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Title:  Intracranial botulinum toxin therapy for focal epilepsy
United States Patent: 
7,357,934
Issued: 
April 15, 2008

Inventors:
 Donovan; Stephen (Capistrano Beach, CA), Francis; Joseph (Aliso Viejo, CA)
Assignee: 
Allergan, Inc. (Irvine, CA)
Appl. No.: 
10/421,504
Filed: 
April 22, 2003


 

Woodbury College's Master of Science in Law


Abstract

Methods for treating and/or curing epilepsy by intracranial administration of a botulinum toxin.

Description of the Invention

SUMMARY

The present invention meets this need and provides methods for effectively treating focal epilepsies by intracranial administration of a Clostridial neurotoxin which has the characteristics of long duration of activity, low rates of diffusion out of an intracranial site where administered and insignificant systemic effects at therapeutic dose levels.

A method within the scope of the present invention can be used to treat epilepsy, including: (1) focal (or partial) epilepsies, such as, benign occipital epilepsy (benign focal epilepsy with occipital paroxysms), benign rolandic epilepsy (benign focal epilepsy with centrotemporal spikes), frontal lobe epilepsy, occipital lobe epilepsy, mesial temporal lobe epilepsy and parietal lobe epilepsy; (2) generalized idiopathic epilepsies, such as benign myoclonic epilepsy in infants, juvenile myoclonic epilepsy, childhood absence epilepsy, juvenile absence epilepsy, and epilepsy with generalized tonic clonic seizures in childhood; (3) generalized symptomatic epilepsies, such as infantile spasms (West syndrome), Lennox-Gastaut syndrome and progressive myoclonus epilepsies, and; (4) unclassified epilepsies, such as febrile fits, epilepsy with continuous spike and waves in slow wave sleep (ESES), Landau Kleffner syndrome, Rasmussen's syndrome and epilepsy and inborn errors in metabolism

A method for treating a movement disorder within the scope of the present invention can be by intracranial administration of a neurotoxin to a patient to thereby alleviate a symptom of the movement disorder. The neurotoxin is made by a bacterium selected from the group consisting of Clostridium botulinum, Clostridium butyricum and Clostridium beratti, or can be expressed by a suitable host (i.e. a recombinantly altered E. coli) which encodes for a neurotoxin made by Clostridium botulinum, Clostridium butyricum or Clostridium beratti. Preferably, the neurotoxin is a botulinum toxin, such as a botulinum toxin type A, B, C.sub.1, D, E, F and G.

The neurotoxin can be administered to various brain areas for therapeutic treatment of a movement disorder, including to a lower brain region, to a pontine region, to a mesopontine region, to a globus pallidus and/or to a thalamic region of the brain.

The neurotoxin can be a modified neurotoxin, that is a neurotoxin which has at least one of its amino acids deleted, modified or replaced, as compared to a native or the modified neurotoxin can be a recombinant produced neurotoxin or a derivative or fragment thereof.

Intracranial administration of a neurotoxin according to the present invention can include the step of implantation of controlled release botulinum toxin system. A detailed embodiment of the present invention can be a method for treating a movement disorder by intracranial administration of a therapeutically effective amount of a botulinum toxin to a patient to thereby treating a symptom of a movement disorder. The movement disorders treated can include Parkinson's disease, Huntington's Chorea, progressive supranuclear palsy, Wilson's disease, Tourette's syndrome, epilepsy, chronic tremor, tics, dystonias and spasticity

A further embodiment within the scope of the present invention can be a method for treating epilepsy, the method comprising the steps of: selecting a neurotoxin with tremor suppressant activity; choosing an intracranial target tissue which influences a movement disorder; and; intracranially administering to the target tissue a therapeutically effective amount of the neurotoxin selected, thereby treating the epilepsy.

Thus, a method for treating an epilepsy according to the present invention can have the step of intracranial administration of a neurotoxin to a mammal, thereby alleviating a symptom of an epilepsy experienced by the mammal. Most preferably, the botulinum toxin used is botulinum toxin type A because of the high potency, ready availability and long history of clinical use of botulinum toxin type A to treat various disorders.

We have surprisingly found that a botulinum toxin, such as botulinum toxin type A, can be intracranially administered in amounts between about 10.sup.-3 U/kg and about 10 U/kg to alleviate a focal epilepsy disorder experienced by a human patient. Preferably, the botulinum toxin used is intracranially administered in an amount of between about 10.sup.-2 U/kg and about 1 U/kg. More preferably, the botulinum toxin is administered in an amount of between about 10.sup.-1 U/kg and about 1 U/kg. Most preferably, the botulinum toxin is administered in an amount of between about 0.1 unit and about 5 units. Significantly, the movement disorder alleviating effect of the present disclosed methods can persist for between about 2 months to about 6 months when administration is of aqueous solution of the neurotoxin, and for up to about five years when the neurotoxin is administered as a controlled release implant.

A further preferred method within the scope of the present invention is a method for treating a movement disorder by selecting a neurotoxin with tremor suppressant activity, choosing an intracranial target tissue which influences a movement disorder; and intracranially administering to the target tissue a therapeutically effective amount of the neurotoxin selected.

Another preferred method within the scope of the present invention is a method for improving patient function, the method comprising the step of intracranially administering a neurotoxin to a patient, thereby improving patient function as determined by improvement in one or more of the factors of reduced pain, reduced time spent in bed, increased ambulation, healthier attitude and a more varied lifestyle.

The present invention encompasses a method for treating epilepsy. The method can comprise the step of intracranial administration of a botulinum toxin to an epileptogenic focus a patient, thereby treating epilepsy. The botulinum toxin is a botulinum toxin types A, B, C, D, E, F or G. Preferably, the botulinum toxin is administered in an amount of between about 10.sup.-3 U/kg and about 100 U/kg of patient weight. This method can alleviate epilepsy for between about 1 month and about 5 years. The botulinum toxin can be administered to a lower brain region, pontine region, mesopontine region, globus pallidus or to a thalamic region of a brain of a patient.

The intracranial administration step can comprise implantation of a controlled release botulinum toxin system. A detailed embodiment of the disclosed method can comprise the step of intracranial administration of a therapeutically effective amount of a botulinum toxin type A to an epileptogenic focus of a patient, thereby treating epilepsy.

A particular detailed method for treating epilepsy according to the present invention can comprise the step of intracranial administration of a therapeutically effective amount of a botulinum toxin to a epileptogenic focus of a patient located in a thalamus of the patient between 3 to 6 mm posterior to the mid anterior commissure-posterior commissure plane, 12 mm to 16 mm lateral to the mid anterior commissure-posterior commissure plane, and 0 to 3 mm above the level of the mid anterior commissure-posterior commissure plane, thereby treating epilepsy.

DESCRIPTION

The present invention is based upon the discovery that local (i.e. intracranial) administration (as through stereotactic delivery) of a botulinum toxin (native or modified) can reduce excess electrical activity (i.e. reduction of hyperexcitability) of an epileptic focus in the brain, thereby treating epilepsy. As set forth herein, stereotactic methodologies permit precise therapeutic delivery of bioactive botulinum toxin into specific epileptic foci for the treatment of epilepsy.

A method within the scope of the present invention is primarily a treatment for intractable seizures, i.e. where surgery is indicated. We have surprising discovered that intracranial administration of a botulinum toxin to aberrant tissue within an identified epileptogenic focus can be used to treat epilepsy. An intractable seizure means that the seizures have failed reasonable attempts at medical (drug control). Significantly, use of a botulinum toxin, unlike surgical resection, to cause a "chemical ectomy", as described herein does not cause irreversible damage to the target neurons.

A method within the scope of the present invention can be used to treat a focal epilepsy as a focal epilepsy results from a localized lesion (a "focus") of functional abnormality. EEG can be used to localize abnormal spiking waves of a target focus followed by intracranial administration of a botulinum toxin to non-surgically (i.e. no tissue resection or ablation is carried out) downregulate the identified hyperexcitable focus.

Botulinum toxin is too large to cross the blood brain barrier and therefore cannot be given systemically to treat an intracranial epileptogenic brain focus. Additionally, systemic administration of a botulinum toxin can be expected to result in symptoms of botulism and possibly death.

Without wishing to be bound by theory, a proposed physiological mechanism for the efficacy of a method within the scope of our invention can be as follows. It is hypothesized that localized delivery of a botulinum toxin (such as a botulinum toxin type A) into or in the vicinity of an active epileptic focus (or foci) disrupts the hyperexcitability of the focus thereby suppressing or limiting seizure propagation.

The specific actions of a botulinum toxin on presynaptic nerve terminals are well characterized at the neuromuscular junction. Briefly, botulinum toxin binds to the presynaptic cholinergic terminals through interactions of its heavy chain binding domain with an, as yet, unspecified membrane receptor complex; gains entry through endocytosis that is independent of vesicular recycling mechanisms; undergoes a pH-dependent conformational shift within the endosomal vesicle that results in the translocation of the enzymatically active light chain to the cytosol; blocks vesicular neurotransmitter release by cleaving the C-termini of SNAP-25 proteins involved in vesicle docking. Although botulinum toxin actions in the periphery are selective for cholinergic neurons of the neuromuscular junction, experimental evidence suggests that the toxin is relatively non-selective in exerting actions on mammalian central nervous system neurons. Thus, botulinum toxin inhibits neurotransmitter release from particulate preparations of brain and spinal cord (Bigalke H., et al., Tetanus toxin and botulinum A toxin inhibit release and uptake of various transmitters, as studied with particulate preparations from rat brain and spinal cord, Naunyn Schmiedebergs Arch Pharmacol 1981 June; 316(3):244-51) and blocks presynaptic vesicle exocytosis in primary neuronal cultures from hippocampus (Owe-Larsson B., et al., Distinct effects of clostridial toxins on activity-dependent modulation of autaptic responses in cultured hippocampal neurons, Eur J Neurosci 1997 August; 9(8):1773-7; Trudeau L. et al., Modulation of an early step in the secretory machinery in hippocampal nerve terminals, Proc Natl Acad Sci USA 1988 Jun. 9; 95(12):7163-8) and spinal cord (Bigalke H., et al., Botulinum A neurotoxin inhibits non-cholinergic synaptic transmission in mouse spinal cord neurons in culture, Brain Res 1985 Dec. 23; 360(1-2):318-24).

While botulinum toxin has been shown to target presynaptic terminals, the toxin may be able to exert postsynaptic actions as well. Activation of the metabotropic glutamate receptor 1 (mGluR1) has been shown to potentiate N-methyl-D-aspartate (NMDA) receptor-mediated postsynaptic responses, and NMDA receptor-mediated responses have been implicated in mechanisms of synaptic plasticity and in learning and memory. It has demonstrated that the potentiation of NMDA responses by mGluR1 activation is due to an enhanced delivery of new NMDA receptors to the postsynaptic cell surface, through regulated vesicular exocytosis (Lan J., et al., Activation of metabotropic glutamate receptor 1 accelerates NMDA receptor trafficking: J Neurosci 2001 Aug. 15; 21(16):6058-68). Lan et al further demonstrated that the light chain of botulinum toxin type A attenuates the potentiating actions of mGlu1 receptor activation on NMDA receptor responses. Thus, botulinum toxin type A administration can potentially effect both pre- and post-synaptic responses. As noted earlier, blockade or inhibition of presynaptic vesicular release at excitatory synapses blocks neurotransmission and produces desynchronization of network activity, such as in the epileptogenic hippocampus, and leads to changes in synaptic plasticity (LTP). Thus, through inhibitory actions on synaptic vesicular release, a botulinum toxin can produce, at least in part, a denervation of the neural network within the treated focus, leading to a "functional (chemically induced) resection", suppression of focal hyperexcitability and lasting changes in synaptic plasticity. At the same time it is significant to note that, axons coursing through the target structure without synapsing would be spared. Thus, because endocytotic processes have been characterized at presynaptic terminals and somatodendritic cell surfaces and are negligible or absent along axons (Huttner W., et al., Exocytotic and endocytotic membrane traffic in neurons, Curr Opin Neurobiol 1991 October; 1(3):388-92; Parton R., et al., Cell biology of neuronal endocytosis, J Neurosci Res 1993 Sep. 1; 36(1):1-9. and because botulinum toxin entry into neurons is mediated through endocytosis, the toxin would not be expected to enter axons, arising from cell bodies in distant nuclei, that are strictly coursing through, but not synapsing within, the injected focus.

The reduction of focal hyperactivity will, expectedly, disrupt the pathological recruitment of downstream neuronal paths, resulting in a suppression of seizure propagation and yielding a desired anticonvulsant/antiepileptic effect. This outcome is based upon our current understanding of neuroanatomical circuitry and mechanisms of seizure propagation. In all models of cortical (and hippocampal) epileptogenesis, seizure generation and propagation is dependent upon neurotransmission (McCormick D. A., et al., On the cellular and network bases of epileptic seizures, Annu Rev Physiol 63: 815-46; 2001). Thus, inhibition of neurotransmission within a focus would lead to inhibition of signal transmission to target cell populations outside of the focus, and concomitant activity-dependent reduction in hyperexcitability. Additionally, there would be a reduction in ephaptic neuronal recruitment, due to a reduction in activity-dependent field effects, resulting in decreased neuronal synchronization in perifocal tissues. Burst discharges are sensitive to inhibition resulting from the depletion of the readily-releasable vesicle pool in presynaptic terminals, as has been demonstrated in the hippocampus (Staley et al 1998, Ibid). Thus, burst discharges arising from a targeted focus would be subject to similar inhibition upon botulinum toxin administration, since blockade of vesicular release produces a functional effect similar to depletion of the readily-releasable vesicular pool.

Botulinum toxin injection into a epileptogenic focus can be viewed as an adjunct or alternative to resective surgery, depending upon the observed characteristics of the underlying hyperexcitable tissue upon localization and examination. As well, intrafocal toxin injection can be supplemented with standard AED pharmacotherapy postoperatively, to suppress residual seizure activity while allowing for the toxin effect to occur.

It has been reported that "Since the thalamus and the cortex are strongly innervated by cholinergic neurons projecting from the brainstem and basal forebrain, an imbalance between excitation and inhibition, brought about by the presence of mutant (neuronal nicotinic acetylcholine) receptors (which display an increased acetylcholine sensitivity) could generate seizures by facilitating and synchronizing spontaneous oscillations in thalmo-cortical circuits." Raggenbass M., et al., Nicotinic receptors in circuit excitability and epilepsy, J Neurobiol. 2002 December; 53(4):580-9. This publication clearly supports the proposed efficacy of the present invention.

Intracranial administration of a botulinum toxin downregulates hyperexcitable neurons in an epileptogenic focus and can provide a cure for epilepsy due to synaptic plasticity which results in a "rewiring" of neuronal circuitry as new neuronal circuits are established to bypass the chemically deactivated epileptogenic focus.

Focal application of botulinum toxin can be used to treat many indications, such as focal, generalized idiopathic, generalized symptomatic, and unclassified epilepsies.

Thus, the present invention is based on the discovery that significant and long lasting relief from a variety of different movement disorders can be achieved by intracranial administration of a neurotoxin. Intracranial administration permits the blood brain barrier to be bypassed and delivers much more toxin to the brain than is possible by a systemic route of administration. Furthermore, systemic administration of a neurotoxin, such as a botulinum toxin, is contraindicated due to the severe complications (i.e. botulism) which can result from entry of a botulinum toxin into the general circulation. Additionally, since botulinum toxin does not penetrate the blood brain barrier to any significant extent, systemic administration of a botulinum toxin has no practical application to treat an intracranial target tissue.

The present invention encompasses any suitable method for intracranial administration of a neurotoxin to a selected target tissue, including injection of an aqueous solution of a neurotoxin and implantation of a controlled release system, such as a neurotoxin incorporating polymeric implant at the selected target site. Use of a controlled release implant reduces the need for repeat injections.

Intracranial implants are known. For example, brachytherapy for malignant gliomas can include stereotactically implanted, temporary, iodine-125 interstitial catheters. Scharfen. C. O., et al., High Activity Iodine-125 Interstitial Implant For Gliomas, Int. J. Radiation Oncology Biol Phys 24(4); 583-591:1992. Additionally, permanent, intracranial, low dose .sup.125I seeded catheter implants have been used to treat brain tumors. Gaspar, et al., Permanent .sup.125I Implants for Recurrent Malignant Gliomas, Int J Radiation Oncology Biol Phys 43(5); 977-982:1999. See also chapter 66, pages 577-580, Bellezza D., et al., Stereotactic Interstitial Brachytherapy, in Gildenberg P. L. et al., Textbook of Stereotactic and Functional Neurosurgery, McGraw-Hill (1998).

Furthermore, local administration of an anti cancer drug to treat malignant gliomas by interstitial chemotherapy using surgically implanted, biodegradable implants is known. For example, intracranial administration of 3-bis(chloro-ethyl)-1-nitrosourea (BCNU) (Carmustine) containing polyanhydride wafers, has found therapeutic application. Brem, H. et al., The Safety of Interstitial Chemotherapy with BCNU-Loaded Polymer Followed by Radiation Therapy in the Treatment of Newly Diagnosed Malignant Gliomas: Phase I Trial, J Neuro-Oncology 26:111-123:1995.

A polyanhydride polymer, GLIADEL.RTM. (Stolle R & D, Inc., Cincinnati, Ohio, (a copolymer of poly-carboxyphenoxypropane and sebacic acid in a ratio of 20:80), has been used to make implants, intracranially implanted to treat malignant gliomas. Polymer and BCNU can be co-dissolved in methylene chloride and spray-dried into microspheres. The microspheres can then be pressed into discs 1.4 cm in diameter and 1.0 mm thick by compression molding, packaged in aluminum foil pouches under nitrogen atmosphere and sterilized by 2.2 megaRads of gamma irradiation. The polymer permits release of carmustine over a 2-3 week period, although it can take more than a year for the polymer to be largely degraded. Brem, H., et al, Placebo-Controlled Trial of Safety and Efficacy of Inrraoperative Controlled Delivery by Biodegradable Polymers of Chemotherapy for Recurrent Gliomas, Lancet 345; 1008-1012:1995.

An implant can be prepared by mixing a desired amount of a stabilized neurotoxin (such as non-reconstituted BOTOX.RTM.) into a solution of a suitable polymer dissolved in methylene chloride, at room temperature. The solution can then be transferred to a Petri dish and the methylene chloride evaporated in a vacuum desiccator. Depending upon the implant size desired and hence the amount of incorporated neurotoxin, a suitable amount of the dried neurotoxin incorporating implant is compressed at about 8000 p.s.i. for 5 seconds or at 3000 p.s.i. for 17 seconds in a mold to form implant discs encapsulating the neurotoxin. See e.g. Fung L. K. et al., Pharmacokinetics of Interstitial Delivery of Carmustine 4-Hydroperoxycyclophosphamide and Paclitaxel From a Biodegradable Polymer Implant in the Monkey Brain, Cancer Research 58; 672-684:1998.

Diffusion of biological activity of a botulinum toxin within a tissue appears to be a function of dose and can be graduated. Jankovic J., et al Therapy With Botulinum Toxin, Marcel Dekker, Inc., (1994), page 150.

Local, intracranial delivery of a neurotoxin, such as a botulinum toxin, can provide a high, local therapeutic level of the toxin and can significantly prevent the occurrence of any systemic toxicity since many neurotoxins, such as the botulinum toxins are too large to cross the blood brain barrier. A controlled release polymer capable of long term, local delivery of a neurotoxin to an intracranial site can circumvent the restrictions imposed by systemic toxicity and the blood brain barrier, and permit effective dosing of an intracranial target tissue. A suitable implant, as set forth in co-pending U.S. patent application Ser. No. 09/587,250 entitled "Neurotoxin Implant", allows the direct introduction of a chemotherapeutic agent to a brain target tissue via a controlled release polymer. The implant polymers used are preferably hydrophobic so as to protect the polymer incorporated neurotoxin from water induced decomposition until the toxin is released into the target tissue environment.

Local intracranial administration of a botulinum toxin, according to the present invention, by injection or implant to e.g. the cholinergic thalamus presents as a superior alternative to thalamotomy in the management of inter alia tremor associated with Parkinson's disease.

A method within the scope of the present invention includes stereotactic placement of a neurotoxin containing implant using the Riechert-Mundinger unit and the ZD (Zamorano-Dujovny) multipurpose localizing unit. A contrast-enhanced computerized tomography (CT) scan, injecting 120 ml of omnipaque, 350 mg iodine/ml, with 2 mm slice thickness can allow three dimensional multiplanar treatment planning (STP, Fischer, Freiburg, Germany). This equipment permits planning on the basis of magnetic resonance imaging studies, merging the CT and MRI target information for clear target confirmation.

The Leksell stereotactic system (Downs Surgical, Inc., Decatur, Ga.) modified for use with a GE CT scanner (General Electric Company, Milwaukee, Wis.) as well as the Brown-Roberts-Wells (BRW) stereotactic system (Radionics, Burlington, Mass.) can be used for this purpose. Thus, on the morning of the implant, the annular base ring of the BRW stereotactic frame can be attached to the patient's skull. Serial CT sections can be obtained at 3 mm intervals though the (target tissue) region with a graphite rod localizer frame clamped to the base plate. A computerized treatment planning program can be run on a VAX 11/780 computer (Digital Equipment Corporation, Maynard, Mass.) using CT coordinates of the graphite rod images to map between CT space and BRW space.

Within wishing to be bound by theory, a further mechanism can be proposed for the therapeutic effects of a method practiced according to the present invention. Thus, a neurotoxin, such as a botulinum toxin, can inhibit neuronal exocytosis of several different CNS neurotransmitters, in particular acetylcholine. It is known that cholinergic neurons are present in the thalamus. Additionally, cholinergic nuclei exist in the basal ganglia or in the basal forebrain, with protections to motor and sensory cerebral regions. Thus, target tissues for a method within the scope of the present invention can include neurotoxin induced, reversible denervation of intracranial motor areas (such as the thalamus) as well as brain cholinergic systems themselves (such as basal nuclei) which project to the intracranial motor areas. For example, injection or implantation of a neurotoxin to a cholinergically innervated thalamic nuclei (such as Vim) can result in (1) downregulation of Vim activity due to the action of the toxin upon cholinergic terminals projecting into the thalamus from basal ganglia, and; (2) attenuation of thalamic output due to the action of the toxin upon thalamic somata, both cholinergic and non-cholinergic, thereby producing a chemical thalamotomy.

Preferably, a neurotoxin used to practice a method within the scope of the present invention is a botulinum toxin, such as one of the serotype A, B, C, D, E, F or G botulinum toxins. Preferably, the botulinum toxin used is botulinum toxin type A, because of its high potency in humans, ready availability, and known use for the treatment of skeletal and smooth muscle disorders when locally administered by intramuscular injection. Botulinum toxin type B is a less preferred neurotoxin to use in the practice of the disclosed methods because type B is known to have a significantly lower potency and efficacy as compared, to type A, is not readily available, and has a limited history of clinical use in humans. Furthermore, the higher protein load with regard to type B can cause immunogenic reaction to occur with development of antibodies to the type B neurotoxin.

The amount of a neurotoxin selected for intracranial administration to a target tissue according to the present disclosed invention can be varied based upon criteria such as the movement disorder being treated, its severity, the extent of brain tissue involvement or to be treated, solubility characteristics of the neurotoxin toxin chosen as well as the age, sex, weight and health of the patient. For example, the extent of the area of brain tissue influenced is believed to be proportional to the volume of neurotoxin injected, while the quantity of the tremor suppressant effect is, for most dose ranges, believed to be proportional to the concentration of neurotoxin injected. Methods for determining the appropriate route of administration and dosage are generally determined on a case by case basis by the attending physician. Such determinations are routine to one of ordinary skill in the art (see for example, Harrison's Principles of Internal Medicine (1998), edited by Anthony Fauci et al., 14.sup.th edition, published by McGraw Hill).

We have found that a neurotoxin, such as a botulinum toxin, can be intracranially administered according to the present disclosed methods in amounts of between about 10.sup.-3 U/kg to about 10 U/kg. A dose of about 10.sup.-3 U/kg can result in an epileptic tremor suppressant effect if delivered to a small intracranial nuclei. Intracranial administration of less than about 10.sup.-3 U/kg does not result in a significant or lasting therapeutic result. An intracranial dose of more than 10 U/kg of a neurotoxin, such as a botulinum toxin, poses a significant risk of denervation of sensory or desirable motor functions of neurons adjacent to the target.

A preferred range for intracranial administration of a botulinum toxin, such as botulinum toxin type A, so as to achieve a tremor suppressant effect in the patient treated is from about 10.sup.-2 U/kg to about 1 U/kg. Less than about 10.sup.-2 U/kg can result in a relatively minor, though still observable, tremor suppressant effect. A more preferred range for intracranial administration of a botulinum toxin, such as botulinum toxin type A, so as to achieve an antinociceptive effect in the patient treated is from about 10.sup.-1 U/kg to about 1 U/kg. Less than about 10.sup.-1 U/kg can result in the desired therapeutic effect being of less than the optimal or longest possible duration. A most preferred range for intracranial administration of a botulinum toxin, such as botulinum toxin type A, so as to achieve a desired tremor suppressant effect in the patient treated is from about 0.1 units to about 100 units. Intracranial administration of a botulinum toxin, such as botulinum toxin type A, in this preferred range can provide dramatic therapeutic success.

The present invention includes within its scope the use of any neurotoxin which has a long duration tremor suppressant effect when locally applied intracranially to the patient. For example, neurotoxins made by any of the species of the toxin producing Clostridium bacteria, such as Clostridium botulinum, Clostridium butyricum, and Clostridium beratti can be used or adapted for use in the methods of the present invention. Additionally, all of the botulinum serotypes A, B, C.sub.1, D, E, F and G can be advantageously used in the practice of the present invention, although type A is the most preferred and type B the least preferred serotype, as explained above. Practice of the present invention can provide a tremor suppressant effect, per injection, for 3 months or longer in humans.

Significantly, a method within the scope of the present invention can provide improved patient function. "Improved patient function" can be defined as an improvement measured by factors such as a reduced pain, reduced time spent in bed, increased ambulation, healthier attitude, more varied lifestyle and/or healing permitted by normal muscle tone. Improved patient function is synonymous with an improved quality of life (QOL). QOL can be assesses using, for example, the known SF-12 or SF-36 health survey scoring procedures. SF-36 assesses a patient's physical and mental health in the eight domains of physical functioning, role limitations due to physical problems, social functioning, bodily pain, general mental health, role limitations due to emotional problems, vitality, and general health perceptions. Scores obtained can be compared to published values available for various general and patient populations.

As set forth above, we have discovered that a surprisingly effective and long lasting treatment of a focal epilepsy can be achieved by intracranial administration of a neurotoxin to an afflicted patient. In its most preferred embodiment, the present invention is practiced by intracranial injection or implantation of botulinum toxin type A.

The present invention does include within its scope: (a) neurotoxin obtained or processed by bacterial culturing, toxin extraction, concentration, preservation, freeze drying and/or reconstitution and; (b) modified or recombinant neurotoxin, that is neurotoxin that has had one or more amino acids or amino acid sequences deliberately deleted, modified or replaced by known chemical/biochemical amino acid modification procedures or by use of known host cell/recombinant vector recombinant technologies, as well as derivatives or fragments of neurotoxins so made.

Botulinum toxins for use according to the present invention can be stored in lyophilized, vacuum dried form in containers under vacuum pressure or as stable liquids. Prior to lyophilization the botulinum toxin can be combined with pharmaceutically acceptable excipients, stabilizers and/or carriers, such as albumin. The lyophilized material can be reconstituted with saline or water.
 

Claim 1 of 19 Claims

1. A method for treating focal epilepsy, the method comprising the step of intracranial administration of a botulinum toxin into intracranial target tissue having an epileptogenic focus located at a brain region selected from the group consisting of a lower brain region, a pontine region, a globus pallidus and a thalamus of a patient, thereby treating the focal epilepsy.

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