide response, if the
patient is prone to such a response. Alpha blockers have been tried
Clonidine has been extremely effective. Hytrin (Terazosin), Ismelin
(Guanethidine). Minipress (Prazosin), have been all tried, with
less successful results. Cardura (Doxazosin) is still being tried,
but initial results are just now coming available. Dibenzyline
(Phenoxybenzamine) has also been tried, and appears to be
relatively mild, similar in action on the vasospasm as Hytrin
(Terazosin). Angiotensin Converting Enzyme Inhibitors (ACE)
inhibitors have been tried including Accupril (Quinapril), Altace
(Ramipril), Capoten(Captopril), Lotensin (Benazepril), Monopril
(Fosinopril), Prinivil (Lisinopril), Zestril (Lisinopril timed
released), Univasc (Moexipril), Vasotec (Elalapril), Cozaar
(Losartan). Accupril (Quinapril) has consistently been the most
effective.
[0215] With use of Accupril (Quinapril) and concomitant
administration of low dose Nitroglycerin, {fraction (1/10)}th inch
once a day to several times a day, most patients may be eventually
weaned from the use of oral medications, although Applicant do tend
to maintain them on low dose Nitroglycerin in perpetuity, as the
inciting cause of the vasospasm usually remains and usually causes
redevelopment of symptoms. However, these symptoms and radiological
as well as symptomatic vasospasm may be controlled with low dose
medication if Accupril (Quinapril) is used initially. The timed
release medications such as Zestril (Lisinopril) are extremely
effective in part due to increased patient compliance. Although
Applicant personally finds these two aforementioned medications the
most helpful, Capoten (Captoptil), Lotensin (Benzepril), Prinivil
(Lisinopril) are close second tier medications. The other ACE
inhibitors tend to be effective, but a third tier alternative drug.
However, as a patient becomes intolerant to the stronger ACE
inhibitors, these second and third tier drugs may be very helpful
in preventing and controlling the vasospasm without developing
intolerance to the medication. Similarly, in less severe cases,
these are excellent first line drugs. Calcium channel blockers have
been tried. In the most severe cases, Dynacirc (Isradapine) has
been extremely effective. Adult (Nifedipine) in standard doses and
timed release dosages has been helpful but as a second line drug.
Careen (Nicardipine), Nimotop (Nimodopine), Cardizem (Diltiazem),
Norvasc (Amlodipine) have been less effective in relieving the
vasospasm or in allowing a degree of vascular relaxation sufficient
to allow the patient to taper from the medication over time. Sular
(Nisoldipine) and Plendil (Felodipine) appears to be slightly
milder than Dynacirc (Isradapine) and has been effective in those
that could not tolerate Dynacirc. Verapamil in its many
manifestations is only rarely used, due to its minimal direct
effect on vasodilating the vasculature as documented by
Transcranial Doppler or in its ability to affect the outcome of
these disorders. Vascor (Bepridil) is just now being tried on some
patients. Of course, the general comments concerning ACE inhibitors
also apply to these medicines. Applicant's first line medications
may be too strong for the other physicians' patient populations if
those practices don't tend to attract as severely impaired
individuals. Thus, the second and third tier medications may be
better tolerated in less severely affected people, and similarly,
as patients are able to taper from medications, they may taper into
more mild medications from the same classes as previously were
shown to be successful. Other Vasodilators that have not been
previously discussed have also been tried. Hydralazine is
effective, but tends to cause significant blood pressure changes in
these patients.
[0216] Interestingly through, Hydralazine tends to improve the
morphology of the diastolic flow component dramatically, which, in
view of Hydralazine's effect on arterioles, bolsters the
perspective that the diastolic phase of the Transcranial Doppler is
a good indicator of downstream runoff. Flolan (Epoprostenol) has
not yet been tried, nor has IV Papaverine or Inocor (Amrinone).
Reserpine has been extensively used. It can be very effective. It's
initial effect is parasympathomimetic. A later effect is
sympatholytic. Its role is that it may be very effectively used as
an adjunctive drug especially when patients have difficulty
tolerating stronger vasodilators. The dose which initially is most
effective of Reserpine frequently needs to be decreased
dramatically (generally 50%) approximately 6 weeks into therapy as
the sympatholytic activities start to become significant.
Antipsychotic agents have also been used. Several of Applicant's
patients who Applicant will be reporting on later, were psychotic,
and responded well to these medications and had significant
vasospasm identified on ultrasound which improved after the
administration of medication. Of the antipsychotic. Mellaril
(Thioridizine) has not been effective. Thorazine Chlorpromazine)
has been moderately effected Navane (Thiothixene) has been
extremely effective, and Respiradol (Respiradone) has generally
improved the patient's symptoms, but had no significant improvement
on ultrasound. It has been less well-tolerated in comparison with
Thorazine and Navane, interestingly enough, most of the patients
who were placed on Navane, did not continue to require Navane two
to three months after starting the medication, and were able to be
weaned from that and had better response to their other
vasodilators. In general, Navane was used as a first line drug in
patients who had severe elevations of Transcranial Doppler Artery
mean flow velocities greater than 1.3, and we would generally
expect 50% improvement in the Transcranial Doppler Artery
Ultrasound within a half hour of administering Navane by liquid
solution. The solution was made by stirring 2 mg of Navane in 4
ounces of water then administered orally. The patients were usually
afterwards placed on vasodilators such as ace inhibitors and
calcium channel blockers.
[0217] Problems
[0218] The approach used in Applicant's clinical practice of over
2,000 patients, is the approach of using vasodilators to treat
migraine headache, to cause improvement in closed head injury
symptoms, and to treat vasospasm from any cause. This has also been
effective in Attention Deficit Disorder (ADD) and multiple other
disorders with cerebral ischemia or vasospasm as a component. A
partial list of these disorders, include Vascular Seizures,
Vertigo, Tinnitis, Post Subarachnoid Hemmorhage Vasospasm secondary
to both aneurysm rupture or trauma, Stroke, reversal of a chronic
stroke penumbra, autism, depression, Post-Traumatic Stress
Syndrome, autism, dyslexia, visual disturbances and blindness,
Autism, Tourette's Syndrome, Tics, Tremors. Ataxia and multiple
other neurocognitive, neuropsychiatric, and neurological disorders
that have vasospasm and ischemia as a common aetiology, systemic
disorders with diffuse vascular involvement, i.e. some types of
Fibromyalgia and Prinz Metal Angina may also be treated with this
approach. The approach to treatment and results are essentially
identical in these cases, with minor variations.
[0219] However, 10% of patients placed on antihypertensives will
develop peripheral hypotension before the vasospasm is successfully
treated. In those patients, Navane (Thiothixene) and other
antipsychotics of that group, have been found to be an extremely
effective central vasodilator without causing peripheral blood
pressure changes. These patients may do well on low dose
Angiotensin Converting Enzyme Inhibitors. Calcium Channel Blockers.
Alpha blockers and/or Nitrates with the use of Navane (Thiothixene)
and the other anti=A9psychotics of that group and have excellent
resolution of vasospasm.
[0220] 02747E14E5C
EXAMPLE
Whip-Lash/Breast Implants/Migraine
[0221] Applicant has a baseline practice consisting of mainly
post-traumatic, closed-head injuries and post-traumatic migraine
disorders of which many have attention deficit disorders, (ADD).
However, several years ago Applicant had a large number of patients
who presented with ADD of which the origin of their problems was
associated with silicon breast implants (silicon toxicity). What
became evident in evaluating of these patients was that the
neuropsychological tests, computerized EEG and Transcranial Artery
Doppler results were essentially identical. Another common
characteristic in these patients was the waxing and waning nature
of at least some of their complaints. Those patients with Attention
Deficit Disorder both post-traumatic and in particularly those
patients with silicon breast implant disease with MS-like syndrome
would have normal neurological examination one day and on another
day the exam would be normal. This finding substantiated the
patients' complaints of waxing and waning of symptoms and seemed to
be related to the degree of physiological or psychological stress
the patient experienced when being interviewed or tested.
[0222] The degree of abnormality of neurological exams would extend
to the point of normal or abnormal Romberg and Tandem Gaits, reflex
examinations and Babinski examinations in the same patient. Evoked
potential test results varied from normal to abnormal on different
days and the testing was performed by the same examiners.
[0223] In this same time frames a series of new medications were
developed to treat migraine headaches. As headache was a major
complaint of many of these patients, Applicant tried these
medications out including Imitrex (Sumatriptan), IM Toradol
(Ketoralac) and other medications under direct monitoring. As these
patients tend to be intractable, it was not expected that any of
these medications would have dramatic results. Rather, it was
expected that one or another set of medications might help point
the way into using specific classes of medications or approaches.
Accordingly, each of these patients, equivalent of a large number
of patients, is monitored continuously across the day. The patients
are hooked up with EEG's or Brain Stem Auditory Evoked Responses,
or VEP's, or Transcranial Dopplers, and across the day would have
many of the different short-acting medications tried on them to see
which would work and which monitoring tool would be most effective
in identifying the improvement.
[0224] With respect to the different monitoring tools, some were
more helpful than others. It was found that the EEG was not very
sensitive. The Brain Stem Auditory Evoked Response and other evoked
potential tests were very insensitive tools for monitoring, because
of the length of time required to perform the test after
short-acting medications were given in IM or sublingual or nasal
spray administration route. The Transcranial Doppler consistently
appeared to give the best indication as to which medications would
work. If an ultrasound showed improvement, the patient invariably
also reported improvement in their clinical symptoms. These
symptoms included not only headache, but also sensations of
confusion, balance disorder, abnormal Romberg or Tandem Gait or
other neurological abnormalities. If the medications showed
evidence of increasing vasoconstriction on the doppler, the
patients who had a headache, frequently reported improvement in the
headache, but a worsening of their confusional state or a worsening
of other neurological symptoms. Those patients were identified as
having improvement on ultrasound with doppler also showed
resolution of their headache, but did not show the deterioration in
other neurological effects.
[0225] This was completely unexpected. The general approach towards
migraine and headache has always been that the headache represents
a vasodilation and frequently a hyperperfusion state. The aura, of
course, represents a vasoconstrictive phase. What our results
seemed to suggest was that the doppler, which looks at essentially
the area of blood vessels around the base of the brain, was showing
vasoconstriction. Vasoconstrictive medicines would relieve the
headache presumably through a similar mechanism, as a
vasoconstrictive medication probably relieved coronary artery
disease. It would relieve it by decreasing the vasodilation that
occurs downstream from the area we are able to directly insonate.
Unfortunately, if cerebral artery disease is anything like coronary
artery disease, that downstream dilation represents an attempt by
the body to compensate and maintain perfusion to thus becoming
ischemic.
[0226] In Applicant's patient population, all medications which
resulted in vasoconstriction, relieved the headache, but caused
neurological deterioration. As the medication wore off, as
documented by the patient's clinical symptoms, sonography data, the
patient's neurological abnormalities improved. Similarly, those
medicines which resulted in direct vasodilation such as Hydralazine
(Apresoline), Nitroglycerin and other medications all resulted in
improvement in the patient's headache, but also resulted in
improvement of any other neurological abnormalities including
balance disorders, gait disorders, hemiparesis, abnormal Babinski's
and abnormal reflexes.
Observations Noted Concerning Transcranial Dopplers
[0227] A special word about Transcranial Doppler needs to be made.
We found that morphology of a Transcranial Doppler Artery
Ultrasound is as important as mean flow velocities. In our
patients, as they became more normal, and as their fixed deficits
and neuropsychological abnormalities resolved etc., the morphology
of the wave form would be similar to that of an internal carotid
artery tracing. We did not find that there would be elevation of
flow readings throughout diastole, as is more commonly published.
It is important to identify that the original normative data
obtained in 1979, used for "Normals" patients with post-traumatic
migraine disorders, "psychogenic seizures", and the interictal
migraine phase may not be appropriate. It is important to note that
other labs which have done less extensive studies of normal versus
non-normal, may have unknowingly used many patients with a history
of migraines or whiplash headaches.
[0228] Some have not identified the close relationship between
degree of vasospasm and clinical abnormalities. This may be due to
less lengthy monitoring or evaluations being carried out by those
labs in comparison to our own. Equally, the trend clinical
correlation is a general one. Remembering hemodynamics, it is
important to note that if the blood vessel is constricted, patients
do have a limited ability to compensate for the effects of that
vasoconstriction by dilating distally to the constricted area.
Patients will not be abnormal clinically during the early stages of
constriction of an artery. It is only once the downstream area is
no longer able to dilate to a degree enough to maintain a
significant pressure gradient across the vasoconstricted area that
the patient will develop symptoms. It is important to continue to
monitor and treat these patients until the sonographic studies
return to normal and beyond. Realizing that blood vessels constrict
across the day in response to sympathetic nervous system
variability, internal steroid release, physiological and
psychological stress, including the physiological stress of photic
stimulation, driving etc. and thus to obtain an ultrasound at one
moment, must be correlated with the patient's clinical symptoms and
any complaints of variability across the day.
[0229] We also found that over time, chronic, untreated patient
studies frequently falsely appear to normalize with a dropping of
mean flow velocities. This occurs as the body develops compensating
mechanisms to relieve the ischemia. Thus morphology becomes
extremely important in identifying those who have ongoing
vasoconstrictive disorder intracranially.
[0230] The development of a pattern as time goes on is to have a
blunted upstroke in the systolic portion of the ultrasound, but
with an overall mean flow velocity of less than 0.6 meters per
second. That blunting, which is also seen in disseminated vascular
disease from any cause, is highly suspicious for severe vasospastic
disorder. A computerized EEG or standard EEG consistent with brain
dysfunction or ischemia, and/or neuropsych testing consistent with
variability of cognitive injury (especially with fluctuating
cognitive deficits across several hours or days of testing) with
ischemia is often helpful as a corroborating study. These are
patients who should not be treated initially with Nitroglycerin or
other potent medications, but should first have other medications
which are direct vasodilators instituted as low doses and slowly
advanced as the patient is able to tolerate it. This institution
with alternative vasodilators, tends to decrease the incidence of a
potentially dangerous nitric oxide sensitivity reaction.
[0231] With respect to Nitroglycerin, what we have seen is several
time courses of the effect of Nitroglycerin. The first is an acute
effect which lasts between 15 and 45 minutes. The method of
administration being a patch, pill or sublingual spray determines
the rapidity of absorption and distribution. It seems to have a
lingering effect for approximately 2 to 3 hours. Nitroglycerin then
gets converted into a variety of subsidiary byproducts, all with
some vasodilating properties. Each of these medications themselves
can accumulate in patients to toxic doses, and can cause a reactive
cerebral vasoconstriction. Thus, it is easier to maintain patients
on intermittent low dose Nitroglycerin applications, then chronic
applications of medication, as the clinical data and clinical
response to the vasodilator challenge becomes confused. With
respect to Nitric Oxide sensitivity, those patients in Applicant's
clinical practice who have not been premedicated with a beta
blocker, an alpha blocker or a direct vasodilator such as a calcium
channel blocker or an ACE inhibitor, who are given their first dose
of Nitric Oxide and developed acute erythema of the nose or face,
are having a reactive vasoconstriction and distal vasodilation
occurring at the same time. Those patients on Transcranial Doppler
Artery Ultrasound will have acute spasm of the arteries and active
constrictions and dilations may frequently be seen. Those patients
may have a seizure or a stroke or a blackout spell. This problem
can be immediately reversed with IM Toradol(ketoralac). Toradol in
90 to 120 mg IM doses causes acute vasodilation on ultrasound in
most patients. In lower doses, the Transcranial Doppler Artery
Ultrasounds generally do not show significant changes, but the
patient reports a symptomatic improvement.
[0232] IV Toradol in 30 to 60 mg doses does not cause any
improvement on Transcranial Doppler Artery Ultrasound, and patients
generally report a sensation of vertebrogenic syndrome with
increase in spaciness, confusion, worsening headache and worsening
spasm. Although I have not identified this directly, their clinical
course is that of a development of a vasoconstricted vertebral or
basilar artery syndrome. This probably relates to a carrier drug in
the I.V. Toradol solution. Without a change in formulation,
Applicant would not recommend the I.V. use of Toradol to reverse
acute and life threatening vasospasm or stroke.
[0233] Multiple medications over the last several years have now
been tried for the vasodilators. A discussion of these will follow.
It should be recognized, that Applicant's patients tend to be the
most severe cases it our area. Accordingly, for me, the medications
that have been most effective have also been among the strongest.
The less strong medication will undoubtedly be very helpful in less
severe cases. In all cases, as the vasospasm may be subclinical or
affecting portions of their cognitive abilities that they do not
routinely use. patients can not be considered as reliable in
identifying when the vasospasm is resolved. Accordingly, ongoing
monitoring of therapy with functional tests such as EEG or
Neuropsych testing and imaging tests like ultrasound are vital for
evaluation of response to therapy.
[0234] With respect to Beta Blockers, Inderal (Propranolol),
Tenormin (Atenolol), Lopressor (Metoprolol Tartrate) and Normodyne
(Labetolol) have all been tried. None of these have been
significantly effective at vasodilation. However, when using
vasodilators, patients will frequently notice waxing and waning of
their effectiveness. This is especially noticeable in patients who
are beginning to be tapered off their medications due to good
responses, and thus cannot tolerate higher doses of medications of
vasodilators, but still have residual vasospasm. In these patients,
Inderal has been extremely effective in smoothing out the
sympathetic nervous system excitability that may be seen. The other
medications have not been as effective, although probably are
useful in blunting any acute response to Nitroglycerin
administration from a hypersensitive Nitric Oxide response, if the
patient is prone to such a response.
[0235] Alpha blockers have been tried Hytrin (Terazosin) has not
been found to be effective. Catapress (Clonidine) has been
extremely effective. Minipress (Prazosin) has been significantly
effective and frequently better tolerated in the long run than
Clonidine, although in Applicant's patients, it seems to treat the
problem successfully enough to prevent the symptoms, but not enough
to allow complete resolution of the vasospasm. Cardura (Doxazosin)
has been a relatively mild medication. Aldomet (Methyldopa) has
been useful in some patient. Reserpine has been an extremely
effective medication. In the short term, it is helpful due to the
parasympathomimetic effect, which tends to decrease the activity of
the Sumpathetic nervous system. Later, its direct sympatholytic
action is very effective. Frequently, a dose needs to be adjusted
downward approximately 6-10 weeks after institution of therapy. It
has even been useful in treating migraine induced depression due to
chronic vasospasm with or without headache in those patients who
could not tolerate other vasodilators. Clonidine has also been
useful in these depressed patients who could not respond to other
vasodilating medications.
[0236] ACE inhibitors have been tried. With use of ACE inhibitors
and concomitant administration of low dose Nitroglycerin, {fraction
(1/10)}th inch once a day to several times a day, most patients may
be eventually weaned from the use of oral medications, although
Applicant do tend to maintain them on low dose Nitroglycerin in
perpetuity. Other Angiotensin Converting Enzyme Inhibitors,
including Capoten (Captopril), Altace (Ramipril), Lotensin
(Benazepril), Monopril (Fosinopril), Prinivil (Lisinopril),
Vasotech (Enalapril) and an ACE inhibitor have also been tried. I
suspect that ACE inhibitors work the best due to its activity on
the Nitric Oxide pathway. It is most effective at reversing the
vasospasm when used in conjunction with low dose nitrates.
[0237] Calcium channel blocker have been tried. The most effective
has been Dynacirc (Isradapine). Much less effective have been, in
descending order of effectiveness, Nifedipine. Nimodopine, Plendil
(Felodipine), Dilacor (Diltiazem), Cardene (Nicardipine) and.
Norvasc (Amlodopine) and finally, Verapamil.
[0238] Other agents that deserve special mention include Toradol IM
in doses of 90-120 mg. In lower doses., this is not so effective.
Unfortunately, due to the new FDA guidelines. Applicant no longer
use this medication in these doses. Hydralazine is effective, but
tends to cause significant blood pressure changes in these
patients. Interestingly though, Hydralazine tends to improve the
morphology of the diastolic flow component dramatically which in
view of Hydralazine's effect on arterioles, bolsters the
perspective that the diastolic phase of the Transcranial Doppler is
a good indicator of downstream runoff.
[0239] Psychiatric agents frequency have vasoactive effects. Prozac
and other non-vasoconstricting medications are helpful. Those known
to cause vasoconstriction tend to aggravate the spasm and
neurological abnormalities. Antipsychotic agents have also been
used. Several of Applicant's patients who ApplicanT will be
reporting on later, were psychotic, and responded well to these
medication s and had significant vasospasm identified on ultrasound
which improved after the administration of medication. Of the
antipsychotics, Navanne (Thiothixene) has been the most effective.
Thorazine (Chlormromazine) has been moderately effective.
Respiradol has generally improved the patient's symptoms but had no
significant improvement on ultrasound. It has been less
well-tolerated in comparison with Thorazine and Navane.
Interestingly enough, most of the patients who were placed on
Navane, did not continue to require Navane two to three months
after starting the medication, and were able to be weaned from that
and had better response to their other vasodilators. In general
Navane was used as a first line drug in patients who had severe
elevations of Transcranial Doppler Artery mean flow velocities
greater than 1.3, and we would generally expect 50% improvement in
the Transcranial Doppler Artery Ultrasound within a half hour of
administering Navane by liquid solution. The solution was made by
stirring 2 mg of Navane in 4 ounces of water then administered
orally. The patients were usually afterwards placed on vasodilators
such as ACE inhibitors and Calcium channel blockers. Mellaril
(Thioridazine) has had no significant effects.
[0240] Of the Anti-epileptic drugs, including Dilantin (Phenytoin),
Tegretol (Carbamazepine) and Depakote (Valproate), none of the
medications in therapeutic doses have changed the vasospasm, but
all have improved in some patients the EEG abnormalities and their
neurocognitive or neurological complaints.
[0241] Problems
[0242] The approach used in Applicant's clinical practice of over
2,000 patients, is the approach of using vasodilators to treat
migraine headache, to cause improvement in closed head injury
symptoms, and to treat disorders diverse and including seizures,
stroke, syncope, attention deficit disorder, vertigo, autism,
depression, psychosis, transient global amnesia. Multiple Sclerosis
and Multiple Sclerosis like syndrome, but not limited to these
disorders.
[0243] However, approximately 10% of patients placed on
antihypertensives will develop peripheral hypotension before the
vasospasm is successfully treated. These patients appear to have
increased peripheral vasodilation to central vasodilation in
response to the medication.
[0244] In these patients, several approaches may be used. The
pharmacological approach is to mix several medications of different
classes at submaximal doses to achieve a synergistic response. An
alternative approach is to use medications such a Toradol or
antipsychotic medications that also dilate primarily the vascular
bed of the Central Nervous System and not that of the peripheral.
In those patients, Navane and the antipsychotic of that group, have
been found to be an extremely effective central vasodilator without
causing peripheral blood pressure changes. Patients placed on these
agents are frequently able to tolerate low dose ACE inhibitors.
Calcium Channel agents, or other peripheral vasodilators without
developing hypotension and still have excellent resolution of
vasospasm. The structural approach is to search for an underlying
aggravating problem affecting the sympathetic nervous system. This
is usually caused by an injured area of the body which may include
joint injuries, disk injuries, nerve injuries, etc. One of
Applicant's patients developed severe neurocognitive problems and
neuropsych abnormalities, EEG problems and vasospasm, from a Carpal
Tunnel Syndrome. The correction of that problem, or any other
irritant to the Sympathetic Nervous system by blocking the irritant
or removing it, may result in a decrease in the autonomic
hyperactivity, and an improved response to medication. A third
approach is to sympathetically denervate the vasculature. This may
be partially performed with Epidural Steroid Injections with or
without anaesthetic, Facet or Perifacet blocks, Rhyzolysis,
Stellate Ganglion Blocks and Neurolyses and similar procedures. In
Applicant's practice, procedures oriented towards the innervation
of the Carotid arteries tend to cause Anterior and Middle Cerebral
artery relaxation. This clinically results in increase
concentration/memory and decreased mood/personality problems and
language problems and other frontal and temporal lobe disorders.
Posterior circulation denervation tends to decrease occipital
headaches, and improve balance, vertigo, and visual complaints and
have secondary cognitive, effects (probably through perforating
vessel contributions). Blocks tend to work for a dramatically
shorter period of time than do neurolysis procedures.
[0245] Chiropractic procedures may be very helpful as may
Biofeedback and counselling procedures to decrease the Autonomic
hyperactivity. These techniques may also be useful adjuncts to
treatment in the chronic patient.
[0246] Stroke. V11
* * * * *