Tumor necrosis factor antagonists for the treatment of neurological disorders

A method for inhibiting the action of TNF for treating neurological conditions in a human by administering a TNF antagonist for reducing damage to neuronal tissue or for modulating the immune response affecting neuronal tissue of the human. The TNF antagonist administered is selected from the group consisting of etanercept and infliximab. The TNF antagonist is administered subcutaneously, intravenously, intrathecally, or intramuscularly. Methotrexate or Leflunomide may be administered concurrently with the TNF antagonist for demyelinating diseases and certain other neurological disorders.

FIELD OF THE INVENTION 
The present invention relates to tumor necrosis factor (TNF) antagonists or 
TNF blockers for the treatment of neurological disorders, trauma, injuries 
or compression; or demyelinating neurological disorders, including 
multiple sclerosis. More particularly, the TNF antagonists or TNF 
blockers, with or without the concurrent administration of methotrexate or 
Leflunomide, are used in a new treatment of these disorders by inhibiting 
the action of TNF in the cells of the human body. The use of these TNF 
antagonists or TNF blockers with methotrexate or Leflunomide results in 
the amelioration of these neurological conditions. 
BACKGROUND OF THE INVENTION 
Neurological disorders due to demyelinating disease (e.g. multiple 
sclerosis), immune disease, inflammation, trauma, or compression, occur in 
different clinical forms depending upon the anatomic site and the cause 
and natural history of the physiological problem. Common to all of these 
disorders is the fact that they can cause permanent neurological damage, 
that damage can occur rapidly and be irreversible, and that current 
treatment of these conditions is unsatisfactory, often requiring surgery 
and/or the use of pharmacologic agents, which are often not completely 
successful. 
These neurological conditions include acute spinal cord trauma, spinal cord 
compression, spinal cord hematoma, cord contusion (these cases are usually 
traumatic, such as motorcycle accidents or sports injuries); nerve 
compression, the most common condition being a herniated disc causing 
sciatic nerve compression, neuropathy, and pain; but also including 
cervical disc herniation, causing nerve compression in the neck; carpal 
tunnel syndrome (non-RA); acute or chronic spinal cord compression from 
cancer (this is usually due to metastases to the spine, such as from 
prostate, breast or lung cancer); autoimmune disease of the nervous 
system; and demyelinating diseases, the most common condition being 
multiple sclerosis. 
Steroid drugs such as cortisone that are used to treat the aforementioned 
neurological problems and conditions are particularly hazardous because 
they are used either at high dosage, with a corresponding increasing risk 
of side effects, or because they are used chronically, also increasing 
their adverse effects. Lastly, steroids are only partially effective or 
completely ineffective. 
There remains a need for a new pharmacologic treatment of these 
aforementioned physiological problems of the nervous system associated 
with autoimmune disease, demyelinating diseases, trauma, injuries and 
compression with the pharmacological use of TNF antagonists or TNF 
blockers, which are greatly beneficial for the large number of patients 
whom these conditions affect. Two new drugs which are powerful TNF 
blockers are etanercept and infliximab. Etanercept or infliximab may be 
used for the immediate, short term and long term (acute and chronic) 
blockade of TNF in order to minimize neurologic damage mediated by TNF 
dependent processes occurring in the aforementioned neurological 
disorders. The use of these TNF antagonists or TNF blockers would result 
in the amelioration of these physiological neurological problems. 
Concurrent administration of methotrexate or Leflunomide with either 
etanercept or infliximab is the preferred treatment for demyelinating 
diseases and certain other neurological disorders. 
DESCRIPTION OF THE PRIOR ART 
Pharmacologic chemical substances, compounds and agents which are used for 
the treatment of neurological disorders, trauma, injuries and compression 
having various organic structures and metabolic functions have been 
disclosed in the prior art. For example, U.S. Pat. Nos. 5,756,482 and 
5,574,022 to ROBERTS et al disclose methods of attenuating physical damage 
to the nervous system and to the spinal cord after injury using steroid 
hormones or steroid precursors such as pregnenolone, and pregnenolone 
sulfate in conjunction with a non-steroidal anti-inflammatory substance 
such as indomethacin. These prior art patents do not teach the use of a 
TNF antagonist or TNF blocker for the suppression and inhibition of the 
action of TNF in the human body to treat neurological disease, trauma, 
injury or compression, or autoimmune neurologic disease as in the present 
invention. 
U.S. Pat. No. 5,605,690 to JACOBS discloses a method for treating 
TNF-dependent inflammatory diseases such as arthritis by administering a 
TNF antagonist, such as soluble human TNFR (a sequence of amino acids), to 
a human. This prior art patent does not teach the use of a TNF antagonist 
or TNF blocker for the suppression and inhibition of the action of TNF in 
the human body to treat neurological disease, trauma, injury or 
compression, or demyelinating neurologic disease, as in the present 
invention. 
U.S. Pat. No. 5,656,272 to LE et al discloses methods of treating 
TNF-alpha-mediated Crohn's disease using chimeric anti-TNF antibodies. 
This prior art patent does not teach the use of a TNF antagonist or TNF 
blocker for the suppression and inhibition of the action of TNF in the 
human body to treat neurological trauma, injury or compression, or 
autoimmune neurologic disease, as in the present invention. 
U.S. Pat. No. 5,650,396 discloses a method of treating multiple sclerosis 
(MS) by blocking and inhibiting the action of TNF in a patient. This prior 
art patent does not teach the use of the TNF antagonist as in the present 
invention. 
None of the prior art patents disclose or teach the use of the TNF 
antagonist or TNF blocker of the present invention with the concurrent 
administration of methotrexate or Leflunomide for suppression and 
inhibition of the action of TNF in a human to treat neurological disease, 
trauma, injury or compression, or demyelinating neurologic disease, in 
which the TNF antagonist gives the patient a better opportunity to heal, 
slows disease progression, prevents neurological damage, or otherwise 
improves the patient's health. 
Accordingly, it is an object of the present invention to provide a TNF 
antagonist, with or without the concurrent administration of methotrexate 
or Leflunomide, for a new pharmacologic treatment of neurological 
disorders, trauma, injuries and compression affecting the nervous system 
of the human body, or demyelinating neurologic disease, such that the use 
of these TNF antagonists will result in the amelioration of these 
neurological conditions. 
Another object of the present invention is to provide a TNF antagonist, 
with or without the concurrent administration of methotrexate or 
Leflunomide, for providing suppression and inhibition of the action of TNF 
in a human to treat neurological injury, trauma or compression, or 
demyelinating neurologic disease. 
Another object of the present invention is to provide a TNF antagonist, 
with or without the concurrent administration of methotrexate or 
Leflunomide, that reduces inflammation to the patient by inhibiting the 
action of TNF in the human body for the immediate, short term (acute 
conditions) and long term (chronic conditions), such that this reduction 
in inflammation will produce clinical improvement in the patient and will 
give the patient a better opportunity to heal, slows disease progression, 
prevents neurological damage, or otherwise improves the patient's health. 
Another object of the present invention is to provide a TNF antagonist, 
with or without the concurrent administration of methotrexate or 
Leflunomide, that can offer acute and chronic treatment regimens for 
neurological conditions caused by neurological trauma, compression, injury 
and/or disease, such conditions including acute spinal cord injury, 
herniated nucleus pulposus (herniated disc), spinal cord compression due 
to metastatic cancer, carpal tunnel syndrome, pituitary adenoma, primary 
or metastatic brain tumors, chronic pain syndromes due to metastatic 
tumor, increased intracranial pressure, demyelinating diseases such as 
multiple sclerosis, inflammatory CNS diseases, such as subacute sclerosing 
panencephalitis, and other related neurological disorders and diseases. 
SUMMARY OF THE INVENTION 
The present invention provides a method for inhibiting the action of TNF 
for treating neurological conditions in a human by administering to the 
human therapeutically effective doses of a TNF antagonist selected from 
the group consisting of etanercept and infliximab, with or without the 
concurrent administration of therapeutically effective doses of 
methotrexate or Leflunomide, for reducing the inflammation of neuronal 
tissue of the human and/or preventing immune system damage to neuronal 
tissue. The TNF antagonist is administered subcutaneously, intravenously, 
intrathecally, or intramuscularly; methotrexate is administered orally or 
intramuscularly; and Leflunomide is administered orally.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
TNF antagonist regimens to be used for neurological disorders are designed 
in two general ways: acute regimens, designed to achieve rapid blood 
levels and rapid action, wherein TNF blockade is desired for hours to 
days; and chronic regimens, where TNF blockade is desired for days, weeks, 
or months. Currently available TNF antagonists which are suitable for 
these regimens are etanercept (ENBREL.TM.) from Immunex Corporation and 
infliximab (REMICADE.TM.) from Centocor, Inc. Methotrexate or Leflunomide 
may be administered concurrently with the TNF antagonist for demyelinating 
diseases and certain other neurological disorders. Methotrexate and 
Leflunomide produce immune system modulation, which is shown to be 
beneficial in the treatment of demyelinating diseases and various 
autoimmune diseases. Additionally, methotrexate and Leflunomide have 
anti-tumor effects for certain malignancies. Lastly, methotrexate and 
Leflunomide have direct anti-inflammatory properties. 
Trauma, injury, compression and other neurological disorders can affect 
individual nerves, nerve roots, the spinal cord, or the brain. The 
conditions which are of most concern here are the following: 
1) acute spinal cord injury, 
2) demyelinating diseases, such as multiple sclerosis, 
3) herniated nucleus pulposus (herniated disc), 
4) spinal cord compression due to metastatic cancer, 
5) carpal tunnel syndrome (non-RA), 
6) pituitary adenoma, 
7) primary or metastatic brain tumors, 
8) chronic pain syndromes due to metastatic tumor, 
9) increased intracranial pressure, and 
10) inflammatory CNS diseases, such as subacute sclerosing panencephalitis. 
TNF antagonists are a novel way to treat neurologic trauma, injury, 
compression and neurological disorders in comparison with steroids. 
Experimental evidence has shown that excessive levels of TNF are released 
by injury to neuronal tissue. Accordingly, the use of TNF antagonists will 
result in amelioration of these neurological conditions. Because of the 
profoundly powerful action of the new TNF antagonists that have recently 
become available, these agents can prevent neurologic injury in a unique 
way, filling an urgent clinical need for more effective therapy. Also, 
because of the extremely safe side effect profile of these agents, they 
can be used either singly or in combination with other pharmacologic 
agents, such as methotrexate or Leflunomide. TNF antagonists can also 
safely be used with steroids, which are the only other class of agents 
which have been shown to be beneficial for certain of these conditions. 
Importantly, the TNF antagonists lack the adverse effects of steroids as 
previously described. Lastly, steroids are only partially effective or 
completely ineffective. 
More detailed discussion of each of these clinical conditions is as 
follows: 
1) Acute Spinal Cord Injury 
About 10,000 cases occur per year in the U.S., with a current population of 
over 200,000 patients with residual neurologic damage, many of whom are 
paralyzed (quadriplegia or paraplegia). Current treatment for the acute 
injury is inadequate. In the early 1990's it was shown that early (within 
8 hours of injury) treatment with high doses of steroids (methyl 
prednisolone) was beneficial for some of these patients. Surgical 
stabilization and spinal decompression is often necessary because of 
excessive swelling (edema) which can itself cause further severe injury to 
the cord due to further compression of the cord against its bony spinal 
canal. The etiology of most of these cases are motor vehicle accidents, 
with the remainder being sports injuries, falls, and other accidents. The 
window of opportunity for treatment is small, since massive swelling can 
occur within minutes. 
The treatment regimen used here would be the acute regimen. This could 
involve any of the TNF antagonists, but currently etanercept would be the 
leading candidate. Etanercept is currently approved only for rheumatoid 
arthritis, and is used as a subcutaneous injection of 25 mg given twice a 
week. This regimen produces peak blood levels in an average of 72 hours. A 
preferred method for acute spinal cord injury involves intravenous 
infusion to produce a serum concentration in the range of 0.5 mg/ml to 50 
mg/ml, such concentrations are achieved more rapidly than can be produced 
by SC injection. This is a new method of dosing that is not being used for 
arthritis. This acute regimen is a unique delivery method for etanercept 
and is uniquely necessary for clinical neurologic conditions requiring 
rapid blockade of TNF. 
2) Demyelinating Disease, Such As Multiple Sclerosis 
Demyelinating neurological diseases, the most important being multiple 
sclerosis, are inadequately treated by currently available therapies, and 
continue to produce progressive, severe, neurologic impairment in a large 
population of patients in the United States and worldwide. There is 
experimental evidence which documents the role of TNF in multiple 
sclerosis. There is a wide body of work which documents the role of both 
cellular and humoral immunity in multiple sclerosis. Using the new TNF 
antagonists etanercept and infliximab, with or without concurrent use of 
methotrexate or Leflunomide, represents a novel approach to the treatment 
of these important disorders. 
Several novel approaches are suggested. For acute demyelinating disease, it 
is paramount to use therapy which is rapidly effective to prevent 
permanent neurological damage. In this case, novel routes of 
administration of the TNF antagonists may be used. These novel routes 
include intrathecal administration of etanercept or infliximab; or 
intravenous administration of etanercept. Addition of methotrexate or 
Leflunomide concurrently with the use of the above TNF antagonists is 
another novel treatment which may be used for acute demyelinating disease. 
For other clinical forms of demyelinating disease, the more familiar 
routes of administration of etanercept (subcutaneous) or infliximab 
(intravenous) may be elected, with or without concurrent use of 
methotrexate or Leflunomide. These novel regimens are designed as such 
because of the complementary mechanisms of action and low toxicity of 
these biopharmaceutical agents. 
3) Herniated Nucleus Pulposus (Herniated Disc) 
Low back pain affects 70% of the population during their lifetime, with 25% 
of this group having pain in the sciatic distribution. Current 
pharmacologic treatment is inadequate, consisting of analgesics and 
anti-inflammatory medications (such as nonsteroidal anti-inflammatories 
(NSAIDS), such as ibuprofen (Motrin, etc.) and epidural steroid injections 
(generally regarded as having limited usefulness). Many of these patients 
eventually have surgery. Complications of lumbar disc herniation include 
permanent damage to the sciatic nerve, causing muscle weakness and atrophy 
in the lower extremity. Acute herniation with rapid onset of pain and 
sciatic nerve symptoms could be treated with the above acute regimen, with 
or without addition of the chronic regimen (described below), if symptoms 
continued. Treatment could also be reserved for patients not responding to 
conventional therapy. The acute treatment regimen, as outlined above, 
could be used for patients in whom rapid control of symptoms was desired. 
Most patients, however, would be treated conservatively and conventionally 
at first, with TNF blockade using one of the chronic regimens below added 
later for nonresponders. Herniated cervical discs would be treated the 
same way as herniated lumbar discs with the need for careful evaluation by 
a neurologist, neurosurgeon, and/or orthopedic surgeon for signs of 
neurologic compromise kept in mind. The chronic treatment regimen includes 
subcutaneous etanercept of 25 mg (dosage range 10 mg to 50 mg) once or 
twice a week; or infliximab administered by intravenous infusion once 
every two months (range once per month to once per six months). 
4) Spinal Cord Compression Due to Metastatic Cancer 
Cord compression due to metastatic cancer is a catastrophic event leading 
to rapid paralysis if not quickly diagnosed and treated. It is most common 
with cancers of the breast, colon, lung and prostate, but can be a 
complication of metastatic disease from a wide variety of malignancies, 
including melanoma and multiple myeloma. Current treatment regimens 
include high dose steroids, emergency radiation treatment, and/or emergent 
surgical decompression. Paralysis can occur within hours, so treatment 
must be initiated within this time period to avoid permanent sequelae. The 
mechanism of action of TNF blockage here would be similar to that above. 
In addition, it is possible that TNF blockade could be directly 
tumoricidal or tumoristatic with certain malignancies. Impending cord 
compression could be treated with the chronic regimen. However, as 
explained above, most patients would need to be emergently treated with 
the acute regimen, as outlined above. 
5) Carpal Tunnel Syndrome (CTS) (non-RA) 
Carpal tunnel syndrome involves compression of the median nerve at the 
wrist, causing pain and neurologic symptoms in the hand. It is a common 
condition, being aggravated by repetitive stress injury (RSI) in the 
workplace (such as typists and writers, manual laborers, etc.), and is 
also a complication of rheumatoid arthritis (RA). Use of TNF blockade for 
carpal tunnel syndrome in patients with established RA would likely be 
covered by the existing arthritis medication for treating RA. But most 
patients with carpal tunnel syndrome do not have RA; they either have 
idiopathic CTS or CTS caused by RSI. CTS is a major cause of disability 
and responds poorly to current treatment regimens, which include NSAIDS, 
wrist splinting, and injection of steroids. The chronic treatment regimen 
as outlined above would be used for the treatment of CTS (non-RA type). 
6) Pituitary Adenoma 
Benign pituitary tumors grow adjacent to the optic chiasm. Unrestrained 
growth causes compression of the optic nerve, causing visual field defects 
and eventuating in blindness. Treatments include radiation, surgical 
decompression and bromocriptine. TNF blockade could prove to be a valuable 
adjunctive therapy, and could be either the acute or chronic treatment 
regimen, depending on the clinical picture. 
7) Primary or Metastatic Brain Tumors 
Primary brain tumors can be either benign (most commonly meningioma) or 
malignant (usually gliomas). Metastatic brain tumors can be from any 
source, most commonly lung cancer, breast cancer, or other malignancies 
such as melanoma. Treatment for these tumors is primarily surgery or 
radiation, with generally poor response to chemotherapy. Many of these 
tumors cause surrounding edema which can cause further neurologic 
deterioration. TNF blockade, either the acute or chronic treatment 
regimen, could be beneficial while these patients are awaiting surgery. 
Additionally, TNF blockade, as discussed above, could have direct tumor 
inhibiting properties. 
In an alternate treatment regimen, methotrexate orally or intramuscularly, 
may be administered concurrently with a TNF antagonist, wherein the dosage 
level of methotrexate is in the range of 2.5 mg to 25 mg, given from once 
weekly to once monthly. If the dose is given orally, the total weekly dose 
may be given in three equal parts over 36 hours, with 12 hours between 
each dose. The preferred dosage range is 7.5 mg to 15 mg administered 
weekly. 
As another alternate treatment, instead of administering methotrexate, 
Leflunomide may be administered orally concurrently with a TNF antagonist, 
wherein the dosage level of Leflunomide is in the range of 10 mg to 100 mg 
per day for the first 3 days, and 5 mg to 20 mg daily thereafter. 
8) Chronic Pain Syndromes Due to Metastatic Tumor 
Pain due to metastatic cancer is inadequately treated by currently used 
agents. It is probable that the mechanism of action of this pain is 
mediated in part by the overproduction of TNF. TNF blockade could be 
beneficial for selected tumors, particularly bone metastases where 
compression is involved. The chronic treatment regimens would be used. One 
general note of caution when treating malignancies is necessary: While TNF 
blockade is likely to have an antitumor effect with certain malignancies, 
it is also possible that TNF blockade could increase growth rates with 
certain malignancies. 
In an alternate treatment regimen, methotrexate orally or intramuscularly, 
may be administered concurrently with a TNF antagonist, wherein the dosage 
level of methotrexate is in the range of 2.5 mg to 25 mg, given from once 
weekly to once monthly. 
As another alternate treatment, instead of administering methotrexate, 
Leflunomide may be administered orally concurrently with a TNF antagonist, 
wherein the dosage level of Leflunomide is in the range of 10 mg to 100 mg 
per day for the first 3 days, and 5 mg to 20 mg daily thereafter. 
9) Elevated Intracranial Pressure (EICP) 
EICP can be idiopathic (Pseudotumor cerebri) or caused by certain drugs 
(vitamin A excess, isotretinoin, tetracyclines, etc.) caused by malignancy 
(as above), or by benign tumors (e.g. cystercircosis). TNF blockade, 
either the acute or chronic treatment regimen, could be helpful. 
OPERATION OF THE PRESENT INVENTION 
1) Chronic Regimen Dosing with Etanercept 
For adults the dose is 25 mg subcutaneously (range 10 mg to 50 mg) 
administered in a range of twice a week to once a month. The initial 
regimen being 25 mg subcutaneously twice a week and for children 0.4 mg/kg 
given twice a week. Expected serum concentrations with this regimen would 
be about 3.0 mcg/ml, with a desired range between 0.5 and 10 mcg/ml. Other 
routes for chronic administration could include IM or IV dosing regimens. 
In an alternate treatment regimen, methotrexate orally or intramuscularly, 
may be administered concurrently with etanercept, wherein the dosage level 
of methotrexate is in the range of 2.5 mg to 25 mg, given from once weekly 
to once monthly. 
As another alternate treatment, instead of administering methotrexate, 
Leflunomide may be administered orally concurrently with a TNF antagonist, 
wherein the dosage level of Leflunomide is in the range of 10 mg to 100 mg 
per day for the first 3 days, and 5 mg to 20 mg daily thereafter. 
2) Acute Regimen Dosing with Etanercept 
Acute treatment regimens include administration of etanercept by SC, IM, IV 
and intrathecal dosing routes for acute administration. 
In an alternate treatment, methotrexate may be administered concurrently, 
orally or intramuscularly, wherein the dosage level is in the range of 2.5 
mg to 25 mg, given from once weekly to once monthly. The concurrent 
treatment with methotrexate may be added to any of these acute treatment 
regimens with etanercept. 
As another alternate treatment, instead of administering methotrexate, 
Leflunomide may be administered orally concurrently with a TNF antagonist, 
wherein the dosage level of Leflunomide is in the range of 10 mg to 100 mg 
per day for the first 3 days, and 5 mg to 20 mg daily thereafter. The 
concurrent treatment with Leflunomide may be added to any of these acute 
treatment regimens with etanercept. 
2A) Acute IV Regimen with Etanercept 
Etanercept is administered by IV infusion in a quantity sufficient to 
produce a serum concentration in the range of 0.5 mg/ml to 50 mg/ml. 
2B) Acute IM Regimen for Etanercept 
Etanercept is given by intramuscular administration in a dose of 50 mg 
having a range of 25 mg to 100 mg. 
2C) Acute Intrathecal Regimen with Etanercept 
There may be clinical use for etanercept in the cerebrospinal fluid, such 
as for treatment of CNS lesions (demyelinating diseases, brain tumors, 
cord compression). Intrathecal therapy means introducing the TNF 
antagonist into the cerebrospinal fluid of the patient. The exact dosage 
is on the order of 10 mg (range 1 mg to 50 mg). 
3) Chronic Treatment Regimen with Infliximab 
Chronic indications for infliximab include herniated nucleus pulposus 
(herniated disk), carpal tunnel syndrome, pituitary adenoma, demyelinating 
disease, primary or metastatic brain tumors and chronic pain syndromes due 
to metastatic tumor. 
Usual dosage for infliximab is 5 mg/kg given by IV infusion every two 
months with a range of 2.5 mg/kg to 20 mg/kg given every 2 weeks to 2 
months. 
In an alternate treatment regimen, methotrexate orally or intramuscularly, 
may be administered concurrently with infliximab, wherein the dosage level 
of methotrexate is in the range of 2.5 mg to 25 mg, given from once weekly 
to once monthly. 
As another alternate treatment, instead of administering methotrexate, 
Leflunomide may be administered orally concurrently with a TNF antagonist, 
wherein the dosage level of Leflunomide is in the range of 10 mg to 100 mg 
per day for the first 3 days, and 5 mg to 20 mg daily thereafter. 
4) Acute Treatment Regimen with Infliximab 
Acute indications for infliximab include acute spinal cord injury, acute 
demyelinating disease, spinal cord compression and increased intracranial 
pressure. 
The dosage for infliximab used for the acute regimen is 10 mg/kg 
administered by IV infusion once (range 2.5 mg/kg to 25 mg/kg). The dose 
for the intrathecal administration of infliximab is 0.3 mg/kg having a 
range of 0.1 mg/kg to 1 mg/kg. 
In an alternate treatment, methotrexate may be administered concurrently, 
orally or intramuscularly, wherein the dosage level is in the range of 2.5 
mg to 25 mg, given from once weekly to once monthly. The concurrent 
treatment with methotrexate may be added to any of these acute treatment 
regimens with infliximab. 
As another alternate treatment, instead of administering methotrexate, 
Leflunomide may be administered orally concurrently with a TNF antagonist, 
wherein the dosage level of Leflunomide is in the range of 10 mg to 100 mg 
per day for the first 3 days, and 5 mg to 20 mg daily thereafter. The 
concurrent treatment with Leflunomide may be added to any of these acute 
treatment regimens with infliximab. 
5) Treatment with Existing Regimens 
The treatment regimens of the present invention may be used in conjunction 
with or in place of existing treatments, such as steroids and surgery. 
When the treatment regimens of the present invention are used concurrently 
with currently available treatments, the results are additive and 
therefore beneficial. 
ADVANTAGES OF THE PRESENT INVENTION 
Accordingly, an advantage of the present invention is that it provides a 
TNF antagonist, with or without the concurrent administration of 
methotrexate or Leflunomide, for a new pharmacologic treatment of 
neurological disorders, trauma, injuries and compression affecting the 
nervous system of the human body, or demyelinating neurologic disease, 
such that the use of these TNF antagonists will result in the amelioration 
of these neurological conditions. 
Another advantage of the present invention is that it provides for a TNF 
antagonist, with or without the concurrent administration of methotrexate 
or Leflunomide, for providing suppression and inhibition of the action of 
TNF in a human to treat neurological injury, trauma or compression, or 
demyelinating neurologic disease, or inflammatory disease of the nervous 
system. 
Another advantage of the present invention is that it provides a TNF 
antagonist, with or without the concurrent administration of methotrexate 
or Leflunomide, that reduces and prevents further neurological 
inflammation to the patient by inhibiting the action of TNF in the human 
body for the immediate, short term (acute conditions) and long term 
(chronic conditions), such that this reduction and prevention of 
inflammation will produce clinical improvement in the patient and will 
give the patient a better opportunity to heal, slows disease progression, 
prevents neurological damage, or otherwise improves the patient's health. 
Another advantage of the present invention is that it provides for a TNF 
antagonist, with or without the concurrent administration of methotrexate 
or Leflunomide, that can offer acute and chronic treatment regimens for 
neurological conditions caused by neurological trauma, compression, injury 
and/or disease, such conditions including acute spinal cord injury, 
herniated nucleus pulposus (herniated disc), spinal cord compression due 
to metastatic cancer, carpal tunnel syndrome (non-RA), demyelinating 
disease, pituitary adenoma, primary or metastatic brain tumors, chronic 
pain syndromes due to metastatic tumor, increased intracranial pressure, 
and other related neurological disorders and diseases. 
Another advantage of the present invention is to provide a TNF antagonist, 
with or without the concurrent administration of methotrexate or 
Leflunomide, to treat neurologic disorders in humans either acutely or 
chronically by blocking the action of TNF and thereby modulating the 
immune response affecting neuronal tissue. 
A latitude of modification, change, and substitution is intended in the 
foregoing disclosure, and in some instances, some features of the 
invention will be employed without a corresponding use of other features. 
Accordingly, it is appropriate that the appended claims be construed 
broadly and in a manner consistent with the spirit and scope of the 
invention herein.