DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This is the first action on the merits.
Claim Rejections - 35 USC § 112
The following is a quotation of the fourth paragraph of 35 U.S.C. 112:
Subject to the [fifth paragraph of 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2-7 are rejected under 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. When there are claims to a "specific polymorphic form" such as the "crystalline form F1 of Lumateperoine ditosylate," a dependent claim that only further lists physical data is not considered further limiting. Therefore claims 2-7 are not further narrowing the scope of the specific crystalline form. The dependent claims with additional peaks, C13 NMR and FT IR data are just pysical properties of the crystalline F1 compound. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 9 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of schizophrenia, bipolar disorder, depression, and sleep and behavioral disturbances in dementia, does not reasonably provide enablement for a method of treating autism or other neuropsychiatric disorders, generally. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Liebel-Flarsheim Co. v. Medrad, Inc., 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the prior art; (4) The level of one of ordinary skill; (5) The level of predictability in the art; (6) The amount of direction provided by the inventor; (7) The existence of working examples; and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
The analysis is as follows:
(A) Breadth of claims.
(a) Scope of the compounds. The compounds are drawn to a crystalline form F1 of lumateperone ditosylate.
(b) Scope of the diseases covered. The scope is drawn to a method of treating autism or other neuropsychiatric disorders, generally.
Neurological Disorders are extremely diverse, and fall into an assortment of categories.
The term "neurodegenerative disorders" covers an immense array of largely unrelated disorders that have different modes of action and different origins. The term covers such diverse disorders as Alzheimer's Disease; Parkinson's Disease; ALS and variants such as forms of ALS-PDC; dementia of the frontal lobe type (DFT) and DFT with motor neuron disease (DFT-MND); Diffuse Lewy Body Disease; Cortical Lewy body disease; Hallervordon-Spatz disease; Senile dementia of the neurofibrillary tangle type (“tangle-only dementia”); progressive familiar myoclonic epilepsy; Corticodentatonigral degeneration; more than a dozen dementias collectively called "frontotemporal dementia” (FTD); Tourette's syndrome; multiple systems atrophy (MSA; once called Shy-Drager syndrome), which exists in two forms: MSA-P type or MSA-C type; Neurological syphilis; Neurosarcoidosis; Pure autonomic failure (Bradbury-Eggleston syndrome); Friedreich ataxia and other spinocerebellar degenerations; Olivopontocerebellar atrophy (OPCA); spasmotic torticollis; Striatonigral degeneration; various types of torsion dystonia; certain spinal muscular atrophies, such as Werdnig-Hoffmann and Wohlfart-Kugelberg-Welander; Hereditary spastic paraplegia, Primary lateral sclerosis; peroneal muscular atrophy (Charcot-Marie-Tooth); Hypertrophic interstitial polyneuropathy (Dejerine-Sottas); ophthalmic disorders such as primary open-angle glaucoma (POAG) and retinitis pigmentosa; Leber's Disease; Wallerian degeneration, and Hypertrophic interstitial polyneuropathy.
There is the neuroacanthocytosis family, a difficult to define group of genetic disorders which includes Bassen-Kornsweig disease (abetalipoproteinemia), Familial hypobetalipoproteinemia, Chorea-acanthocytosis (ChAc), McLeod syndrome (MLS), Huntington disease–like2 (HDL2) and Pantothenate kinase–associated neurodegeneration (PKAN), FHBL1, FHBL2, Familial acanthocytosis with paroxysmal exertion-induced dyskinesias and epilepsy (FAPED), and Anderson disease.
There is a group of Prion diseases, notably Creutzfeldt-Jakob Disease (CJD), which occurs in both sporadic and familial forms; Gerstmann-Straussler-Scheinker Disease (GSS); and fatal familial insomnia.
There is another group called the Taupathy diseases, which includes Pick's disease; cortical-basal ganglionic degeneration (CBGD or CBD); progressive supranuclear palsy (PSP); Parkinsonism-dementia complex (PDC), and the amyotrophic lateral sclerosis/Parkinsonism-dementia complex(ALS-PDC).
Another group is the Polyglutamine diseases: Huntington's disease; spinal-bulbar muscular atrophy (Kennedy's disease or SBMA), Dentatorubral-Pallidoluysian Atrophy (DRPLA), Machado-Joseph disease (MJD, also called spinocerebellar ataxia type 3), and the other SCA diseases, viz SCA-1, SCA-2, SCA-6, and SCA-7.
The leukodystrophies are a group of over 30 assorted genetic disorders that affect the central nervous system by disrupting the growth or maintenance of the myelin sheath. This category includes 18q-Syndrome, Acute disseminated encephalomyeolitis (ADEM), Acute Disseminated Leukoencephalitis, Acute Hemorrhagic Leukoencephalopathy, Adrenoleukodystrophy, Adrenomyeloneuropathy (AMN), Aicardi-Goutieres Syndrome, Alexander Disease, Adult-onset Autosomal Dominant Leukodystrophy (ADLD), Autosomal Dominant Diffure Leukoencephalopathy with neuroaxonal spheroids, Autosomal Dominant late-onset leukoencephalopathy, Childhood Ataxia with diffuse CNS Hypomyelination (CACH or Vanishing White Matter Disease), Canavan Disease, Cerebral Autosomal Dominant Arteriopathy with Subcortical Infacts (CADASIL) and Leukoencephalopathy, Cerebrtendinous Xanthomatosis (CTX), Craniometaphysical dysplasia with leukoencephalopathy, Extensive Cerebral White Matter abnormality without clinical symptoms, Familial adult-onset leukodystrophy manifesting as cerebellar ataxia and dementia, Familial leukodystrophy with adult onset dementia and abnormal glycolipid storage, Globoid Cell Leukodystrophy (Krabbe Disease), Hereditary adult onset leukodystrophy simulating chronic progressive multiple sclerosis, Lipomembranous osteodysplasia with leukodystrophy (Nasu Disease), Metachromatic Leukodystrophy, Megalencephalic leukodystrophy with subcortical cysts (MLC), Neuroaxonal leukoencephalopathy with axonal spheroids,Oculodetatoldigital Dysplasia with cerebral white matter abnormalities, Orthochromatic leukodystrophy with pigmented glia, Ovarioleukodystrophy Syndrome, Pelizaeus-Merzbacher Disease, Refsum Disease, Sjogren-Larsson Syndrome, Sudanophilic Leukodystrophy, Van der Knapp Syndrome, Vanishing White Matter Disease, X-linked Adrenoleukodystrophy (X-ALD), and the Zellweger Spectrum: Zellweger Syndrome, Neonatal Adrenoleukodystrophy, and Infantile Refsum Disease.
The neuronal ceroid lipofuscinoses (NCLs) are the most common neurodegenerative disorders of childhood. These are generally characterized by loss of vision, seizures, motor dysfunction leading to spastic quadriplegia, cognitive loss, and early death. Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), or Batten disease is the most common of these. Different forms arise from different genes: CLN1 most commonly causes infantile onset, but also late Infantile- and Juvenile-Onset, as well as adult-onset. There is also late infantile (CLN2), juvenile-onset disease (CLN3), and late-infantile forms (CLN5). CLN8 underlies a form of progressive myoclonic epilepsy. The adult Kufs disease appears to be associated with CLN4. There are forms of late infantile NCL that are associated with CLN7 and CLN8, and another forms associate with NCL6. Of the 9 identified so far (CLN1-9), only 6 have their gene even identified.
Neurodegeneration can arise from the attack of known or unknown viruses on the brain. For example, HIV-associated dementia (HAD) arises from HIV-1; some strains of influenza A can cause apoptotic neurodegeneration; West Nile virus can cause neurodegeneration, possibly as a result of cytotoxic lymphocytes.
Neurodegeneration can also arise from stroke, and from certain types of spinal cord injuries.
These exhibit a very broad range of effects and origins. For example, some give no dementia and affect only vision, such as POAG. Many give distinctive and different patterns of effect. For example, FTDs, which have bilateral atrophy of the frontal and anterior temporal lobes, produce progressive nonfluent aphasia and semantic dementia, but, in contrast to e.g. Alzheimer's Disease, visuospatial skills and day-to-day memorizing is largely unaffected. Some give muscular wasting without sensory changes, e.g. ALS, and some do have the sensory changes such as Werdnig-Hoffmann. Some affect only vision such as retinitis pigmentosa, while others affect both vision and cognitive functions, such as Posterior cortical atrophy (PCA). Some produce abnormalities of posture, movement or speech, such as Striatonigral degeneration, and others produce progressive ataxias, such as OPCA. Some give an extremely broad range of effects. For example, CBD can give apraxia, alien limb phenomenon, cortical sensory loss, aphasia, myoclonus, bradykinesia, rigidity, dystonia, tremor, memory impairment and/or personality/behavioral changes.
The toxic protein, for those diseases that involve one, also varies. In some cases it is tau, i.e. in Alzheimer's Disease and other taupathies, and some are so linked to tau only sometimes (FTD). Alzheimer's Disease also involves β-amyloid. For Parkinson's disease it is α-synuclein. Prion disease involves PrPSc as its toxic protein, which involves missense. The polyglutamine diseases involve polyglutamine containing proteins. For Huntington's disease, it is huntingtin, for SBMA it is an androgen receptor, for DRPLA it is atrophin, for SCA-1 it is Ataxin-1, for SCA-2 it is Ataxin-2, for SCA-3 it is Ataxin-3, for SCA-6 it is a calcium channel protein, and for SCA-7 it is Ataxin-7.
In other cases, it is a matter of deficiency or absence of a protein. In Friedreich ataxia, the problem is frataxin deficiency, which affects sensory neurons in the dorsal root ganglion responsible for position sense.
The nature of the protein deposits, when these occur, varies as well. In Alzheimer's Disease, there are extracellular plaques from β-amyloid and neurofibrillary tangles (from tau). In Parkinson’s disease it is Lewy bodies and in ALS it is Bunina bodies. Taupathy produces cytoplasmic tangles, and Polyglutamine disease produce neuropil aggregates, intranuclear inclusions and cytoplasmic tangles. Prion disease produces prion plaque. And note that the disease form is not necessarily related to the protein deposits. For example, Alzheimer's Disease and Pick's disease both give progressive dementia without other prominent neurological signs. But the characteristic Alzheimer's neurofibrillary tangles are not seen in Pick's Disease, which has straight fibrils, as opposed to the paired helical filaments of Alzheimer's Disease. Pick's Disease gives lobal atrophy, not seen in Alzheimer's Disease.
The disease genes vary considerably as well. In Alzheimer's Disease, there is toxic gain of function with APP and loss of function of Presenilin 1 and presenilin 2. With Parkinson’s disease, there is toxic gain of function with α-synuclein, and loss of function of Parkin and UCHL1. In the Polyglutamine diseases, there is toxic gain of function with 9 different genes with CAG repeat expansion. In Prion disease, there is toxic gain of function with PRNP. In ALS there is toxic gain of function with SOD1. FTDP-17 arises from mutations at chromosome 17, Huntington's Disease from chromosome 4, and the neurodegenerative disorder that people with Down's syndrome develop later in life is presumably connected in some way to chromosome 21. Certain forms of Retinitis pigmentosa have been linked to deficiency in production of the kinase CERKL. Friedreich ataxia results from a mutation at the centromeric region of chromosome 9; it is the only disease known to be the result of a GAA trinucleotide repeat.
Finally, it must be noted that there are disorders that may or may not be neurodegenerative. Multiple sclerosis is perhaps the best known example; it is regarded by some as an autoimmune disease but by others as a metabolically dependent neurodegeneration.
As can be seen from the above, unlike in some areas of medicine, there is no representative, or “typical” neurodegenerative disorder. Some affect the mind, some affect movement, some affect both, and some effect neither. Alzheimer's Disease is the most common neurodegenerative disorder. However, its etiology involves both tau protein and β-amyloid. Such a statement is not true for any other important neurodegenerative disorder, and indeed the vast majority of neurodegenerative disorders involve neither one of those.
This covers any dysfunction of memory. Memory is the capacity to retain and retrieve an impression of past experiences. Memory is thus inseparable from learning, as learning cannot take place without memory and memory is the expression of learning.
Memory can be classified in two ways. One is, approximately, by duration. The sensory memory (milliseconds to seconds) corresponds to the initial moment that an item is perceived by the sense. Some of this information in the sensory area is transferred to short-term memory (retention for seconds to minutes). The capacity of these memories is quite limited. Some of this information is consolidated into long-term memory (retention for days up to a lifetime). The capacity of long term memory is immense. There is also something called working memory, which refers to a short-term storage needed for certain mental tasks but is not specifically defined in terms of duration, but rather in terms of purpose. It appears to be a form of short-term memory combined with some attentional control.
In addition, long term memory (the most important type) can be classified according to the information type. The two main categories are declarative (explicit) and non-declarative (implicit) memories. Declarative memory requires conscious recall, in that some conscious process must explicitly call back the information. This includes semantic memory, which concerns facts taken independent of context (mostly, general knowledge about the world); and episodic memory, which concerns information specific to a particular context, such as a time and place (mostly, personal memories and personal associations of a particular place or time, sometimes called autobiographical memory). The other main category’s most important type is called procedural memory and is not based on the deliberate recall of information, but on an implicit learning of certain patterns about the world. This form of learning is responsible for improvements in performance due purely to repetition. Examples of this include Classical conditioning and motor learning (e.g. “muscle memory”), and many types of skills. The other type of non-declarative memory is perceptual-representational, a kind of “priming”, so that the experience of an object on one occasion facilitates the perception of the same (or a similar) object on a later occasion.
Memory involves many different parts of the CNS, including basal ganglia, amygdala, the neostriatum, the cerebellum, the mammillary bodies and hippocampus.
The formation of memory requires three steps or stages: 1) Encoding (sensory registration, the processing of received information, including combination if the information comes from e.g. more than one sense organ), 2) Storage (creation of a permanent record of this encoded information), and 3) Retrieval (calling back this stored information in response to some cue for its use). As all of these are essential; a dysfunction of any stage will result in memory impairment. Thus, if the intial encoding does not take place, or if this information is not transferred to short term memory, such as occurs in the various agnosias, then memory impairment will occur. If information cannot be moved from short term to long term memory (a disorder called anterograde amnesia), then memory impairment occurs. If retrieval from long term memory is delayed, if it cannot be performed (memories lost), or if it is defective (false memories), then there is memory impairment.
As a result of the wide range of different types of memories which the brain forms, and the great complexity of the processes for memory, this covers a very wide range of disorders.
These include language memory disorders, such as aphasias (e.g. conduction aphasia), apraxia, dysarthria, alexia, receptive dysphasia, and agraphia.
It includes many types of disorders called amnesias. There is anterograde amnesia (new events are not transferred to long-term memory) and retrograde amnesia (inability to recall events that occurred before the onset of amnesia). There is lacunar amnesia (loss of memory about one specific event), Fugue amnesia (Psychogenic amnesia or hysterical amnesia, including “repressed memories”), Childhood amnesia (inability to remember events from early childhood), Transient epileptic amnesia (TEA), Autobiographical Amnesia, Transient Global Amnesia (total memory loss), Source amnesia (in which someone can recall certain information, but not where or how it was obtained) and amnesias arising from complex partial seizures, and alcoholic blackouts.
It also includes various agnosias, such as Prosopagnosia, Integrative agnosias, asogmatoagnosia, Associative agnosias, Autotopagnosia , Time Agnosia, Apperceptive agnosia, object agnosia, finger agnosia, phonagnosia, central achromatopsia, topographical agnosia, dyslexia, dyscalculia, right-left disorientation, Optic ataxia and Ocular apraxia, Color Agnosia, Simultanagnosia, Anosognosia, Auditory Agnosia (including amusia and word meaning deafness), and Somatosensory Agnosia (including Microsomatagnosia, Macrosomatagnosia, tactile agnosias and astereoagnosia), and constructional dyspraxia.
There is also Korsakoff's syndrome (Memory loss caused by alcoholism) and Post-traumatic stress disorder (spontaneous, vivid retrieval of unwanted traumatic memories), selective memory loss from head trauma, Accelerated Forgetting (excessively rapid decay of memories that appear to have been acquired successfully), and various types of false memory syndromes. There is the very common AAMI (age-associated memory impairment). Certain forms of Confusional States (e.g. those arising from Iatrogenic toxicity from some sedatives) will present acute memory disorders. There is also hyperthymesic syndrome, although there is dispute as to whether this qualifies as a disorder. There is also seizure-induced memory loss, which can erase access, temporarily or permanently, to declarative memory. There is also memory distrust syndrome, sometimes considered a type of delusional disorder.
There is a spectrum of Vascular dementia, which includes (1) mild vascular cognitive impairment, (2) multi-infarct dementia (MID), (3) vascular dementia due to a strategic single infarct, (4) vascular dementia due to lacunar lesions, (5) vascular dementia due to hemorrhagic lesions, (6) Binswanger disease (subcortical leukoencephalopathy), (7) subcortical vascular dementia, and (8) mixed dementia (combination of AD and vascular dementia).
Neurological disorders covers forms of cognitive impairment aside from the above. Anxiety disorders include specific phobia, generalized anxiety disorder, Social Anxiety Disorder, Panic Disorder, Agoraphobia, Obsessive-Compulsive Disorder, Post-traumatic stress disorder.
Mood disorders include Clinical depression (or Major depression), and in milder form, depression can be diagnosed as dysthymia. Bipolar disorder involves abnormally "high" or pressured mood states, known as mania or hypomania, alternating with normal or depressed mood.
Psychotic disorders arise when patterns of belief, language use and perception have become disordered. The principle forms are Schizophrenia (including Paraphrenias and paranoias), and Schizoaffective disorder, with schizotypy as a less severe form.
There are an assortment of delusional disorders. These are generally classified into six types: Erotomanic Type (erotomania); Grandiose Type; Jealous Type; Persecutory Type; Somatic Type (e.g. delusional parasitosis) and Mixed Type (delusions with characteristics of more than one of the above types but with no one theme predominating).
There are an assortment of different personality disorders which arise when a person’s cognition, motivation, and behavior becomes abnormally rigid maladaptive or distorted. These include paranoid personality disorder, schizoid personality disorder, antisocial personality disorder, Borderline personality disorder, Histrionic personality disorder, Narcissistic personality disorder, avoidant personality disorder, obsessive-compulsive personality disorder and others.
Related to these are behavioral disorders, such as the eating disorders which include Anorexia nervosa, Bulimia nervosa, Exercise Bulimia or Binge eating disorder. Urge disorders include kleptomania and Pyromania.
There are also identity disorders, such as Dissociative identity disorder and the somatoform disorders, including Somatization disorder. There are also disorders of the perception of the body, including Body dysmorphic disorder and neurasthenia.
It covers social cognitive disorders and development disorders including autism, Social Learning Disability, Asperger’s Syndrome, Rett syndrome, childhood disintegrative disorder and pervasive developmental disorders (PDD). It includes assorted Hypochondriasis, and Expressive Language Disorder. Other behavioral disorders include Reactive attachment disorder; Separation Anxiety Disorder; Oppositional Defiant Disorder; and Attention Deficit Hyperactivity Disorder.
It covers Delirium, a disturbance of consciousness, which includes a clouded sensorium (lack of clear awareness of surroundings), problems with attention and memory, incoherent speech, inability to think clearly, and perceptual disturbances (usually, auditory or visual hallucinations). Often included under delirium are the Delusional disorders. These can be of quite varied type: Jealous type (including Othello syndrome), Grandiose type, Erotomanic type (including Clerambault syndrome), Persecutory type, and the Somatic type. Included also are Delusional misidentification syndromes (including Capgras syndrome, syndrome of subjective doubles, Fregoli syndrome, and the syndrome of intermetamorphosis), as well as Cotard syndrome.
Somewhat related is Todd's syndrome (Alice in Wonderland syndrome) which affects perception by causing micropsia, macropsia, or other types of size distortion. There may also be marked distortions in the perception of the flow of time, in hearing and in touch.
It includes an assortment of sensory integration disorders (such as Irlen syndrome), including both hyposensitivities and hypersensitivities, Central Auditory Processing Disorder and gravitational insecurity.
It includes a wide array of special syndromes such as Coffin-Lowry syndrome, Rubinstein-Taybi syndrome, Clérambault's syndrome, Kandinsky-Clérambault syndrome, Postconcussional disorder, and Body dysmorphic disorder, and many more.
There are a wide assortment of Demyelinating Diseases, in two broad categories. Primary demyelination is a loss of myelin sheaths with relative preservation of the demyelinated axons, arising either from damage to the oligodendroglia from a direct attack on the myelin itself. Secondary demyelination, occurs following axonal degeneration. For example, Leukodystrophies are diseases of the white matter resulting from an error in the myelin metabolism, giving impaired myelin formation. Each involves the deficiency of a different enzyme. Examples include Krabbe's disease, Adrenoleukodystrophy (which exists in 4 forms), adrenomyeloneuropathy, Alexander Disease, Canavan Disease, Metachromatic Leukodystrophy (which exists in three forms), Pelizaeus-Merzbacher Disease, Refsum Disease, and Zellweger Syndrome. Other examples include Multiple Sclerosis (MS), progressive multifocal leukoencephalopathy, and Acute Disseminated Encephalomyelitis. Some are inherited diseases, such as peroneal muscular atrophy, hypertrophic polyneuropathy and Refsum's diseases.
Another category is the toxic neuropathies. These are quite diverse owing to the huge range of things that cause such neuropathies. Thus, in the category of sensory damage to axons, there are Almitrine, Chloramphenicol, Dioxin, Doxorubicin, Ethambutol, Ethionamide, Etoposide (VP-16), Gemcitabine, Glutethimide, Hydralazine, Ifosfamide, Interferon-a, Isoniazid, Metronidazole, Misonidazole, Nitrous oxide, Phenytoin, Propafenone, Pyridoxine, Statins, and Thalidomide. Causing motor damage to Axons are Almitrine, Chloramphenicol, Dioxin, Doxorubicin, Ethambutol, Ethionamide, Etoposide (VP-16), Gemcitabine, Glutethimide, Hydralazine, Ifosfamide, Interferon-a, Isoniazid, Metronidazole, Misonidazole, Nitrous oxide, Phenytoin, Propafenone, Pyridoxine, Statins, Thalidomid. Causing both types of damage are Acrylamide, Ethanol, Allyl chloride, Arsenic, Cadmium, Carbon disulfide, Chlorphenoxy, Ciguatoxin, Colchicine, Cyanide, Dapsone, Disulfiram, DMAPN, Ethylene oxide, lead, Lithium, Methyl bromide, Nucleosides (ddC; ddI; d4T), Nitrofurantoin, Organophosphates, Platinum analogs (Carboplatin, Cisplatinum, Oxaliplatin), Podophyllin, PCBs, Saxitoxin, Spanish toxic oil, Taxol, Tetrodotoxin, Thallium, Trichloroethylene, TOCP, Vacor (PNU), and Vinca alkaloids. In addition, demyelinating can be caused by Buckthorn, Chloroquine, Diphtheria, FK506 (Tacrolimus), Hexachlorophene, Muzolimine, Perhexiline, Procainamide, Tellurium, and Zimeldine. And moreover, both damage to axons and demylination is seen with Amiodarone, Ethylene glycol, 1,1'-Ethylidinebis[tryptophan], Gold, “Hexacarbons” (n-Hexane, n-butyl ketone, 2,5-hexanedione), Na Cyanate and Suramin. There is also postvaccinal encephalitis where the toxin arises from the vaccination.
There are also metabolic neuropathies. One category is that of the Mitochondrial Encephalomyopathies, which arise from of disorders affecting mitochondrial metabolism, including substrate transport, substrate utilization, defects of the Krebs Cycle, defects of the respiratory chain, and defects of oxidation/phosphorylation coupling. These neuropathies can result in the weakness of e.g. the proximal facioscapulohumeral, orbicularis and extraocular muscles. Other metabolic neuropathies originate from e.g. diabetes mellitus. The metabolic disorder Mucopolysaccharidosis I is the cause of Hurler’s syndrome which causes progressive mental retardation.
The extremely diverse range of sleep disorders covers Dyssomnias, Parasomnias, Medical/Psychiatric Sleep Disorders and others. First there are the Intrinsic Sleep Disorders, including Psychophysiological Insomnia, Sleep State Misperception, Idiopathic Insomnia, Narcolepsy, Recurrent Hypersomnia, Idiopathic Hypersomnia, Posttraumatic Hypersomnia, Obstructive Sleep Apnea Syndrome, Central Sleep Apnea Syndrome, Central Alveolar Hypoventilation Syndrome, Periodic Limb Movement Disorder, Restless Legs Syndrome, and Intrinsic Sleep Disorder NOS. Second there are the Extrinsic Sleep Disorders, including Inadequate Sleep Hygiene, Environmental Sleep Disorder, Altitude Insomnia, Adjustment Sleep Disorder, Insufficient Sleep Syndrome, Limit-Setting Sleep Disorder, Sleep-Onset Association Disorder, Food Allergy Insomnia, Nocturnal Eating (Drinking) Syndrome, Hypnotic-Dependent Sleep Disorder, Stimulant-Dependent Sleep Disorder, Alcohol-Dependent Sleep Disorder, Toxin-Induced Sleep Disorder, and Extrinsic Sleep Disorder NOS. Third, there are Circadian Rhythm Sleep Disorders, including Time Zone Change (Jet Lag) Syndrome, Shift Work Sleep Disorder, Irregular Sleep-Wake Pattern, Delayed Sleep Phase Syndrome, Advanced Sleep Phase Syndrome, Non-24-Hour Sleep-Wake Disorder, and Circadian Rhythm Sleep Disorder NOS. Fourth, there are Arousal Disorders, including Confusional Arousals, Sleepwalking, and Sleep Terrors. Fifth, there are Sleep-Wake Transition Disorders, including Rhythmic Movement Disorder, Sleep Starts, Sleep Talking, and Nocturnal Leg Cramps. Sixth, there are Parasomnias Usually Associated with REM Sleep, including, Nightmares, Sleep Paralysis, Impaired Sleep-Related Penile Erections, Sleep-Related Painful Erections, REM Sleep Related Sinus Arrest, and REM Sleep Behavior Disorder. Seventh, there are Other Parasomnias, including Sleep Bruxism, Sleep Enuresis, Sleep-Related Abnormal Swallowing Syndrome, Nocturnal Paroxysmal Dystonia, Sudden Unexplained Nocturnal Death Syndrome, Primary Snoring, Infant Sleep Apnea, Congenital Central Hypoventilation Syndrome, Sudden Infant Death Syndrome, Benign Neonatal Sleep Myoclonus, and Other Parasomnia NOS. Eighth, there are Sleep Disorders Associated with Mental Disorders, including Psychoses, Mood Disorders, Anxiety Disorders, Panic Disorder and Alcoholism. Ninth, there are Sleep Disorders Associated with Neurological Disorders, including, Cerebral Degenerative Disorders, Dementia, Parkinsonism, Fatal Familial Insomnia, Sleep-Related Epilepsy, Electrical Status Epilepticus of Sleep, and Sleep-Related Headaches. Tenth, there are Sleep Disorders Associated with Other Medical Disorders, including, Sleeping Sickness, Nocturnal Cardiac Ischemia, Chronic Obstructive Pulmonary Disease, Sleep-Related Asthma, Sleep-Related Gastroesophageal Reflux, Peptic Ulcer Disease and Fibrositis Syndrome. In addition, there are an assortment of poorly defined disorders and syndromes, including Short Sleeper, Long Sleeper, Subwakefulness Syndrome, Fragmentary Myoclonus, Sleep Hyperhidrosis, Menstrual-Associated Sleep Disorder, Pregnancy-Associated Sleep Disorder, Terrifying Hypnagogic Hallucinations, Sleep-Related Neurogenic Tachypnea, Sleep-Related Laryngospasm, and Sleep Choking Syndrome.
Central nervous system cancers cover a very diverse range of cancers in many categories and subcategories. There are an immense range of neuroepithelial tumors. Gliomas, the most common subtype of primary brain tumors, most of which are aggressive, highly invasive, and neurologically destructive tumors are considered to be among the deadliest of human cancers. These are any cancers which show evidence (histological, immunohistochemical, ultrastructural) of glial differentiation. These fall mostly into five categories. There are the astrocytic tumors (astrocytomas): pilocytic astrocytoma (including juvenile pilocytic astrocytoma, JPA, and pediatric optic nerve glioma) diffuse astrocytomas (including fibrillary astrocytomas, protoplasmic astrocytomas and gemistocytic astrocytomas), anaplastic astrocytomas (including adult optic nerve glioma), Glioblastoma multiforme (GBM), gliosarcoma and giant cell glioblastoma, and pleomorphic xanthoastrocytoma. GBM exists in two forms, primary and secondary, which have very different clinical histories and different genetics, but GBM is considered to be one clinical entity. Second, there are the oligodendroglial tumors (oligodendrogliomas): low grade oligodendroglioma and anaplastic oligodendroglioma. Third, there is oligoastrocytomas (“mixed glioma”), a type of tumor with both astrocytoma & oligodendroglioma features. The fourth type is the ependymomas, which are intracranial gliomas, including papillary ependymoma, myxopapillary ependymoma, tanycytic ependymoma, anaplastic ependymoma and subependymal giant-cell astrocytomas. A fifth type is the gangliogliomas (glioneuronal tumors or glioneurocytic tumors), which have both glial and neuronal components, and are extremely varied, based in part on what types of glial and what types of neuronal components are present. These include Papillary Glioneuronal Tumor (PGNT), a range of supratentorial gangliogliomas, assorted intramedullary spinal cord gangliogliomas, pineal ganglioglioma, hypothalamic ganglioglioma, cerebellar ganglioglioma, ganglioglioma of the right optic tract, rosetted glioneuronal tumor (“glioneurocytic tumor with neuropil rosettes”), composite pleomorphic xanthoastrocytoma (PXA)-ganglioglioma, desmoplastic ganglioglioma (both infantile (DIG) and non- infantile), angioganglioglioma, and others. There are also some glial tumors which do not comfortably fit into these five categories, notably astroblastoma, gliomatosis cerebri, and chordoid glioma, which is found solely in the hypothalamus and anterior third ventricle. Other neuroepithelial tumors include astrocytic tumors (e.g. astrocytomas) oligodendroglial tumors, ependymal cell tumors (e.g. myxopapillary ependymoma), mixed gliomas (e.g. mixed oligoastrocytoma and ependymo-astrocytomas) tumors of the choroid plexus(choroid plexus papilloma, choroid plexus carcinoma), assorted neuronal and neuroblastic tumors (e.g. gangliocytoma, central neurocytoma, dysembryoplastic neuroepithelial tumor, esthesioneuroblastoma, olfactory neuroblastoma, olfactory neuroepithelioma, and neuroblastomas of the adrenal gland), pineal parenchyma tumors (e.g. pineocytoma, pineoblastoma, and pineal parenchymal tumor of intermediate differentiation), embryonal tumors (e.g. medulloepithelioma, neuroblastoma, ependymoblastoma, atypical teratoid/rhabdoid tumor, desmoplastic medulloblastoma, large cell medulloblastoma, medullomyoblastoma, and melanotic medulloblastoma) and others such as polar spongioblastoma and gliomatosis cerebri. A second Division is tumors of the meninges. this includes tumors of the meningothelial cells, including meningiomas (meningothelial, fibrous (fibroblastic), transitional (mixed), psammomatous, angiomatous, microcystic, secretory, lymphoplasmacyte-rich, metaplastic, clear cell, chordoid, atypical, papillary, rhabdoid, anaplastic meningioma) and the non- meningioma tumors of the meningothelial cells (malignant fibrous histiocytoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, chondroma, chondrosarcoma, osteoma, osteosarcoma, osteochondroma, haemangioma, epithelioid haemangioendothelioma, haemangiopericytoma, angiosarcoma, kaposi sarcoma). There are also mesenchymal, non-meningothelial tumors (liposarcoma, (intracranial) solitary fibrous tumor, and fibrosarcoma) as well as primary melanocytic lesions (diffuse melanocytosis, melanocytoma, malignant melanoma, and meningeal melanomatosis). A third division are the tumors of cranial and spinal nerves. This includes cellular schwannomas, plexiform schwannomas and the melanotic schwannomas (e.g. psammomatous melanotic schwannoma, neuro-axial melanotic schwannoma, dorsal dumb-bell melanotic schwannoma). There is also Perineurioma (Intraneural and Soft tissue) and malignant peripheral nerve sheath tumor (MPNST), including Epithelioid, MPNST with divergent mesenchymal differentiation, and MPNST with epithelial differentiation. A fourth division are germ cell tumors, including germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma (mature teratoma, immature teratoma, and teratoma with malignant transformation). A fifth division are the tumors of the sellar Region, viz. pituitary adenoma, pituitary carcinoma, granular cell myoblastoma and craniopharyngiomas (adamantinomatous and papillary). Yet another division are local extensions from regional tumors, including paraganglioma, chodroma, chordoma, and chondrosarcoma. There are also Primitive Neuroectodermal Tumors (PNETs) including medulloblastomas, medulloepitheliomas, ependymoblastomas and polar spongioblastomas. There are Vascular brain Tumors e.g. the hemangioblastomas, there is CNS Lymphoma (which can be primary or secondary) and Meningeal Carcinomatosis. There are lymphoma and haemopoietic neoplasms including malignant lymphomas (which can be primary or secondary), plasmacytoma, and granulocytic sarcoma. And there are many, many others.
Seizures are evidenced by a sudden change in behavior due (except for the psychogenic non-epileptic seizures and the anoxic seizures) to abnormal electrical activity in the brain. Seizures are the primary symptom of epilepsy, but seizures can arise outside of epilepsy. These are sometimes called nonepileptic seizures. There are a bewildering array of types of epilepsy, each with its own unique combination of seizure type, typical age of onset, EEG findings, treatment, and prognosis.
These can be quite varied. The Absence or petit mal seizure is generally categorized by a lack of awareness of surroundings and sudden halt in conscious activity. Febrile seizures can range from eyes rolling or limbs stiffening to a full-blown convulsion. Generalized tonic-clonic seizures (grand mal) results in loss of consciousness and body stiffening, which is followed by shaking of the arms and legs. Partial (focal) seizure is characterized by abnormal muscle contraction, automatisms (complex, repetitive movements), forced turning of the head or eyes, abnormal sensations such as numbness, tingling, crawling sensation, and hallucinations. In the “simple” version of these, awareness and memory are not affected, but in the “complex” version, awareness and memory are affected. The Temporal lobe seizure beings with an aura, ("simple partial seizure"), which can include epigastric sensory illusions, sensation of deja vu, suddenly recalled memories, emotion disturbances and religious feelings. These sometimes expand to the "complex partial” seizure, which triggers autonomic nervous system symptoms such as abdominal pain or discomfort, dilated pupils, and flushed face along with abnormal sensations such as numbness, tingling, crawling sensation, nausea, rapid heart rate/pulse and sweating. There are also seen changes in movement, including abnormal mouth behaviors and head movements, repetitive movements, and a reduction or loss of consciousness. There are believed to be two separate types, the Mesial temporal lobe epilepsy (MTLE) which arises in the hippocampus, parahippocampal gyrus and amygdala, and the Lateral temporal lobe epilepsy (LTLE) which arises in the neocortex. Atonic seizures (drop seizures) consist of a brief lapse in muscle tone which sometimes causes falling. Gelastic seizures are brief outbursts of emotion, usually in the form of a laugh or a cry. They may be accompanied by forced eye movements, chewing or grinding the teeth, tonic posturing, and clonic jerking. A Jacksonian seizure involves a movement or progression of the seizure location in the brain, through the primary motor cortex in quick progression affecting all the corresponding muscles. Epilepsia partialis continua (Kojevnikov's epilepsia) is characterized by recurrent motor epileptic seizures that are focal (hands and face), and recur every few seconds or minutes for extended periods
There is an entire category of reflex epilepsies. Hot water epilepsy is a form caused by bathing with hot water. Such seizures can be triggered by reading, hearing music, by micturition, toothbrushing, or by other somatosensory, olfactory, or vestibular causes. There are movement-induced reflex seizures, seizures induced by thinking, and eating epilepsy. The most common are visually induced seizures. Touching, rubbing, or pricking skin can cause such seizures (“Rub epilepsy"). Startle epilepsy is usually included in this category.
In addition, there are seizures which have an unknown localization or etiology and thus cannot be fit easily into standard sorts of categories. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an idiopathic inherited epileptic disorder that causes seizures during sleep which consist of complex motor movements, such as hand clenching, arm raising/lowering, and knee bending and vocalizations. Benign centrotemporal lobe epilepsy of childhood (Rolandic epilepsy or Sylvan Seizures) features simple partial seizures that involve facial muscles and frequently cause drooling. Benign occipital epilepsy of childhood (BOEC) is an idiopathic localization-related epilepsy in two subtypes, an early subtype with onset between three and five years, and a late onset between seven and 10 years. Seizures in BOEC usually feature visual symptoms such as scotoma or fortifications or amaurosis, convulsions, forced eye deviation and head turning Catamenial epilepsy (CE) is when seizures cluster around certain phases of a woman's menstrual cycle. Childhood absence epilepsy (CAE) is an idiopathic generalized epilepsy with recurrent absence seizures, sometimes with minor Dravet's syndrome (severe myoclonic epilepsy of infancy (SMEI)), is a neurodevelopmental disorder beginning in infancy and characterized by severe epilepsy that does not respond well to treatment and can produce prolonged seizures, complex-partial seizures and more. Frontal lobe epilepsy, usually a symptomatic or cryptogenic localization-related epilepsy, arises from lesions causing seizures that occur in the frontal lobes of the brain. Juvenile absence epilepsy is an idiopathic generalized epilepsy with later onset than CAE, and generalized tonic-clonic seizures can occur. Juvenile myoclonic epilepsy (JME or Janz syndrome) is an idiopathic generalized epilepsy which produces myoclonic jerks, although generalized tonic-clonic seizures and absence seizures may occur as well. Lennox-Gastaut syndrome (LGS) is a generalized epilepsy that consists of a triad of developmental delay or childhood dementia, mixed generalized seizures, and results from idiopathic, symptomatic, or cryptogenic causes, and is generally characterized by astatic seizurestonic seizures, tonic-clonic seizures, atypical absence seizures, and sometimes, complex partial seizures. Primary reading epilepsy is a reflex epilepsy classified as an idiopathic localization-related epilepsy. Progressive myoclonic epilepsies, including Lafora disease and Unverricht-Lundborg disease, are a group of symptomatic generalized epilepsies characterized by progressive dementia, myoclonic seizures, and tonic-clonic seizures may occur as well. Rasmussen's encephalitis is a symptomatic localization-related epilepsy that is a progressive, inflammatory lesion affecting children with onset before the age of 10. Seizures start as separate simple partial or complex partial seizures and may progress to epilepsia partialis continua (simple partial status epilepticus). Temporal lobe epilepsy (TLE), usually involves complex partial seizures sometimes preceded by an aura, and some TLE patients also suffer from secondary generalized tonic-clonic seizures. If the patient does not respond sufficiently to medical treatment, epilepsy surgery may be considered. West syndrome is a triad of developmental delay, seizures termed infantile spasms, and EEG demonstrating a pattern termed hypsarrhythmia, and may arise from idiopathic, symptomatic, or cryptogenic causes.
There is a family of Focal status epilepticus, which includes, Epilepsia partialis continua of Kojevnikov, Aura continua, Limbic status epilepticus (psychomotor status) and Hemiconvulsive status with hemiparesis.
Sturge-Weber syndrome is manifested right from birth by seizures. Hypothalamic Hamartoma is characterized by partial seizures with laughing. Tuberous Sclerosis (TSC) usually causes epilepsy. Ohtahara syndrome, abdominal epilepsy, Myoclonic Epilepsy with Ragged Red Fibers (MERRF), Leigh Disease and Alpers Disease are characterized by seizures. Landau–Kleffner syndrome (LKS) presents with the development of aphasia and convulsions. Rett syndrome can involve severe seizures. Ring chromosome 20 syndrome (RC20) causes complex partial seizures, episodes of altered consciousness with staring, oral automatisms, focal motor symptoms and/or head turning.
Generalized Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure.
Even getting a clear picture of what a particular seizure syndrome consists of can be difficult. One example is the Jeavons Syndrome, which has eyelid myoclonia, with or without absences; photosensitivity; and either eye closure-induced seizures, EEG paroxysms, or both. It can fall into the category of a myoclonic seizure or a photosensitive seizure, but it is possible that it is not a distinct condition at all, and indeed, is not listed in the ILEA classification scheme.
There are also seizures which are not associated with abnormal, rhythmic discharges of cortical neurons. The psychogenic non-epileptic seizures are considered to arise from a psychiatric disorder.
This list is by no means complete, and there are different ways of ordering the wide variety of seizures. The categories are broad and include different disorders which are sometimes difficult to slot into specific areas, and sometimes very poorly understood.
Neurological disorders cover all drug addictions, Drug addiction is not a single disease or cluster of related disorders, but in fact, a collection with relatively little in common. Addiction to barbiturates, alcohol, cocaine, opiates, amphetamines, benzodiazepines, nicotine, etc all involve different parts of the CNS system; different receptors in the body. For example, cocaine binds at the dopamine reuptake transmitter. Heroin addiction arises from binding at the opiate receptors, cigarette addiction arises from some interaction at the nicotinic acid receptors, many tranquilizers involve the benzodiazepine receptor, alcohol involves yet another system, etc.
There is a family of the Polymicrogyrias, a malformation of cortical development characterized by excessive cortical folding and by shallow sulci. Children with polymicrogyria commonly have some degree of global developmental disabilities or delays, seizures, feeding difficulties, respiratory problems, motor dysfunction and mental retardation, often severe. This includes Bilateral Perisylvian polymicrogyria (also known as Congenital Bilateral Perisylvian Syndrome (CBPS) and Worster-Drought Syndrome) which often causes problems using the muscles of the face, throat, jaws and tongue (leading to severe dysarthria or even anarthria; Bilateral Frontoparietal polymicrogyria which can cause dysconjugate gaze, and bilateral pyramidal and cerebellar signs; Bilateral Posterior Parietal polymicrogyria; Bilateral mesial occipital polymicrogyria; Bilateral diffuse polymicrogyria; Bilateral parieto-occipital polymicrogyria; Bilateral parasagittal parietooccipital polymicrogyria; Bilateral frontal polymicrogyria; and Unilateral perisylvian polymicrogyria (also known as multilobar polymicrogyria). Causes include a genetic disorder, viral (CMV) in