GANAXOLONE FOR USE IN THE TREATMENT OF TUBEROUS SCLEROSIS COMPLEX

Abstract

The description of methods for treating tuberous sclerosis complex or tuberous sclerosis complex-related epilepsy, comprising administering to a subject in need a therapeutically effective amount of a pharmaceutically acceptable pregnenolone neurosteroid, such as ganaxolone, to reduce one or more symptoms of tuberous sclerosis complex or tuberous sclerosis complex-related epilepsy.

Description

GANAXOLONE FOR USE IN THE TREATMENT OF TUBEROUS SCLEROSIS COMPLEX This application claims the benefit of U.S. provisional application No. 62 / 944,549, filed on December 6, 2019, the contents of which are incorporated herein by reference in their entirety. BACKGROUND Tuberous sclerosis, also known as tuberous sclerosis complex (TSC), is a rare multisystem genetic disorder characterized by the growth of numerous noncancerous (benign) tumors in many parts of the body (Northrup et al., (2013), Pediatr Neurol., 49(4):243-254). These tumors can occur in the skin, brain, kidneys, and other organs, often causing significant health problems. Id. Epilepsy is the most common neurological symptom in patients with TSC (TSC-related epilepsy) and significantly contributes to morbidity and mortality. Jülich and Sahin (2014), Pediatric Neurol., 50:290-296. Infantile spasms are the most common seizure type in childhood and represent the first manifestation of epilepsy in 50% of patients. Id. In older children and adults, focal seizures with impaired consciousness (formerly known as complex partial seizures) are the most common. Id. Other focal and generalized seizures may also occur. Id. Seizure-related epilepsy affects up to approximately 90% of patients, of whom around 70% are treatment-resistant (Portocarrero et al., 2018, An Bras DermatoL, 93(3):323-331). Furthermore, there is a higher prevalence of intellectual disability, such as autism, intellectual disability, and mood disorders, among patients with refractory epilepsy compared to those with control epilepsy, and the disease persists throughout an affected individual's life. The negative impact of epilepsy on cognitive development, as well as on quality of life, makes seizure prevention and management an important goal in the treatment of seizure disorders (Vergeer et al., 2019, Epilepsia Open, 4:581-592). There is no cure for this disorder. The first-line therapy for infantile spasms associated with TSC is vigabatrin (Uliel-Sibony et al., (2020), Child's Nervous IVIA / a / ZUZZ / UUOU 14 System, 36:2511-2517). However, vigabatrin is associated with serious adverse side effects. Id. For example, it is associated with irreversible retinal damage in approximately 21-34% of patients. Other potential side effects include brain abnormalities in the thalamus, basal ganglia, brainstem tegmentum, and dentate nuclei of the cerebellum, hyperkinetic movement disorders, and acute encephalopathy. Id. Furthermore, no other anticonvulsant drug has dramatically reduced the severity or rate of TSC-related epilepsy. Therefore, there is a significant unmet need for effective therapies to treat TSC. BRIEF DESCRIPTION This description relates to methods for treating TSC and / or TSC-related epilepsy. As explained above, TSC-related epilepsy is an extremely complex and challenging condition to treat. In 70% of cases, patients are resistant to treatment, and the epilepsy is refractory. Refractory epilepsy is generally associated with significant behavioral and developmental consequences. As described and exemplified herein, the inventors believe that ganaxolone could provide an effective therapy for TSC and / or TSC-related epilepsy. Given the complexity and difficulties in treating TSC and TSC-related epilepsy, the inventors believed that a high dose of drug (e.g., ganaxolone) would be necessary for effective treatment. For example, in a clinical trial in adults with focal seizures, ganaxolone was administered at a daily dose of 1800 mg (administered as 900 mg twice daily), but the clinical endpoint was not met. The inventors have now surprisingly discovered that administering ganaxolone at a lower daily dose but with more frequent administration can provide effective therapy for TSC and TSC-related epilepsy.Without wishing to limit oneself to any particular theory or mechanism, it is believed that more frequent administration of ganaxolone (e.g., three times daily) but at a lower daily dose than previously used improves drug exposure by maintaining a serum ganaxolone level (e.g., trough levels) above a threshold level for longer periods, resulting in effective treatment. For example, administering oral ganaxolone three times daily (or more) with a total daily dose of no more than 1800 mg, or no more than 1700 mg, or no more than 1600 mg, or no more than 1500 mg, or no more than 63 mg / kg / day of ganaxolone can produce a plasma ganaxolone concentration of at least approximately 100 ng / mL for about 70% or more during a 24-hour day and provides effective seizure reduction.Furthermore, less ganaxolone is typically required to achieve the minimum elevated concentration using three-times-daily (or more frequent) administration, which is also beneficial for the patient. In fact, trough ganaxolone levels with twice-daily dosing typically remained below 100 ng / ml during the 24-hour treatment period. The inventors have also surprisingly discovered that a subpopulation of patients who have TSC-related epilepsy have a low plasma concentration of allopregnanolone sulfate (Allo-S) (e.g., less than 2500 pg / ml) and may respond better to treatment with ganaxolone. Accordingly, this description relates to methods for effectively treating CSD and / or CSD-related epilepsy. The methods described herein comprise administering to a subject in need a therapeutically effective amount of a neurosteroid, preferably ganaxolone, or a pharmaceutically acceptable salt thereof. Ganaxolone is preferably administered in an amount that will provide a minimum ganaxolone level (e.g., a plasma ganaxolone concentration) of approximately 100 ng / ml or more for approximately 70% or more of a 24-hour day. To achieve a plasma concentration of ganaxolone of approximately 100 ng / mL or higher for approximately 70% or more over a 24-hour period, ganaxolone may be administered three or more times daily at a maximum dose of approximately 1800 mg per day. In subjects weighing less than 40 kg, ganaxolone may be administered three or more times daily at a maximum dose of 63 mg / kg / day. Typically, up to approximately 1500 mg per day of ganaxolone can produce a plasma concentration of approximately 100 ng / mL or higher for approximately 70% or more over a 24-hour period when administered three times daily. Ganoxone may also be administered at a dose of approximately 500 mg three times daily. A skilled physician will understand that the amount of ganaxolone administered three times a day (e.g., orally) can be adjusted to achieve the desired minimum level of ganaxolone as long as the total amount does not exceed the maximum daily dose of ganaxolone. Ganaxolone is preferably administered orally (for example, as a MA / a / ZUZZ / UUOUI 4 oral suspension or one oral capsule). Beyond theory, the inventors believe that three-times dosing results in enhanced anticonvulsant activity (i.e., reduces seizure frequency and / or severity) due to increased plasma exposure to ganaxolone. This contradicts previous treatment protocols that dictate administering ganaxolone at high doses (e.g., doses per day) to achieve therapeutic efficacy. For example, administering ganaxolone at a higher dose twice daily. Administering ganaxolone in an amount sufficient to achieve a plasma concentration of at least approximately 100 ng / ml or higher for approximately 70% or more over a 24-hour period reduces the frequency and / or severity of seizures in the subject compared to baseline. Typically, a reduction in seizure frequency of at least 20% or more compared to baseline can be achieved. During treatment, the subject's plasma concentration and / or seizure activity can be monitored using EEG. If the subject appears to be exhibiting signs of seizures (e.g., recurrence of seizures), the amount of ganaxolone administered can be adjusted accordingly. The methods described herein are suitable for treating any form of seizure associated with TSC or TSC-related epilepsy. For example, but not limited to, infantile spasms, focal seizures with altered consciousness, focal seizures, or generalized seizures. One objective of this description is to provide a treatment for tuberous sclerosis. One objective of this description is to provide a treatment for epilepsy related to complex tuberous sclerosis (TSC). One additional objective of this description is to provide a treatment for seizures associated with TSC-related epilepsy. Another objective of this description is to utilize the ergic mechanism of action of gamma-aminobutyric acid (GASA) from ganaxolone to provide a therapeutic benefit to humans with TSC and TSC-related epilepsy. In accordance with the above and other objectives, the description is directed in part to a method for treating a human being suffering from tuberous sclerosis, comprising administering a therapeutically effective amount of a pharmaceutically acceptable pregnenolone neurosteroid to the human in an amount effective to relieve or reduce one or more symptoms of tuberous sclerosis in the human. The pharmaceutically acceptable pregnenolone neurosteroid can be administered parenterally and / or orally in amounts from about 1 mg / day to about 5000 mg / day. Humans particularly predisposed to receive a therapeutic benefit from the administration of the pharmaceutically acceptable pregnenolone neurosteroid are those who have a low level of allopregnanolone sulfate. Plasma allopregnanolone sulfate levels appear to correlate positively with plasma allopregnanolone levels and may qualitatively represent allopregnanolone levels in the brain. Therefore, a low allopregnanolone sulfate level may indicate an allopregnanolone deficiency in the brain. A plasma allopregnanolone sulfate level of approximately 2500 pg / ml or less is considered low and may indicate an endogenous neurosteroid deficiency in a human. The low level of allopregnanolone sulfate may be 2400 pg / ml or less, 2300 pg / ml or less, 2200 pg / ml or less, 2100 pg / ml or less, 2000 pg / ml or less, 1900 pg / ml or less, 1800 pg / ml or less, 1700 pg / ml or less, 1600 pg / ml or less, 1500 pg / ml or less, 1400 pg / ml or less, 1300 pg / ml or less, 1200 pg / ml or less, 1100 pg / ml or less, 1000 pg / ml or less, 900 pg / ml or less, 850 pg / ml or less, 800 pg / ml or less, 750 pg / ml or less, 700 pg / ml or less, 650 pg / ml or less,600 pg / ml or less, 550 pg / ml or less, 500 pg / ml or less, 450 pg / ml or less, 400 pg / ml or less, 350 pg / ml or less, 300 pg / ml or less, 250 pg / ml or less, 200 pg / ml or less, 150 pg / ml or less, 100 pg / ml or less, 90 pg / ml or less, 80 pg / ml or less, 70 pg / ml or less, 60 pg / ml or less, 50 pg / ml or less, 40 pg / ml or less, 30 pg / ml or less, 20 pg / ml or less, 15 pg / ml, 10 pg / ml or less, 9 pg / ml or less, 8 pg / ml or less, 7 pg / ml or less, 6 pg / ml or less, 5 pg / ml or less, 4 pg / ml or less, 3 pg / ml or less, 2 pg / ml or less, 1 pg / ml or less., Because an allopregnanolone deficiency in the brain can cause one or more symptoms of tuberous sclerosis, administration of a pharmaceutically acceptable pregnenolone neurosteroid according to the methods described herein can correct this deficiency and, consequently, alleviate and / or reduce the severity and / or reduce the frequency of one or more symptoms of tuberous sclerosis. Symptoms of tuberous sclerosis that may be alleviated or reduced by administration of the pharmaceutically acceptable pregnenolone neurosteroid include, but are not limited to, seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, lung disease, and kidney disease.Seizures may include, for example, focal motor seizures without impairment of consciousness or awareness, focal seizures with impairment of consciousness or awareness, focal seizures that evolve into bilateral generalized convulsive seizures, tonic-clonic convulsive seizures, and generalized seizures with a motor component that are countable, including, for example, tonic-clonic, bilateral tonic, bilateral clonic, or atonic / drop seizures. The description also refers to a method for treating a human being suffering from tuberous sclerosis, comprising administering a therapeutically effective amount of ganaxolone to the human in a quantity effective to relieve or reduce one or more symptoms of tuberous sclerosis. Ganaxolone can be administered parenterally and / or orally. Humans particularly likely to receive a therapeutic benefit from the administration of ganaxolone are those with a low level of allopregnanolone sulfate. When ganaxolone is administered orally, the therapeutically effective amount can range, for example, from approximately 600 mg / day to approximately 2000 mg / day. In certain formulations, the dose may be increased to approximately 2100 mg / day, 2200 mg / day, 2300 mg / day, or more to provide an improved response at a lower dose, the limiting factor being the increased side effects associated with the higher dose. Ganoxone is typically administered at doses up to approximately 1500 mg / day or 1800 mg / day. In certain formulations, the dose may be reduced to approximately 550 mg / day, 500 mg / day, 450 mg / day, 300 mg / day, or less than 300 mg / day to alleviate or lessen the severity of side effects experienced by humans at a higher dose.The symptoms of tuberous sclerosis that may be relieved and / or whose frequency and / or severity may be reduced by the administration of ganaxolone according to the methods described herein include, for example, seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, lung disease, and kidney disease. Seizures may include, for example, focal motor seizures without impairment of consciousness or awareness, focal seizures with impairment of consciousness or awareness, focal seizures that evolve into bilateral generalized convulsive seizures, tonic-clonic convulsive seizures, and generalized seizures with a motor component that are countable, including, for example, tonic-clonic and bilateral tonic seizures. MA / a / ZUZZ / UUOUI 4 bilateral or atonic / drop clonic. The description is also directed to a method for treating a human being who has TSC or TSC-related epilepsy, comprising chronically administering a pharmaceutically acceptable pregnenolone neurosteroid (e.g., ganaxolone) to the human in an amount effective to reduce the frequency of seizures in the human, where the human has a low plasma level of an endogenous neurosteroid (e.g., allopregnanolone sulfate (Allo-S), as described above). This description is also directed to a method for treating a human being with TSC or TSC-related epilepsy, the method comprising administering orally to the human a solid, immediate-release oral formulation comprising a pharmaceutically acceptable pregnenolone neurosteroid (e.g., ganaxolone) in twice-daily doses (e.g., every 10-13 hours), wherein the neurosteroid has a half-life of about 18 hours to about 24 hours, the formulation releases not less than about 70% or about 80% of ganaxolone within 45 minutes of placing the formulation in simulated gastrointestinal fluid (SGF and / or SIF), and administration results in a decrease of at least about 35%, about 40%, about 45%, or about 50% in seizure frequency every 28 days in humans.compared to the frequency of seizures during a period of 28 days prior to the first administration. This description is further directed to a method for treating a human being with TSC or TSC-related epilepsy, the method comprising administering orally to the human an immediate-release liquid oral formulation comprising a pharmaceutically acceptable pregnenolone neurosteroid (e.g., ganaxolone) three times daily (e.g., every 6 to 8 hours), wherein the neurosteroid has a half-life of about 18 hours to about 24 hours, the formulation releases not less than about 70% or about 80% of ganaxolone within 45 minutes of placing the formulation in simulated gastrointestinal fluid (SGF and / or SIF), and the administration results in a decrease of at least about 35%, about 40%, about 45%, or about 50% in the frequency of seizures every 28 days in humans.compared to the frequency of seizures during a period of 28 days prior to the first administration. This description is also directed to a method for treating a human being with a pregnenolone neurosteroid, where the human suffers from TSC or TSC-related epilepsy, where the method comprises the steps of: determining whether the human has a low level of endogenous neurosteroid (e.g., Allo-S) by obtaining or having obtained a biological sample (e.g., a blood sample) from the human; and performing or having performed an assay on the biological sample to determine the plasma level of one or more endogenous neurosteroids in the biological sample.An endogenous neurosteroid level of 2500 pg mL-1 or less, 2000 pg mL-1 or less, 1500 pg mL-1 or less, 1000 pg mL-1 or less, 900 pg mL-1 or less, 800 pg mL-1 or less, 700 pg mL-1 or less, 600 pg mL-1 or less, 500 pg mL-1 or less, 400 pg mL-1 or less, 300 pg mL-1 or less, 200 pg mL-1 or less, 100 pg mL-1 or less, 75 pg mL-1 or less, 50 pg mL-1 or less, or 25 pg mL-1 or less indicates that the human has a low level of endogenous steroid.A subject (e.g., a human) who has a low level of endogenous steroid (e.g., Allo-S) may be orally administered a pregnenolone neurosteroid (e.g., ganaxolone) at a dose of 1 mg / kg / day to about 63 mg / kg / day, from about 2 mg / kg / day to about 63 mg / kg / day, from about 3 mg / kg / day to about 63 mg / kg / day, from about 4 mg / kg / day to about 63 mg / kg / day, from about 5 mg / kg / day to about 63 mg / kg / day, from about 6 mg / kg / day to about 63 mg / kg / day, or from about 7 mg / kg / day to about 63 mg / kg / day for at least one day in two or three divided doses. In some of these modalities, an endogenous neurosteroid level of 2500 pg mL-1 or less, 2000 pg mL-1 or less, 1500 pg mL-1 or less, 1000 pg mL-1 or less, 900 pg mL-1 or less, 800 pg mL-1 or less, 700 pg mL-1 or less, 600 pg mL-1 or less, 500 pg mL-1 or less, 400 pg mL-1 or less, 300 pg mL-1 or less, 200 pg mL-1 or less, 100 pg mL-1 or less, 75 pg mL-1 or less, 50 pg mL-1 or less, or 25 pg mL-1 or less indicates that administration of such ganaxolone is likely to reduce the frequency of seizures in the patient, for example, by 35%. or more; about 40% or more; about 45% or more; or about 50% or more; after administration for 28 days, compared to the frequency of seizures during a period of time of 28 days before the first administration.The endogenous neurosteroid can be selected from the group comprising or consisting of pregnanolone, pregnanolone sulfate, 5-alphaDHP, allopregnanolone, allopregnanolone-S, pregnanolone, pregnanolone-S, DHEA and combinations thereof; and the pregnenolone neurosteroid can, for example, be selected from the group comprising or consisting of allopregnanolone, ganaxolone, alfaxalone, alfadolone, hydroxydione, minaxolone, pregnanolone, acebrocol or. IVIA / a / ZUZZ / UUOU 14 tetrahydrocorticosterone, and pharmaceutically acceptable salts thereof. In some of these modalities, the method further comprises communicating the trial results to the patient or physician before or after administration of the pregnenolone neurosteroid. Ganoxolone is the preferred pregnenolone neurosteroid. The present description is also directed to a method for treating a human being with ganaxolone, where the human suffers from CTS or CTS-related epilepsy, wherein the method comprises the steps of: determining whether the human has an allopregnanolone sulfate (Allo-S) level of 2500 pg mL-1 or less, and if the human has an allopregnanolone sulfate level of 2500 pg mL-1 or less, then administering ganaxolone orally to the human at a dose from 1 mg / kg / day to about 63 mg / kg / day, from about 2 mg / kg / day to about 63 mg / kg / day, from about 3 mg / kg / day to about 63 mg / kg / day, from about 4 mg / kg / day to about 63 mg / kg / day, from about 5 mg / kg / day to about 63 mg / kg / day, from about 6 mg / kg / day to around 63 mg / kg / day, or from around 7 mg / kg / day to around 63 mg / kg / day for at least one day in two or three divided doses.In some of these formulations, an allopregnanolone sulfate level of 2500 pg mL-1 or lower indicates that administration of such allopregnanolone is likely to reduce the frequency of seizures in humans, for example, by at least about 35%, about 40%, about 45%, or about 50% after administration for 28 days, compared to the frequency of seizures during a period of 28 days prior to the first administration. The present description is further directed to a method for treating a human being suffering from TSC or TSC-related epilepsy, the method comprising the steps of: determining if the human has an allopregnanolone sulfate level of 2500 pg mL-1 or less, and if the human has an allopregnanolone sulfate level of 2500 pg mL-1 or less, then orally administering an endogenous neurosteroid (e.g., allopregnanolone, pregnanolone, etc.) or a synthetic neurosteroid (e.g., Co26749 / WAY-141839, Co134444, Co177843, Sage-217 (3a-Hydroxy-3p-methyl-21-(4-cyano1H-pyrazol-T-yl)-19-nor-5P-pregnan-20-one), ganaxolone, etc.) to humans at a dose from 1 mg / kg / day to about 200 mg / kg / day, from about 2 mg / kg / day to about 150 mg / kg / day, from about 3 mg / kg / day to about 100 mg / kg / day, from about 4 mg / kg / day to about 90 mg / kg / day, from about 5 mg / kg / day to about 80 mg / kg / day, from about 6 mg / kg / day to about 70 mg / kg / day, or from about 7 mg / kg / day to about 65 mg / kg / day for at least one day in two or three divided doses, and if the human has an allopregnanolone sulfate level above 2500 pg ml_-1, refrain from administering the endogenous or synthetic neurosteroid to the human and / or administer a different anticonvulsant agent. A different anticonvulsant agent can be selected, for example, from the group consisting of benzodiazepines (e.g., clobazam, diazepam, clonazepam, midazolam, etc.).Clorazepic acid, levetiracetam, felbamate, lamotrigine, a fatty acid derivative (e.g., valproic acid), a carboxamide derivative (rufinamide, carbamazepine, oxcarbazepine, etc.), an amino acid derivative (e.g., levocarnitine), a barbiturate (e.g., phenobarbital), or a combination of two or more of the above agents may be used. Any number of other anticonvulsant agents may be administered. A person skilled in the art will be familiar with anticonvulsant agents. The description is also directed to a method for treating a human being suffering from TSC or TSC-related epilepsy, wherein the method comprises the steps of: determining whether the human has an allopregnanolone sulfate level of 2500 pg mL-1 or less, and if the human has an allopregnanolone sulfate level of 2500 pg mL-1 or less, then administering ganaxolone orally to the human at a dose of from 1 mg / kg / day to about 63 mg / kg / day, from about 2 mg / kg / day to about 63 mg / kg / day, from about 3 mg / kg / day to about 63 mg / kg / day, from about 4 mg / kg / day to about 63 mg / kg / day, from about 5 mg / kg / day to about 63 mg / kg / day, from about 6 mg / kg / day to about 63 mg / kg / day, or from around 7 mg / kg / day to around 63 mg / kg / day for at least one day in two or three divided doses.In some of these formulations, an allopregnanolone sulfate level of 2500 pg mL-1 or lower indicates that administration of such allopregnanolone is likely to reduce the frequency of seizures in humans, for example, by at least about 35%, about 40%, about 45%, or about 50% after administration for 28 days, compared to the frequency of seizures during a period of 28 days prior to the first administration. The present description is also directed to a method for treating a human being suffering from CTS or CTS-related epilepsy, wherein the method comprises the steps of: determining whether the human has an allopregnanolone level of 200 pg mL-1 or less, and if the human has an allopregnanolone level of 200 pg mL-1 or less, then administering ganaxolone orally to the human in a dose from 1 IVIA / a / ZUZZ / UUOU 14 mg / kg / day to about 80 mg / kg / day, from about 2 mg / kg / day to about 75 mg / kg / day, from about 3 mg / kg / day to about 70 mg / kg / day, from about 4 mg / kg / day to about 65 mg / kg / day, from about 5 mg / kg / day to about 63 mg / kg / day, from about 6 mg / kg / day to about 63 mg / kg / day, or from about 7 mg / kg / day to about 63 mg / kg / day for at least one day in two or three divided doses, and if the human has an allopregnanolone level above 200 pg mL-1, refrain from administering ganaxolone to the human.In some of these formulations, an allopregnanolone level of 200 pg mL-1 or lower indicates that administration of such allopregnanolone is likely to reduce the frequency of seizures in humans, for example, by at least about 35%, about 40%, about 45%, or about 50% after administration for 28 days, compared to the frequency of seizures during a period of 28 days prior to the first administration. The methods described herein may further include a step of measuring plasma allopregnanolone levels in a human with TSC or TSC-related epilepsy. A plasma allopregnanolone level of approximately 200 pg / ml or less is considered low and may indicate that the human may have an endogenous neurosteroid deficiency. Therefore, in some modalities, the low endogenous neurosteroid level in humans may be, for example, 200 pg / ml or less, 199 pg / ml or less, 198 pg / ml or less, 197 pg / ml or less, 196 pg / ml or less, 195 pg / ml or less, 194 pg / ml or less, 193 pg / ml or less, 192 pg / ml or less, 191 pg / ml or less, 190 pg / ml or less, 189 pg / ml or less, 188 pg / ml or less, 187 pg / ml or less, 186 pg / ml or less, 185 pg / ml or less, 184 pg / ml or less, 183 pg / ml or less, 182 pg / ml or less, 181 pg / ml or less, 180 pg / ml or less, 179 pg / ml or less, 178 pg / ml or less, 177 pg / ml or less, 176 pg / ml or less, 175 pg / ml or less, 174 pg / ml or less,173 pg / ml or less, 172 pg / ml or less, 171 pg / ml or less, 170 pg / ml or less, 169 pg / ml or less, 168 pg / mi or less, 167 pg / ml or less, 166 pg / ml or less, 165 pg / ml or less, 164 pg / ml or less, 163 pg / ml or less, 162 pg / ml or less, 161 pg / mi or less, 160 pg / ml or less, 159 pg / ml or less, 158 pg / ml or less, 157 pg / ml or less, 156 pg / ml or less, 155 pg / ml or less, 154 pg / ml or less, 153 pg / mi or less, 152 pg / ml or less, 151 pg / ml or less, 150 pg / ml or less, 149 pg / ml or less, 148 pg / ml or less, 147 pg / ml or less, 146 pg / ml or less, 145 pg / ml or less, 144 pg / ml or less, 143 pg / ml or less, 142 pg / ml or less, 141 pg / ml or less, 140 pg / ml or less, 139 pg / ml or less, 138 pg / ml or less, 137 pg / ml or less, 136 pg / ml or IVIA / a / ZUZZ / UUOU 14 less, 135 pg / ml or less, 134 pg / ml or less, 133 pg / ml or less, 132 pg / ml or less, 131 pg / ml or less, 130 pg / ml or less, 129 pg / ml or less, 128 pg / ml or less, 127 pg / ml or less, 126 pg / ml or less, 125 pg / ml or less, 124 pg / ml or less, 123 pg / ml or less, 122 pg / ml or less, 121 pg / ml or less, 120 pg / ml or less, 119 pg / ml or less, 118 pg / ml or less, 117 pg / ml or less, 116 pg / ml or less, 115 pg / ml or less, 114 pg / ml or less, 113 pg / ml or less, 112 pg / ml or less, 111 pg / ml or less, 110 pg / mi or less, 109 pg / ml or less, 108 pg / ml or less, 107 pg / ml or less, 106 pg / ml or less, 105 pg / ml or less, 104 pg / ml or less, 103 pg / mi or less, 102 pg / ml or less, 101 pg / ml or less, 100 pg / ml or less, 99 pg / ml or less, 98 pg / ml or less, 97 pg / ml or less, 96 pg / ml or less, 95 pg / ml or less, 94 pg / ml or less, 93 pg / ml or less, 92 pg / ml or less, 91 pg / ml or less, 90 pg / ml or less, 89 pg / ml or less, 88 pg / ml or less, 87 pg / ml or less, 86 pg / ml or less, 85 pg / ml or less, 84 pg / ml or less,83 pg / ml or less, 82 pg / ml or less, 81 pg / ml or less, 80 pg / ml or less, 79 pg / mi or less, 78 pg / ml or less, 77 pg / ml or less, 76 pg / ml or less, 75 pg / ml or less, 74 pg / ml or less, 73 pg / ml or less, 72 pg / ml or less, 71 pg / ml or less, 70 pg / ml or less, 69 pg / ml or less, 68 pg / ml or less, 67 pg / ml or less, 66 pg / ml or less, 65 pg / ml or less less, 64 pg / ml or less, 63 pg / ml or less, 62 pg / ml or less, 61 pg / ml or less, 60 pg / ml or less, 59 pg / ml or less, 58 pg / ml or less, 57 pg / ml or less, 56 pg / ml or less, 55 pg / ml or less, 54 pg / ml or less, 53 pg / ml or less, 52 pg / ml or less, 51 pg / ml or less, 50 pg / ml or less, 49 pg / ml or less, 48 ​​pg / ml or less, 47 pg / ml or less, 46 pg / ml or less, 45 pg / ml or less, 44 pg / ml or less, 43 pg / ml or less, 42 pg / ml or less, 41 pg / ml or less, 40 pg / ml or less, 39 pg / ml or less, 38 pg / ml or less, 37 pg / ml or less, 36 pg / ml or less, 35 pg / ml or less, 34 pg / ml or less, 33 pg / ml or less, 32 pg / ml or less, 31 pg / ml or less, 30 pg / ml or less, 29 pg / ml or less,28 pg / ml or less, 27 pg / ml or less, 26 pg / ml or less, 25 pg / ml or less, 24 pg / ml or less, 23 pg / ml or less, 22 pg / ml or less, 21 pg / ml or less, 20 pg / ml or less, 19 pg / ml or less, 18 pg / ml or less, 17 pg / ml or less, 16 pg / ml or less, 15 pg / ml or less, 14 pg / ml or less, 13 pg / ml or less, 12 pg / ml or less, 11 pg / ml or less, 10 pg / ml or less, 9 pg / ml or less, 8 pg / ml or less, 7 pg / ml or less, 6 pg / ml or less, 5 pg / ml or less, 4 pg / ml or less, 3 pg / ml or less, 2 pg / ml or less, 1 pg / ml or less, or 0 pg / ml., The present description is also directed to a method for treating CSD or CSD-related epilepsy, wherein the method comprises the steps of: determining whether the human has an allopregnanolone level of 200 pg mL-1 or less, and if the human has an allopregnanolone level of 200 pg mL-1 or less, then administering allopregnanolone orally to the human at a dose from 1 mg / kg / day to about 100 mg / kg / day, from about 2 mg / kg / day to about 80 mg / kg / day, from about 3 mg / kg / day to about 70 mg / kg / day, from about 4 mg / kg / day to about 65 mg / kg / day, from about 5 mg / kg / day to about 65 mg / kg / day, from about 6 mg / kg / day to about 65 mg / kg / day, or from about 7 mg / kg / day to around 65 mg / kg / day for at least one day. The present description is also directed to a method for treating endogenous neurosteroid deficiency in a human in need, comprising administering a pharmaceutically acceptable pregnenolone neurosteroid (e.g., ganaxolone) to the human at a dose of about 1800 mg, or less, per day, for at least 1 day, wherein the human has a genetic mutation in the TSC1 gene, located on chromosome 9q34 and / or in the TSC2 gene located on chromosome 16p13.3, and in one or more selected symptoms from the group consisting of hypomelanotic macules (>3, at least 5 mm in diameter), angiofibromas (>3) or fibrous cephalic plaque, nail fibromas (>2), shagreen patch, multiple retinal hamartomas, cortical dysplasias, subependymal nodules, subependymal giant cell astrocytomas, cardiac rhabdomyoma, lymphangioleiomyomatosis (LAM), angiomyolipomas (>2), “confetti” skin lesions, pits in dental enamel (>3), intraoral fibromas (>2), retinal achromic plaque, multiple renal cysts, non-renal hamartomas. In some of these formulations, the pharmaceutically acceptable pregnenolone neurosteroid is ganaxolone and is administered orally in amounts ranging from about 200 mg / day to about 2500 mg / day, from about 200 mg / day to about 2250 mg / day, from about 200 mg / day to about 2000 mg / day, from about 300 mg / day to about 1800 mg / day, from about 400 mg / day to about 1800 mg / day, from about 450 mg / day to about 1800 mg / day, from about 675 mg / day to about 1800 mg / day, from about 900 mg / day to about 1800 mg / day, from about 1125 mg / day to about 1800 mg / day, and from about 1350 mg / day to around 1800 mg / day, from around 1575 mg / day to around 1800 mg / day, or around 1800 mg / day, in two or three divided doses.In some modalities, humans experience seizures and administration of the pharmaceutically acceptable neurosteroid pregnenolone results in a reduction of 35% or better (e.g., about 40%, about 45%). IVIA / a / ZUZZ / UUOU 14 (approximately 50%, approximately 55%) in the mean frequency of seizures over 28 days, compared to the frequency of seizures during a 28-day period prior to the first administration. In some modalities, the improvement is 50% or more. The methods described herein may also include periodic measurements of plasma levels of the administered pharmaceutically acceptable pregnenolone neurosteroids (e.g., ganaxolone) and / or concomitant AED medication, if any, and / or allopregnanolone (3α-hydroxy-5α-pregnan-20-one) and / or related endogenous CNS-active spheroids. In some modalities, plasma levels of liver enzymes (AST, ALT, and ALK Phos) are also measured before, during, or after initiation of treatment with the pharmaceutically acceptable pregnenolone neurosteroid. Plasma levels may, for example, be measured weekly, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, every 10 weeks, every 11 weeks, or every 12 weeks. The neurosteroid pregnenolone (e.g., ganaxolone) can be administered orally or parenterally using the methods described herein on a chronic basis. In certain preferred formulations, the neurosteroid pregnenolone is ganaxolone and is administered as an oral suspension or a solid oral dosage form (e.g., oral capsule) at a dose of up to a total of 63 mg / kg / day, with ganaxolone preferably administered up to a maximum of 1800 mg / day. Ganaxolone is preferably administered chronically, for example, as long as the patient receives therapeutic benefit from the treatment without adverse side effects requiring discontinuation of treatment.In certain formulations, ganaxolone is administered for at least one day, at least two days, at least three days, two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least ten weeks, at least eleven weeks, or at least twelve weeks. In some formulations, ganaxolone can be administered for a period of time from two weeks to 100 years, or for the entire lifespan of the individual. When the neurosteroid pregnenolone is administered as an oral suspension, it can be administered, for example, anywhere from one to three times a day. In certain preferred formulations, when the neurosteroid pregnenolone (for example, ganaxolone) is administered orally, it can be administered with food (for MA / a / ZUZZ / UUOUI 4 (for better absorption) or without food. When pregnenolone neurosteroid is administered as an oral tablet or capsule, it can be administered, for example, anywhere from one to four times a day. When pregnenolone neurosteroid is administered parenterally, it can be administered, for example, anywhere from about one to three times a day, or as needed. The description also addresses in part immediate-release formulations comprising particles comprising (i) a pregnenolone neurosteroid (e.g., ganaxolone) and (ii) one or more pharmaceutically acceptable excipients (e.g., oral suspensions, tablets, or capsules), wherein the particles have a particle size that ensures the absence of agglomeration following dispersion in simulated gastrointestinal fluids (SGF and / or SIF) and does not change with storage of the formulation at 25°C / 60% RH for 1 month for use in TSC and / or TSC-related epilepsy. In preferred modalities, the formulation releases not less than about 70% or about 80% of the pregnenolone neurosteroid within 45 minutes of placing the formulation in 500 ml of a dissolving medium (e.g., 5% SLS in SGF (simulated gastric fluid) and / or 5% SLS in SIF (simulated intestinal fluid)) at 37°C + 0.5 °C in the USP 1 apparatus (basket) at 100 rpm and, after single and / or multiple dose administrations, provides a plasma level of the pregnenolone neurosteroid from about 55 ng / ml, about 60 ng / ml, or about 65 ng / ml to a plasma level of the pregnenolone neurosteroid from about 240 ng / ml to 400 ng / ml (e.g., 262 ng / ml) for a period of at least about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, or about 12 hours. In some of these modalities, the volume-weighted mean particle diameter is about 250 nm to about 450 nm (e.g., about 332 nm).In some of the modalities, the particles have a D(10) particle size from around 200 nm to around 220 nm, a D(50) particle size from around 250 nm to around 450 nm, and a D(90) particle size from around 480 nm to around 700 nm, and the formulation is free of cyclodextrins, which includes sulfoalkyl ether cyclodextrins and modified forms thereof, and is for treating TSC-related epilepsy. This description also applies in part to an immediate-release oral formulation comprising particles comprising (i) ganaxolone and (ii) one or more pharmaceutically acceptable excipients (e.g., oral suspensions, tablets, or IVIA / a / ¿U¿¿ / UUOU 14 capsules) for use in TSC and / or TSC-related epilepsy, wherein the particles have a mean particle size of about 0.3 microns (i.e., volume-weighted mean diameter (D50) of about 0.3 microns); the particle size does not change with storage of the formulation at 25°C / 60% RH for 1 month; the formulation releases not less than about 70% or about 80% of ganaxolone within 45 minutes of placing the formulation in 500 ml of a dissolving medium (e.g., 5% SLS in SGF (simulated gastric fluid) and / or 5% SLS in SIF (simulated intestinal fluid)) at 37°C + 0.5°C in the USP Apparatus 1 (Basket) at 100 rpm; the formulation provides, after a single and / or multiple doses, a plasma level of ganaxolone from about 55 ng / mL, about 60 ng / mL or about 65 ng / mL to a plasma level from about 240 ng / mL to 400 ng / mL (e.g., 262 ng / mL) for at least 6 to 12 hours after administration, and is for the treatment of TSC or TSC-related epilepsy. The plasma level of ganaxolone from around 55 ng / ml, around 60 ng / ml or around 65 ng / ml to a plasma level of around 240 ng / ml to 400 ng / ml (e.g., 262 ng / ml) can be provided after administration of the formulation on an empty stomach and / or with food. In some of these modalities, the average particle size of about 0.3 microns is critical to provide dissolution of not less than about 70% or about 80% of the pregnenolone neurosteroid 45 minutes after placing the formulation in simulated gastrointestinal fluid (SGF and / or SIF) and the plasma level of pregnenolone neurosteroid from about 55 ng / mL, about 60 ng / mL or about 65 ng / mL to a plasma level of pregnenolone neurosteroid from about 240 ng / mL to 400 ng / mL (e.g., 262 ng / mL) for a period of time of at least about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, or about 12 hours. The description is also directed in part to immediate-release formulations comprising particles comprising (i) ganaxolone and (ii) one or more pharmaceutically acceptable excipients (e.g., oral suspensions, tablets, or capsules) for use in TSC and / or TSC-related epilepsy, wherein the particles have an average particle size of about 0.3 microns; the particle size does not change with storage of the formulation at 25°C / 60% RH for 2 months and / or 3 months and / or 4 months; the formulation releases not less than 80% of ganaxolone within 45 minutes of placing the formulation in 500 ml of a dissolving medium (e.g., 5% SLS in SGF (simulated gastric fluid) and / or 5% SLS in SIF (simulated intestinal fluid)) at 37°C + 0.5°C in the USP Apparatus 1 (Basket) at 100 rpm; the formulation provides a plasma level of ganaxolone from about 55 ng / mL, about 60 ng / mL or about 65 ng / mL to a plasma level from about 240 ng / mL to 400 ng / mL (e.g., 262 ng / mL) for at least 6 to 12 hours after administration. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the baseline endogenous allopregnanolone sulfate (Allo-S) levels in female patients with PCDH19-related epilepsy, stratified as responders versus non-responders. When patients were stratified with allopregnanolone sulfate (Allo-S) levels <2.5 ng mL⁻¹, a median 50% reduction in seizure frequency (n=7) was observed compared to baseline. This analysis was performed retrospectively in a small open cohort. However, the 1.5–2 order-of-magnitude difference in allopregnanolone sulfate levels between responders and non-responders suggests that plasma allopregnanolone sulfate levels can be used to predict the efficacy of a pharmaceutically acceptable pregnenolone neurosteroid.These data provide preliminary evidence that a plasma level of allopregnanolone sulfate can be used as a predictive biomarker to prospectively identify patients who may experience an enhanced effect from ganaxolone treatment. Figure 2 shows allopregnanolone sulfate (Allo-S) levels in patients with TSC versus controls, based on plasma samples from the Biological Sample Repository. The aim was to quantify endogenous neurosteroid levels using validated proprietary analytical methods (LC / MS / MS) and compare these levels with healthy (unaffected) control samples of the same age. Plasma samples from TSC patients with epilepsy showed a trend toward reduced Allo-S levels (n=47, median 1.8 ng mL⁻¹) compared to controls (n=60, median 4.1 ng mL⁻¹). This finding was accentuated when only patients / subjects aged 1 to 14 years were isolated (n=28 TSC, n=28 controls). The patients / subjects included 29 females and 18 males. The median age of the women was 15 years (range 2-27 years). The median age of the men was 10.5 years (range 2-33 years).Fluctuations in neurosteroid levels after puberty can confound the analysis in all patients. Figure 3 represents the distribution of Allo-S in patients with TSC and unaffected subjects (all people). iviA / a / ¿u¿¿ / uuom 4 Figure 4 shows the comparison of allopregnanolone sulfate (Allo-S) in PCDH19 and TSC and the potential opportunity for expansion to explore the Allo-S biomarker in TSC. Figure 5 shows a positive correlation between allopregnanolone (Alio) and allopregnanolone sulfate (Allo-S). DETAILED DESCRIPTION Effective treatment of cerebral palsy (CP) and / or CP-related epilepsy has been challenging, and conventional treatment protocols are ineffective for many patients. In fact, approximately 70% of patients are treatment-resistant, with refractory epilepsy. Most seizures begin within the first 12 months of life, and consequently, there is a high prevalence of intellectual disability. Seizure control can mitigate these developmental consequences. Therefore, there is an urgent need for improved methods to treat CP and / or CP-related epilepsy. This description refers to novel methods for treating epilepsy syndrome (ES). As exemplified and described herein, treatment according to these methods provides a reduction in seizure frequency and / or suppression of seizures in brain shock-related epilepsy. These methods can be used to treat any form of brain shock-related epilepsy. For example, but not limited to, infantile spasms, focal motor seizures without impairment of consciousness or awareness, focal seizures with impairment of consciousness or awareness, focal seizures that evolve into bilateral seizures, tonic-clonic seizures, and generalized motor seizures, including tonic-clonic seizures, bilateral tonic seizures, bilateral clonic seizures, countable atonic / drop seizures, myoclonic seizures, or epileptic seizures. The method described herein involves administering a therapeutically effective amount of a neurosteroid to a subject. Ganoxone is the preferred neurosteroid. The methods described herein may further include the administration of ganaxolone in a therapeutically effective amount to achieve a plasma ganaxolone concentration of 100 ng / ml or higher for approximately 70% or more during a 24-hour day. This can be achieved by administering ganaxolone at least three times daily. Three times daily is preferred, although in some cases it may be appropriate. MA / a / ZUZZ / UUOUI 4 Administering ganaxolone more than three times daily is necessary to achieve the minimum desired concentration of ganaxolone. A plasma concentration of at least approximately 100 ng / ml or higher for approximately 70% or more of a 24-hour day results in improved seizure reduction and / or seizure suppression. For example, a seizure reduction of at least 20% or more compared to baseline seizure frequency can be achieved. A lower maximum dose of ganaxolone administered three times daily can achieve the minimum desired concentration of ganaxolone. Typically, a maximum daily dose of approximately 1800 mg, and preferably 1500 mg, of ganaxolone is administered. The maximum daily dose of ganaxolone is administered in equal or varying doses at at least three intervals in a 24-hour day. The methods described herein may further include determining whether a patient with CSD or CSD-related epilepsy will benefit from treatment with a neurosteroid (e.g., ganaxolone). A subpopulation of patients with CSD-related epilepsy have a low plasma concentration of Allo-S (e.g., less than 2500 pg / ml) and may respond better to treatment with ganaxolone. The methods described herein may include measuring the subject's endogenous neurosteroid level before initiating treatment with a neurosteroid (e.g., ganaxolone). A low endogenous neurosteroid level may indicate that the subject will respond to neurosteroid treatment. Once the subject has been determined to have a low endogenous neurosteroid level, a therapeutically effective amount of a neurosteroid may be administered. This document provides a further description of the method and guidance for its practice. To facilitate presentation, additional details and guidance are provided regarding a preferred aspect of ganaxolone use. It is intended that these additional details and guidance also apply to treatment with other neurosteroids. I. Definitions The mention of value ranges is intended merely as a shorthand method for referring individually to each separate value within the range, unless otherwise stated herein, and each separate value is incorporated into the description as if it were mentioned individually herein. The endpoints of all ranges are included within the range and may be combined independently. All methods described herein may be performed in any suitable order unless otherwise stated herein or clearly contradicted by the context. The use of any and all examples, or example language (e.g., such as), is intended to be merely illustrative and does not constitute a limitation on the scope of the invention unless otherwise claimed.No expression in the descriptive memorandum should be interpreted as indicating that any unclaimed element is essential to the implementation of the invention. The terms "un" and "una" do not denote a quantity limitation but rather the presence of at least one of the elements being referred to. The expression "around" is used synonymously with "approximately." As a person skilled in the art would understand, the exact limit of "around" will depend on the component of the composition. For illustrative purposes, the use of the term "around" indicates that values ​​slightly outside the quoted values, i.e., plus or minus 0.1% to 10%, are also effective and safe. Therefore, compositions slightly outside the quoted ranges are also included within the scope of these claims. An “active agent” is any compound, element, or mixture that, when administered to a patient alone or in combination with another agent, confers, directly or indirectly, a physiological effect on the patient. When the active agent is a compound, this includes salts, solvates (including hydrates) of the free compound or salt, crystalline and non-crystalline forms, as well as various polymorphs of the compound. Compounds may contain one or more asymmetric elements, such as stereogenic centers, stereogenic axes, and the like—for example, asymmetric carbon atoms—so that the compounds can exist in different stereoisomeric forms. These compounds may be, for example, racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds may also be mixtures of diastereomers.For compounds with asymmetric centers, it should be understood that all optical isomers in pure form and their mixtures are included. Furthermore, compounds with carbon-carbon double bonds may exist in Z and E forms, and all isomeric forms of these compounds are included in the present invention. In these cases, the individual enantiomers, i.e., the optically active forms, can be obtained by asymmetric synthesis, synthesis from optically pure precursors, or by resolution of the racemates. Resolution of the racemates can also be achieved, for example, by conventional methods such as crystallization in the presence of a resolving agent or chromatography using, for example, a chiral HPLC column. The term endogenous neurosteroid means a spheroid produced within the brain and capable of modulating neuronal excitability by interacting with neuronal membrane receptors and ion channels, primarily GABA-A receptors, and includes, for example, pregnane neurosteroids (e.g., allopregnanolone, allotetrahydrodeoxycorticosterone, etc.), androstane neurosteroids (e.g., androstanediol, etiocholanone, etc.) and sulfated neurosteroids (e.g., pregnanolone sulfate, dehydroepiandrosterone sulfate (DHEAS)). The term pregnenolone neurosteroid means an endogenous or exogenous steroid capable of modulating neuronal excitability by interacting with neuronal membrane receptors and ion channels, primarily GABA-A receptors, and encompasses, for example, endogenous neurosteroids and synthetic neurosteroids synthesized or derived from pregnenolone in vitro and in vivo. The term biomarker refers to a serum or plasma level of a neurosteroid that differentiates a patient who responds to a drug from one who does not. The terms serum and plasma, as described herein, may be used interchangeably. The terms comprising, including, and containing are not exhaustive. Other elements not listed may be present in the modalities claimed by these transitional phrases. When comprising, containing, or including are used as transitional phrases, other elements may be included and still form a modality within the scope of the claim. The open transitional phrase comprising encompasses the intermediate transitional phrase consisting essentially of and the closed phrase consisting of. A bolus dose is a relatively large dose of medication that is administered over a short period, for example, 1 to 30 minutes. “Cmax” is the concentration of an active agent in the plasma at the point of maximum concentration. “Ganaxolone” is also known as 3a-hydroxy-5a-pregnan-20-one, and is alternatively referred to as “GNX” herein. Infusion administration is a non-oral method, typically intravenous, although some modalities include other non-oral routes, such as epidural administration. Infusion administration occurs over a longer period than bolus administration, for example, at least 15 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 3 hours, or at least 4 hours. A “patient” is a human or non-human animal that requires medical treatment. Medical treatment includes the treatment of an existing condition, such as a disorder or injury. In certain modalities, treatment also includes prophylactic or preventive treatment, or diagnostic treatment. A child means a human being from 1 day to 18 years old (for example, from 1 day to 15 years old), which includes 18 years old. An adult means a human being over 18 years of age. “Pharmaceutical compositions” are compositions comprising at least one active agent, such as a compound or salt, solvate, or hydrate of Formula (I), and at least one other substance, such as a carrier. Pharmaceutical compositions optionally contain one or more additional active agents. When specified, pharmaceutical compositions comply with U.S. FDA GMP (Good Manufacturing Practice) standards for human and nonhuman drugs. Pharmaceutical combinations are combinations of at least two active agents that may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat a disorder, such as a seizure disorder. Povidone, also known as polyvinylpyrrolidone (PVP), is a water-soluble polymer made from the monomer N-vinylpyrrolidone. Plasdone C-12 and C-17 are pharmaceutical-grade homopolymers of N-vinylpyrrolidone. Plasdone C-12 has a K value of 10⁻²–13.8 and a nominal molecular weight of 4000 d. Plasdone C-17 has a K value of 15.5–17.5 and a nominal molecular weight of 10,000 d. “Sterilize” means to substantially inactivate all biological contaminants in a sample, formulation, or product. A 1 million-fold reduction in bioburden is also considered sterile for most pharmaceutical applications. The term “reducing” seizures or seizure activity refers to a detectable decrease in the frequency, severity, and / or duration of seizures. A reduction in the frequency, severity, and / or duration of seizures can be measured. MA / a / ZUZZ / UUOUI 4 through self-assessment (e.g., through patient reports) or by a trained clinical observer. The determination of a reduction in the frequency, severity, and / or duration of seizures can be made by comparing the patient's condition before and after treatment. A therapeutically effective amount (TEA) is the quantity of a pharmaceutical agent required to achieve a pharmacological effect. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An effective amount of neurosteroid is the quantity necessary to achieve a desired pharmacological effect or therapeutic improvement without undue adverse side effects. The effective amount of neurosteroid will be selected by experts in the technique depending on the individual patient and the condition. It is understood that an effective amount or a therapeutically effective amount may vary from one individual to another due to variations in neurosteroid metabolism, age, weight, the individual's general condition, the condition being treated, the severity of the condition being treated, and the treating physician's judgment. Treating or treatment refers to any treatment of a disorder or disease, such as inhibiting the disorder or disease, for example, stopping the development of the disorder or disease, relieving the disorder or disease, causing the regression of the disorder or disease, alleviating a condition caused by the disease or disorder, or reducing the symptoms of the disease or disorder. “Alkyl” is a saturated aliphatic hydrocarbon group, either straight-chain or branched, having a specified number of carbon atoms, generally from 1 to about 8 carbon atoms. The term Ci-Ce alkyl, as used herein, indicates an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Other forms include alkyl groups having 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 or 2 carbon atoms, for example, Ci-Cs alkyl, C1-C4 alkyl, and C1-C2 alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, t-butyl, n-pentyl, and sec-pentyl. “Aryl” indicates aromatic groups containing only carbon in the aromatic ring or rings. Typical aryl groups contain 1 to 3 separate, fused, or dangling rings and 6 to about 18 ring atoms, with no heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Aryl groups include, for example, phenyl, naphthyl, which includes 1-naphthyl, 2-naphthyl, and biphenyl. An arylalkyl substituent is an aryl group as defined herein, linked to the group it replaces via an alkylene linker. The alkylene is an alkyl group as described herein except that it is divalent. “Cycloalkyl” is a saturated hydrocarbon ring group with a specified number of carbon atoms. Monocyclic cycloalkyl groups typically have 3 to about 8 carbon atoms in the ring, or 3 to 6 (3, 4, 5, or 6) carbon atoms in the ring. Cycloalkyl substituents can be either a substituted nitrogen, oxygen, or carbon atom, or a substituted carbon atom. A cycloalkyl group can have two substituents attached to the ring, which is linked as a spiro group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A heteroalkyl group is an alkyl group as described with at least one carbon replaced by a heteroatom, e.g., N, O, or S. The term "substituted," as used herein, means that one or more hydrogens on the designated atom or group are replaced with a selection from the indicated group, provided that the normal valency of the designated atom is not exceeded. When the substituent is oxo (i.e., =0), then two hydrogens on the atom are replaced. When an oxo group substitutes a heteroaromatic moiety, the resulting molecule may sometimes adopt tautomeric forms. For example, a pyridyl group substituted by oxo at position 2 or 4 may sometimes be written as a pyridine or hydroxypyridine. Combinations of substituents and / or variables are permitted only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is intended to denote a compound that is robust enough to survive isolation from a reaction mixture and subsequent formulation into an effective therapeutic agent.Unless otherwise stated, substituents are named after the core structure. For example, it should be understood that aminoalkyl means that the point of attachment of this substituent to the core structure is on the alkyl portion, and alkylamino means that the point of attachment is a bond to the nitrogen of the amino group. Suitable groups that may be present in a substituted or optionally substituted position include, but are not limited to, for example, halogen; cyano; -OH; oxo; -NH2; nitro; azido; alkanoyl (such as a C2-Ce alkanoyl group); C(O)NH2; alkyl groups (including cycloalkyl and (cycloalkyl)alkyl groups) having from 1 to 8 atoms MA / a / ZUZZ / UUOUI 4 carbon, or from 1 to 6 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated bonds and from 2 to about 8, or from 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen bonds and from 1 to about 8, or from 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those having one or more thioether bonds and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those having one or more sulfinil bonds and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; alkylsulfonyl groups that include those having one or more sulfonyl linkages and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms;aminoalkyl groups including groups having one or more N atoms and from 1 to about 8, or from 1 to about 6 carbon atoms; mono- or dialkylamino groups including groups having alkyl groups from 1 to about 6 carbon atoms; mono- or dialkylaminocarbonyl groups (i.e., alkylINHCO- or (alkyl1)(alkyl2)NCO-) having alkyl groups from about 1 to about 6 carbon atoms; aryl having 6 or more carbons. II. Tuberous sclerosis complex Tuberous sclerosis complex (TSC) is a multisystem disorder of embryonic cortical development that can affect many organs through the overgrowth of benign tumors known as hamartomas. A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, lung disease, and kidney disease. While the TSC disease phenotype can be extremely variable, neurological manifestations such as epilepsy are observed in up to 90% of patients with TSC (Krueger et al., 2013). The condition is caused by inherited mutations in the TSC1 gene, located on chromosome 9q34, or in the TSC2 gene, located on chromosome 16p13.3. TSC occurs with a frequency of 1 in 6,000, and a mutation is found in 85% of patients (Jülich & Sahin, 2014).The gene products hamartin (TSC1) and tuberin (TSC2) form a regulatory complex responsible for limiting the activity of mammalian target of rapamycin complex 1 (mTORCI), an important intracellular regulator of growth and metabolism, through its inhibition of the brain-enriched Ras homolog (Rheb) small GTPase (Krueger et al., 2013). Everolimus, an mTOR inhibitor, has been shown to reduce seizures (French et al., 2016; Mizuguchi et al., 2019). TSC is one of the most common genetic causes of epilepsy, with a MA / a / ZUZZ / UUOUI 4 Seizure semiology varies according to age of onset (Jülich & Sahin, 2014). Effective treatment options include the use of adrenocorticotropic hormone (ACTH), which includes a possible mechanism that aligns with the use of allopregnanolone. ACTH has been shown to have stimulatory effects on deoxycorticosterone (DOC), which undergoes further synthesis into several neurosteroids. Specifically, ACTH has been shown to rapidly increase endogenous plasma and brain levels of allopregnanolone, which could potentially further explain its beneficial effect on seizure insufficiency. Infantile spasms (IS) are the most common type of seizure in childhood and represent the first manifestation of epilepsy in 50% of patients. In older children and adults, focal seizures with impaired consciousness (formerly known as complex partial seizures) are the most common. Other focal and generalized seizures can also occur, and more than 30% of patients develop treatment-refractory epilepsy (Jülich & Sahin, 2014). While seizures have generally been attributed to the tubercles and surrounding cortex, epilepsy in TSC can be considered multifactorial, as seizures can originate in other brain areas or can occur in patients with TSC without tubercles (Jülich & Sahin, 2014). Definitive clinical diagnosis of TSC that includes two major features or one major feature with >2 minor features from Table 7 below. Table 7. IVIA / a / ZUZZ / UUOU 14 Main features Minor features 1. Hypomelanotic macules (>3, at least 5 mm in diameter) 2. Angiofibromas (^3) or fibrous cephalic plaque 3. Nail fibromas (>2) 4. Shad skin patch 5. Multiple retinal hamartomas 6. Cortical dysplasias* 7. Subependymal nodules 1. Confetti-like skin lesions 2. Dental enamel pits (>3) 3. Intraoral fibromas (>2) 4. Achromic retinal patch 5. Multiple renal cysts 6. Non-renal hamartomas 8. Subependymal giant cell astrocytomas 9. Cardiac rhabdomyoma 10. Lymphangioleiomyomatosis (LAM)** 11. Angiomyolipomas (>2)** IVIA / a / ZUZZ / UUOU 14 *Includes tubercles and radial migration lines of cerebral white matter **A combination of the two main clinical features (LAM and angiomyolipomas) without other features that does not meet the criteria for a definitive diagnosis. Gamma-aminobutyric acid (GABA) appears to play a central role in the development of TSC-related epilepsy, possibly due to altered expression of endogenous GABAa receptor modulators (di Michele et al., 2003). There is evidence supporting a deficiency of the neuroactive steroid 3α,5α-tetrahydroprogesterone (THP), or allopregnanolone, as a contributor to epileptogenesis in TSC. Allopregnanolone is a positive modulator of the GABAA receptor and has been shown to have antiepileptic effects in experimental animals and humans. There is a decrease in allopregnanolone relative to its functional GABAA antagonist, 3β-THP, in patients with TSC-related epilepsy, but not in TSC patients without epilepsy or in controls (di Michele et al., 2003). This reduced ratio could alter neuronal excitability mediated by GABAA receptors, leading to the development of epilepsy. The role of GABAA receptor mediation is also supported by the greater efficacy of vigabatrin, a specific and irreversible inhibitor of GABAaminotransferase, in TSC seizures compared to other epilepsies (di Michele et al., 2003). Patients with TSC and epilepsy have reduced levels of endogenous neurosteroids, particularly Alio, similar to previous reports in PCDH19. About 25% of all patients with TSC have a plasma level of allopregnenalone sulfate below 6 ng / ml. Neuroactive spheroids with anticonvulsant properties may be useful in the treatment of cerebral palsy (CP) and CP-related epilepsy. These spheroids can enhance GABAA-mediated signaling and improve not only seizure control but also behavioral abnormalities in individuals with CP and CP-related epilepsy. Upregulation of the TSC-mTOR pathway leads to an increased inflammatory response, with evidence of enhanced pro-inflammatory signaling of TLR4 receptor. Neurosteroids, including Alio, have been shown to act as inhibitors of several neuroinflammatory pathways, including TLR4, expanding the mechanism of action of these compounds beyond the upregulation of GABAA receptors. III. Neurosteroids Endogenous neurosteroids play a fundamental role in maintaining brain activity homeostasis. Neurosteroids have the capacity to rapidly induce brain changes in response to alterations in the brain environment. They lack interactions with classical steroid hormone receptors that regulate gene transcription; instead, they modulate brain excitability primarily through interaction with neuronal membrane receptors and ion channels.Neurosteroids can be positive or negative regulators of GABAa receptor function, depending on the chemical structure of the spheroid molecule (Pinna and Rasmussen, 2014; Reddy, 2003). The GABAa receptor mediates most synaptic inhibition in the CNS. Structurally, GABAa receptors are heteropentamers of five protein subunits that form chloride ion channels. There are seven different classes of subunits, some of which have multiple homologous variants (α16, β1–3, γ1–3, σ1–3, δ, ε, δ); most GABAa receptors are composed of α, β, and either γ or δ subunits. The neurotransmitter GABA activates the opening of chloride ion channels, allowing chloride ions to enter and resulting in hyperpolarization. GABAa receptors prevent the generation of an action potential by diverting the depolarization produced by excitatory neurotransmission.There are two types of inhibitory neurotransmission mediated by GABAa receptors: synoptic (phasic) and extrasynaptic (tonic) inhibition. Neurosteroids modulate both synoptic and extrasynaptic GABAa receptors and thus potentiate both phasic and tonic currents. Phasic inhibition results from the activation of γ2-containing receptors at the synapse through the intermittent release of millimolar concentrations of GABA from the axon terminals of presynaptic GABAergic interneurons. Tonic inhibition, on the other hand, is mediated by the continuous activation of extrasynaptic receptors. MA / a / ZUZZ / UUOUI 4 contain δ outside the synaptic cleft due to low levels of ambient GABA that escaped reuptake by GABA transporters. Tonic inhibition plays a unique role in controlling hippocampal excitability by establishing a baseline excitability value (Reddy 2010). Neurosteroids such as ganaxolone are potent positive allosteric modulators of GABAa receptors (Akk et al., 2009). The first observation that neurosteroids enhance GABA-evoked responses mediated by GABAa receptors was reported in 1984 with alfaxolone (Harrison and Simmonds, 1984). This modulatory effect of neurosteroids occurs by binding to discrete sites on the GABAa receptor located within the transmembrane domains of the α and β subunits (Hosier et al., 2007; Hosier et al., 2009). The binding sites of neurosteroids are distinct from those of GABA, benzodiazepines, and barbiturates. Although the exact locations of neurosteroid binding sites are currently unknown, a highly conserved glutamine at position 241 in the M1 domain of the a subunit has been shown to play a key role in neurosteroid modulation (Hosie et al, 2009).In addition to their binding sites, neurosteroids and benzodiazepines also differ in their interactions with GABAa receptors. While neurosteroids modulate most GABAa receptor isoforms, benzodiazepines act only on GABAa receptors containing α2 subunits and lacking α4 or α6 subunits (Lambert et al., 2003; Reddy, 2010). The specific α subunit can influence the efficacy of neurosteroids, while the type of γ subunit can affect both the efficacy and potency of neurosteroid modulation of GABAa receptors (Lambert et al., 2003). Recent studies have indicated the existence of at least three neurosteroid binding sites on the GABAa receptor: one for allosteric enhancement of GABAa-evoked currents by allopregnanolone, one for direct activation by allopregnanolone, and one for antagonistic action of sulfated neurosteroids such as pregnanolone sulfate at low (nM) concentrations (Lambert et al., 2003; Hosie et al., 2007). Neurosteroid enhancement of GABAa receptor chloride currents occurs through increases in both channel opening frequency and channel opening duration (Reddy, 2010). Therefore, neurosteroids greatly increase the likelihood of GABAa receptor chloride channel opening, allowing a massive influx of chloride ions, which promotes increased inhibitory GABAergic transmission. These effects occur at physiological concentrations of neurosteroids.Therefore, endogenous neurosteroid levels continuously modulate the function of GABAa receptors (Reddy, 2010). The extrasynaptic δ subunit containing GABAa receptors exhibits increased sensitivity to neurosteroids, suggesting a key modulatory role in tonic inhibition (Wohlfarth et al., 2002). GABAa receptors containing the δ subunit are more sensitive to neurosteroid-induced potentiation of GABA responses (Stell et al., 2003). Mice lacking the δ subunit show drastically reduced sensitivity to neurosteroids (Mihalek et al., 1999). The δ subunit does not contribute to the neurosteroid binding site, but it appears to confer greater transduction of neurosteroid action after the neurosteroid has bound to the receptor. GABAa receptors containing the δ subunit have a low degree of desensitization, which facilitates the mediation of tonic GABAa receptor currents that are activated by ambient concentrations of GABA in the extracellular space.The tonic current of the GABAa receptor causes constant inhibition of neurons and reduces their excitability. GABA is a relatively low-efficacy agonist of δa-containing GABAa receptors, despite binding with high affinity (Glykys and Mody, 2007). Therefore, neurosteroids can markedly increase the current generated by δa-containing GABAa receptors even in the presence of saturated GABA concentrations. During neuronal activity, substantial GABA release is expected from active GABAergic interneurons, which can interact with the perisynaptic and extrasynaptic δa subunits of GABAa receptors. Overall, the robust effect of neurosteroids is likely due to their action on synaptic and perisynaptic / extrasynaptic GABAa receptors (Reddy, 2010). Pregnane neurosteroids and pregnenolone neurosteroids are a class of compounds useful as anesthetics, sedatives, hypnotics, anxiolytics, antidepressants, antitremor agents, treatments for autistic behavior, and anticonvulsants. These compounds are characterized by very low aqueous solubility, which limits their formulation options. Nanoparticle formulations of pregnane and pregnenolone neurosteroids, which are bioavailable orally and parenterally, can be used. Injectable formulations of pregnane neurosteroids and pregnenolone neurosteroids are particularly desirable since these compounds are used for clinical indications where oral administration is excluded, such as anesthesia and IVIA / a / ZUZZ / UUOU 14 particularly for the emergency treatment of active seizures. The description includes injectable nanoparticle neurosteroid formulations. The pregnane neurosteroid and the pregnenolone neurosteroid of the present invention may each be a compound of Formula IA: Formula IA or a pharmaceutically acceptable salt thereof, where: XesO, SoNR10; R1 is hydrogen, hydroxyl, -CH2A, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl or optionally substituted arylalkyl; A is hydroxyl, O, S, NR11, or five-membered heteroaryl containing optionally substituted nitrogen or bicyclic heteroaryl containing optionally substituted nitrogen or bicyclic heterocyclyl, R4 is hydrogen, hydroxyl, oxo, optionally substituted alkyl or optionally substituted heteroalkyl, R2, R3, R5, R6 and R7 are each independently absent, hydrogen, hydroxyl, halogen, an optionally substituted Ci-Ce alkyl, an optionally substituted Ci-Ce alkoxyl (e.g., methoxyl) or an optionally substituted heteroalkyl; R8 and R9 are each independently selected from a group consisting of hydrogen, a Ci-Ce alkyl (e.g., methyl), a halogenated C1-C6 alkyl (e.g., trifluoromethyl) or a Ci-Ce alkoxy (e.g., methoxy), or R8 and R9 form an oxo group; R10 is hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl or optionally substituted arylalkyl where each alkyl is a C1-C10 alkyl, C3-C6 cycloalkyl, Cs-C6 cycloalkyl, C1-C4 alkyl, and optionally contains a single bond replaced by a double or triple bond; each heteroalkyl group is an alkyl group in which one or more methyl groups are replaced by independently chosen -O-, -S-, -N(R10)-, -S(=O)- or -S(=O)2-, where R10 is hydrogen, alkyl or alkyl in which one or more methylene groups are replaced by -O-, -S-, -NH or -N-alkyl; R11es -H2o-HR12; R12is Ci-Ce alkyl or Ci-Ce alkoxy. The pregnane neurosteroid and the pregnenolone neurosteroid of the present invention may each be a compound of Formula IA, where XesO; R1is hydrogen, -CH3, -CH2OH, 1H-imidazol-1-yl, 1-oxidoquinolin-6-yloxyl and 4-cyano-1 / 7pyrazol-T-yl. R4 is hydrogen, hydroxyl, oxo, optionally substituted alkyl or optionally substituted heteroalkyl, R2, R3, R5, R6 and R7 are each independently absent, hydrogen, hydroxyl, halogen, an optionally substituted C1-C6 alkyl, an optionally substituted C1Ce alkoxyl (e.g., methoxyl) or an optionally substituted heteroalkyl; R8 and R9 are each independently selected from a group consisting of hydrogen, a Ci-Ce alkyl (e.g., methyl), a halogenated Ci-Ce alkyl (e.g., trifluoromethyl) or a Ci-Ce alkoxy (e.g., methoxy), or R8 and R9 form an oxo group; R10 is hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl or optionally substituted arylalkyl where each alkyl is a C1-C10 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)C1-C4 alkyl, and optionally contains a single bond replaced by a double or triple bond; Each heteroalkyl group is an alkyl group in which one or more methyl groups are replaced by independently chosen -O-, -S-, -N(R10)-, -S(=O)- or -S(=O)2-, where R10 is hydrogen, alkyl or alkyl in which one or more methylene groups are replaced by -O-, -S-, -NH or -N-alkyl. The pregnane neurosteroid and the pregnenolone neurosteroid of the present invention may each be a compound of Formula IB MA / a / ZUZZ / UUOUI 4 MA / a / ZUZZ / UUOUI 4 or a pharmaceutically acceptable salt thereof, where: XesO, SoNR10; R1 is hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl or optionally substituted arylalkyl; R4 is hydrogen, hydroxyl, oxo, optionally substituted alkyl or optionally substituted heteroalkyl, R2, R3, R5, R6 and R7 are each independently hydrogen, hydroxyl, halogen, optionally substituted alkyl or optionally substituted heteroalkyl; R8 is hydrogen or alkyl and R9 is hydroxyl; or R8 and R9 are taken together to form an oxo group; R10 is hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl or optionally substituted arylalkyl where each alkyl is a C1-C10 alkyl, Ca-Ce cycloalkyl, (Cs-Ce cycloalkyl or C1-C4 alkyl, and optionally contains a single bond replaced by a double or triple bond; Each heteroalkyl group is an alkyl group in which one or more methyl groups are replaced by independently chosen -O-, -S-, -N(R10)-, -S(=O)- or -S(=O)2-, where R10 is hydrogen, alkyl or alkyl in which one or more methylene groups are replaced by -O-, -S-, -NH or -N-alkyl. Compounds of formula IA and IB include, for example, allopregnanolone, ganaxolone, alfaxalone, alfadolone, hydroxydione, minaxolone, pregnanolone, acebrochol or tetrahydrocorticosterone and their pharmaceutically acceptable salts. The pregnane neurosteroid and the pregnenolone neurosteroid of the present invention may also each be a compound of Formula II: IVIA / a / ZUZZ / UUOU 14 Formula II or a pharmaceutically acceptable salt thereof, where: XesO, SoNR10; R1 is hydrogen, hydroxyl, -CH2A, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl or optionally substituted arylalkyl; A is hydroxyl, O, S, NR11o bicyclic heteroaryl containing optionally substituted nitrogen or bicyclic heterocyclyl, R4 is hydrogen, hydroxyl, oxo, optionally substituted alkyl or optionally substituted heteroalkyl, R2, R3, R5, R6 and R7 are each independently absent, hydrogen, hydroxyl, halogen, an optionally substituted Ci-Ce alkyl, an optionally substituted C1Ce alkoxyl (e.g., methoxyl) or an optionally substituted heteroalkyl; R8 and R9 are each independently selected from a group consisting of hydrogen, a Ci-Ce alkyl (e.g., methyl), a halogenated Ci-Ce alkyl (e.g., trifluoromethyl) or a Ci-Ce alkoxy (e.g., methoxy), or R8 and R9 form an oxo group; R10 is hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl or optionally substituted arylalkyl where each alkyl is a C1-C10 alkyl, C3-C6 cycloalkyl, Cs-C6 cycloalkyl, C1-C4 alkyl, and optionally contains a single bond replaced by a double or triple bond; each heteroalkyl group is an alkyl group in which one or more methyl groups are replaced by independently chosen -O-, -S-, -N(R10)-, -S(=O)- or -S(=O)2-, where R10 is hydrogen, alkyl or alkyl in which one or more methylene groups are replaced by -O-, -S-, -NH or -N-alkyl; R11es -H20-HR12: R12is Ci-Ce alkyl or Ci-Ce alkoxy. The pregnane neurosteroid and the pregnenolone neurosteroid of the present invention may also each be a compound of Formula III: r! ινΐΛ / a / zuzz / uuou 14 Formula III or a pharmaceutically acceptable salt thereof, where: XesO.SoNR10; R1 is hydrogen, hydroxyl, -CH2A, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl or optionally substituted arylalkyl; A is hydroxyl, O, S, NR11o bicyclic heteroaryl containing optionally substituted nitrogen or bicyclic heterocyclyl, R4 is hydrogen, hydroxyl, oxo, optionally substituted alkyl or optionally substituted heteroalkyl, R2, R3, R5, R6 and R7 are each independently absent, hydrogen, hydroxyl, halogen, an optionally substituted Ci-Ce alkyl, an optionally substituted C1Ce alkoxyl (e.g., methoxyl) or an optionally substituted heteroalkyl; R8 and R9 are each independently selected from a group consisting of hydrogen, a Ci-Ce alkyl (e.g., methyl), a halogenated C1-C6 alkyl (e.g., trifluoromethyl) or a Ci-Ce alkoxy (e.g., methoxy), or R8 and R9 form an oxo group; R10 is hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl or optionally substituted arylalkyl where each alkyl is a C1-C10 alkyl, C3-C6 cycloalkyl, Cs-C6 cycloalkyl, C1-C4 alkyl, and optionally contains a single bond replaced by a double or triple bond; each heteroalkyl group is an alkyl group in which one or more methyl groups are replaced by independently chosen -O-, -S-, -N(R10)-, -S(=O)- or -S(=O)2-, where R10 is hydrogen, alkyl or alkyl in which one or more methylene groups are replaced by -O-, -S-, -NH or -N-alkyl; R11es -H2o-HR12: R12 is C1-C6 alkyl or C1-C6 alkoxy. a) Ganaxolone Ganaxolone (CAS reg. 38398-32-2, 3α-hydroxy-3p-methyl-5α-pregnan-20-one) is the synthetic 3p-methylated analogue of allopregnanolone, an endogenous allosteric modulator of CNS GABAA receptors. The structural formula of ganaxolone is: either hydroxy. 311-methyl-5u-picgii;in-2ii-one Ganaxolone Ganaxolone has comparable potency and efficacy to allopregnanolone in activating synaptic and extrasynaptic GABAA receptors at a site distinct from that of benzodiazepines and barbiturates (Carter 1997). Ganaxolone has protective activity in various rodent seizure models (Reddy 2012, Bialer 2010). Clinical studies have demonstrated that ganaxolone has anticonvulsant activity with an acceptable safety and tolerability profile in the 900–1800 mg dose range in adults and children (Sperling 2017, Laxer 2000, Kerrigan 2000, Pieribone 2007). Furthermore, ganaxolone reduces seizures in children with systemic ischemic attack (SI) and refractory pediatric epilepsy. In an open-label (OL) study, pediatric patients aged 2 to 60 months with refractory seizures and a history of IS were treated with ganaxolone doses up to 36 mg / kg for up to 3 months (Kerrigan 2000).Sixteen of the 20 patients completed treatment, 15 of whom had a history of ischemic stroke. Five of the 15 patients experienced a reduction from baseline in the number of spasms of >50%, five experienced a reduction of 25–50%, and five experienced a reduction of <25%. One patient became spasm-free, and one non-responder (with a reduction of <25%) was spasm-free between weeks 2 and 7. In addition to its anticonvulsant activity, ganaxolone has been shown to reduce anxiety, hyperactivity, and attention deficit in children with Fragile X syndrome (Ligsay 2016). Similar behavioral problems occur in individuals with TSC, with rates of approximately 50% for ADHD and autism (Jülich & Sahin, 2014). Therefore, ganaxolone treatment may increase GABAA-mediated signaling and improve not only seizure control but also behavioral abnormalities in individuals with TSC and TSC-related epilepsy. Ganaxolone has the same core chemical structure as allopregnanolone, but with the addition of a 3β methyl group designed to prevent conversion back to an active entity at nuclear hormone receptors, thus eliminating the possibility of unwanted hormonal effects and improving the bioavailability of the neurosteroid and preserving its desired CNS activity. Like allopregnanolone, ganaxolone (a neuroactive steroid) exhibits potent antiepileptic, anxiolytic, sedative, and hypnotic activities in animals through allosteric modulation of gamma-aminobutyric acid type A (GABAA) receptors in the central nervous system (CNS). Ganaxolone has comparable potency and efficacy to allopregnanolone in activating synaptic and extrasynaptic GABAA receptors at a site distinct from the benzodiazepine site. Ganaxolone acts by interacting with synaptic and extrasynaptic GABAa receptors at binding sites that are unique to this class. Outside the synapse, ganaxolone can be absorbed into the cell membrane and diffuse to activate extrasynaptic GABAa receptors, providing a steady or tonal modulation of the inhibitory GABA signal that calms overexcited neurons. Ganaxolone is insoluble in water. Its solubility in 95% alcohol, propylene glycol, and polyethylene glycol is 13 mg / mL, 3.5 mg / mL, and 3.1 mg / mL, respectively. Ganaxolone is primarily metabolized by the CYP3A family of liver enzymes, but interactions based on liver metabolism are limited to those caused by induction or inhibition of CYP3A4 / 5 by other drugs such as ketoconazole. In vitro, ganaxolone elimination appears to be primarily driven by CYP3A4. In clinical studies in adults, grapefruit administration increased ganaxolone exposure in healthy volunteers. Ganaxolone levels were reduced in patients concomitantly treated with enzyme-inducing AEDs. These data further support the hypothesis that CYP3A4 is a major contributor to ganaxolone elimination in humans. In adults, plasma concentrations of ganaxolone after oral administration are characterized by high variability. Single-dose pharmacokinetic parameters were strongly influenced by the rate and extent of ganaxolone absorption, and whether subjects were fasting or had eaten. In the pediatric population, CYP3A4 expression levels approach those of adults at approximately 2 years of age (de Wildt et al., 2003), although with a high degree of interindividual variability. Therefore, patients older than 2 years would be expected to have ganaxolone elimination rates similar to those of adults. Ganaxone has a relatively long half-life: approximately 20 hours in human plasma after oral administration (Nohria, V. and Giller, E., Neurotherapeutics, (2007) 4(1): 102-105). Furthermore, ganaxolone has a short Tmax, meaning that therapeutic blood levels are reached rapidly. Therefore, initial bolus doses (loading doses) may not be required, which is an advantage over other treatments. Ganaxone is useful for treating seizures in adult and pediatric epileptic patients. Ganaxolone affects GABAA receptors by interacting with a recognition site that is distinct from other allosteric modulators of GABAA receptors, such as benzodiazepines. Ganaxolone binds to both intra- and extrasynaptic receptors, mediating both phasic and tonic modulation, respectively. Ganaxolone's unique binding to these two receptors does not lead to the tolerance observed with benzodiazepines. Unlike allopregnanolone, ganaxolone is orally bioavailable and cannot be converted in the body to intermediates such as progesterone, which has classic steroid hormone activity. As such, it does not directly or indirectly activate the progesterone receptor through metabolic conversion. Ganaxone administered intravenously was also evaluated and shown to induce electroencephalogram (EEG) patterns similar to burst suppression in otherwise normal rats and to block the seizure response in models representing clinical status epilepticus (SE). Ganaxone induced a sedative response but did not induce a complete anesthetic response. In addition to its anticonvulsant activity, ganaxolone has been shown to have anxiolytic properties and to improve behaviors associated with autism. In a mouse model of post-traumatic stress disorder (PTSD), treatment with ganaxolone decreased aggression and anxiety-like behavior induced by social isolation (Pinna & Rasmussen, 2014). In another study, ganaxolone treatment improved sociability in the BTBR mouse model of autism (Kazdoba et al., 2016). A clinical study of ganaxolone treatment in children and adolescents with fragile X syndrome (FXS) showed that ganaxolone reduced anxiety and hyperactivity and improved attention in those with higher baseline anxiety (Ligsay et al., 2017). Ganaxalone did not interact with the human ether-a-go-go gene-related receptor (hERG) at a measured concentration of 70 nM (n=2). Ganaxalone had no effect on cardiovascular parameters in dogs after a single dose of up to 15 mg / kg (peak concentration [Cmax] of 1000 ng / mL and area under the concentration-time curve [AUC] (0-24) of 10,000 ng-h / mL). In the 1-year toxicity study in dogs (Cmax >1500 ng / mL), transient sinus tachycardia (>190 beats per minute [bpm]) was observed after 3 months of dosing in 4 animals and was accompanied by a decrease in PR and QT intervals, but no treatment effect on QRS duration or corrected QT interval (QTc). No pulmonary effects were observed in female rats at doses up to 40 mg / kg. There was a physiologically normal shortening of the PR and QT intervals in response to the higher heart rate. There was no effect on QRS duration or QTc interval. No pulmonary effects were observed in female rats at doses up to 40 mg / kg. Ganaxalone induces the major cytochrome P450 (CYP) isoenzymes 1A1 / 2 and 2B1 / 2 in female rats but not in males. Autoinduction has also been observed in mice and rats, while not in dogs. Tissue distribution studies in mice and rats have shown that [14C]ganaxolone was rapidly distributed throughout the body in highly perfused organs, intestine, and adipose tissue, with brain concentrations of ganaxolone approximately 5 times higher than those in plasma. Most of the radioactivity excreted in all species is done through feces (>70%) and the rest is excreted in urine. The most common effect following ganaxalone treatment in toxicology studies was dose-related sedation, an expected pharmacological effect of a positive modulator of GABAa receptors. In both the oral and IV regimens, there was little evidence of systemic or target organ toxicity associated with single- or multiple-dose ganaxalone treatment. No functional or anatomical changes were observed in hematopoietic tissue or in any specific organs such as the liver, kidneys, or gastrointestinal (GI) systems in repeated-dose studies. In rats, ganaxalone MA / a / ZUZZ / UUOUI 4 induced liver enzymes, with more pronounced effects in females, which correlated with increased liver weight and dose-related hepatocellular hypertrophy in a 6-month study. In the chronic oral toxicity study in dogs, mean Cmax levels above 1500 ng / mL (10 and 15 mg / kg / day) were associated with increased weight and total plasma cholesterol levels. When administered intravenously to rats and dogs, the primary dose-limiting toxicity finding was sedation. The no observed adverse effect level (NOAEL) after IV dosing in rats for 14 days was established at 42 mg / kg / day for males and 30 mg / kg / day for females. The NOAEL in dogs after IV bolus administration of ganaxalone followed by continuous IV infusion for 28 days was 7.20 mg / kg / day, corresponding to steady-state concentrations of approximately 330 ng / mL and 333 ng / mL. No findings were observed in a local tolerance study in rabbits. Finally, ganaxalone did not cause hemolysis in vitro and was compatible with human plasma. Ganaxalone was not teratogenic in rats or mice and did not significantly affect offspring development. Ganaxalone had no effect on fertility or early embryonic development in rats. No mutagenic potential was detected. Treatment of newborn rats with ganaxalone produced the expected signs of sedation but did not affect development or show any postmortem changes. b) Allopregnalone Allopregnanolone (CAS Reg. No. 516-54-1, 3a,5a-tetrahydroprogesterone) is an endogenous progesterone derivative with anticonvulsant activity. ..1' ..................! i......rII II I in II u / .5( / -Tetrahydroprogesterone Allopregnanolone Allopregnanolone has a relatively short half-life, of about 45 minutes in human plasma. Allopregnanolone exhibits potent antiepileptic, anxiolytic, sedative, and hypnotic activities in animals by virtue of its GABAA receptor modulating activity. In addition to its efficacy in treating seizures, allopregnanolone is being evaluated for use in treating neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, and for treating lysosomal storage disorders characterized by abnormalities in cholesterol synthesis, such as Niemann-Pick A, B, and C, Gaucher disease, and Tay-Sachs disease. (See US 8,604,011, which is incorporated herein by reference for its teachings regarding the use of allopregnanolone to treat neurologic disorders.) The relationship between progesterone and its metabolite, allopregnanolone, and seizures has been extensively studied in women with catamenial epilepsy, a condition in which seizure frequency changes with different phases of the menstrual cycle. Sometimes, during the menstrual cycle, when progesterone levels are lower (e.g., perimenopause), the likelihood of seizures tends to increase (French 2005). Circulating levels of allopregnanolone parallel those of progesterone. While the reproductive effects of progesterone are related to its interaction with intracellular progesterone receptors, the anticonvulsant effects of progesterone are not (Reddy and Rogawski 2009). The anticonvulsant activity of progesterone results from its conversion to the neurosteroid allopregnanolone (Kokate et al., 1999).Allopregnanolone has been shown to protect against seizure activity in several animal models due to its effects on GABAA receptors (Reddy and Rogawski 2009). Ganaxolone, a synthetic analogue of allopregnanolone without progesterone-related effects, may be useful in the treatment of TSC-related epilepsy. c) Alfaxalone Alfaxalone, also known as alfaxalone, (CAS Reg. No. 23930-19-0, 3α-hydroxy-5α-pregnan-11,20-dione) is a neurosteroid with anesthetic activity. It is used as a general anesthetic in veterinary practice. Anesthetics are frequently administered in combination with anticonvulsants for the treatment of refractory seizures. An injectable nanoparticle neurosteroid dosage form containing alfaxalone alone or in combination with alfaxalone or allopregnanolone is within the scope of the MA / a / ZUZZ / UUOUI 4 present description. (· 'V...... 1 < ...........! ......Ϊ.....ΐ-- / II II ||( II IVIA / a / ZUZZ / UUOU 14 μ / - hydroxy -?u- pregnane -1 1.2(t-dione Alfaxalone d) Alfadolone Alphadolone, also known as Alfadolone, (CAS Reg. No. 14107-37-0, 3α,21-dihydroxy-5α-pregnan-11,20-dione) is a neurosteroid with anesthetic properties. Its salt, alfadolone acetate, is used as a veterinary anesthetic in combination with alfaxalone. < )ll t 1 () II 3iz. 21-dihydroxy-5 <x pregnano -I 1.20-diona Alfadolone e) Additional neurosteroids Additional neurosteroids that may be used in the nanoparticle neurosteroid formulation of the present description and methods described herein include, but are not limited to, pregnenolone, hydroxydione (CAS Reg. No. 303-01-5, (53)-21-hydroxypregnane-3,20-dione), minaxolone (CAS Reg. No. 62571-87-3, 2β,3α,5α,11α)11-(dimethylamino)-2-ethoxy-3-hydroxypregnane-20-one), pregnanolone (CAS Reg. No. 128-20-1, (3α,5P)-d-hydroxypregnane-20-one), renanolone (CAS Reg. No. 565-99-1, 3a-hydroxy-5Ppregnan-11,20-dione), or tetrahydrocorticosterone (CAS Reg. No. 68-42-8, 3a,5a-pregnan-20dione). Additional neurosteroids that can be used in the nanoparticle neurosteroid formulation described herein and the methods described herein include Co26749 / WAY-141839, Col 34444, Col 77843, and Sage-217, Sage-324, and Sage-718. Co26749 / WAY-141839, Co134444, Co177843, and Sage-217 have the following structures: MA / a / ZUZZ / UUOUI 4 Additional neurosteroids that may be used in the nanoparticle neurosteroid formulation of the present description and methods described herein include compounds described in U.S. Patent Publication No. 2016-0229887 (U.S. Serial No. 14 / 913,920, filed February 23, 2016), incorporated herein by reference in its entirety. IV. Dosage The neurosteroid pregnenolone used in the methods described herein can be administered in amounts ranging from approximately 1 mg / day to approximately 5000 mg / day in one, two, three, or four divided doses. In certain regimens, doses of 1600 mg / day and 2000 mg / day may be associated with drowsiness, and a dose of 1800 mg / day defines the optimal combination of drug exposure, dosing convenience, and tolerability. When the pregnenolone neurosteroid is ganaxolone, a target and maximum dose of ganaxolone is approximately 1800 mg / day. In these modalities, this dose provides the highest feasible exposure based on the nonlinear kinetics of ganaxolone.Therefore, when the pregnenolone neurosteroid is ganaxolone, the amount of ganaxolone administered in the methods described herein is generally from about 200 mg / day to about 1800 mg / day, from about 300 mg / day to about 1800 mg / day, from about 400 mg / day to about 1800 mg / day, from about 450 mg / day to about 1800 mg / day, from about 675 mg / day to about 1800 mg / day, from about 900 mg / day to about 1800 mg / day, from about 1125 mg / day to about 1800 mg / day, from about 1350 mg / day to about 1800 mg / day, from about 1575 mg / day to about 1800 mg / day, or about 1800 mg / day, at a dose from 1 mg / kg / day to around 80 mg / kg / day in one, two, three or four divided doses.In certain modalities, the target and maximum dose of ganaxolone may be higher, if necessary, to achieve enhanced therapeutic benefit, as it is limited by side effects (e.g., drowsiness). In certain formulations, approximately 300 mg to approximately 2000 mg, approximately 900 mg to approximately 1800 mg, approximately 950 mg to approximately 1800 mg, approximately 1000 mg to approximately 1800 mg, approximately 1100 mg to approximately 1800 mg, or approximately 1200 mg of ganaxolone is administered orally per day for two or more consecutive days (e.g., for a period of 1 week to 50 years, or for the patient's lifetime). Ganaxolone can be administered orally or parenterally in one, two, three, or four doses per day. Whether a human receives ganaxolone two or three times a day depends on the formulation. For patients receiving immediate-release oral capsules, ganaxolone is generally administered twice daily, with each dose separated from the previous and / or subsequent doses by 8 to 12 hours. For patients taking the oral suspension, ganaxolone is generally administered three times daily, with each dose separated from the previous and / or subsequent doses by 4 to 8 hours. MA / a / ZUZZ / UUOUI 4 When the pregnenolone neurosteroid is ganaxolone, the methods described herein comprise administering ganaxolone at a dose from about 1 mg / kg / day to about 80 mg / kg / day, provided that the total amount of ganaxolone administered does not exceed 2000 mg / day. The methods described herein may further comprise the administration of ganaxolone in a therapeutically effective amount to achieve a plasma ganaxolone concentration of 100 ng / ml or higher for approximately 70% or more during a 24-hour period. In some cases, the plasma ganaxolone concentration may be greater than 100 ng / ml for at least approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 95%, or more during a 24-hour period. To achieve a plasma concentration of 100 ng / ml or higher for approximately 70% or more over a 24-hour period, ganaxolone can be administered at least three times daily. Three times daily is preferred; however, if necessary or desired, ganaxolone can be administered more than three times daily to achieve the desired minimum concentration. For example, ganaxolone can be administered three, four, five, six, seven, eight, or more times daily. Ganaxone administered according to the methods described herein may be given at the same or a lower daily dose than that used in clinical trials, and may increase drug exposure by maintaining a serum concentration of ganaxolone of at least approximately 100 ng / ml, for example, for at least approximately 70% or more of a 24-hour day. A total daily dose of approximately 1800 mg, approximately 1700 mg, approximately 1600 mg, approximately 1500 mg, or 63 mg / kg / day of ganaxolone may be administered, provided that the total daily dose is given in three or more separate doses (preferably each containing the same amount of ganaxolone) to produce a serum concentration of ganaxolone of at least approximately 100 ng / ml for at least 70% or more of a 24-hour day.Typically, a total daily dose of 1500 mg per day of ganaxolone can produce a plasma concentration of at least around 100 ng / ml or more for approximately 70% or more during a 24-hour day when administered three times a day during the day. For example, when administering a total daily dose of 1500 mg of ganaxolone, a dose of approximately 500 mg can be administered three times a day. For example, when administering a total daily dose of 1800 mg of ganaxolone, a dose of 600 mg can be administered three times a day. The maximum daily dose of ganaxolone is administered in equal or varying doses at least three times a day within a 24-hour period. A skilled physician will understand that the amount of ganaxolone administered at least three times a day can be adjusted to achieve the desired minimum level of ganaxolone, provided that the total amount does not exceed the maximum daily dose of ganaxolone. While a plasma concentration of at least around 100 ng / ml is preferable, there may be some variability based, for example, on differences in weight, metabolism, age, seizure duration and seizure severity of the subjects. Ganaxone can be administered orally (e.g., as an oral suspension or oral capsule) or intravenously. Ganaxone is preferably administered orally. Oral administration may include, but is not limited to, oral suspension and oral capsule formulations. A plasma concentration of at least approximately 100 ng / ml or higher for approximately 70% or more of a 24-hour day results in improved seizure reduction and / or seizure suppression. For example, a reduction in seizure frequency of at least 20% or more can be achieved compared to baseline values. For example, a reduction in seizure frequency of at least 35% or more can be achieved compared to baseline values. Seizure burden and / or frequency can be monitored by EEG. The pharmacokinetics of ganaxolone in formulations comprising immediate-release 0.3 µm particles (e.g., the formulation in Example 2) are linear up to approximately 1200 mg / day (administered twice daily [BID]), with a modest increase in exposure at a dose of 1600 mg / day, and little or no further increase at a dose of 2000 mg / day. Therefore, to maintain the highest possible minimum level in all subjects, a dose of 1800 mg / day is generally targeted, but may be adjusted higher or lower in certain individuals to provide an optimal therapeutic effect. In certain formulations, ganaxolone is administered at a dose of more than 5 mg / kg / day, for example, a dose of around 6 mg / kg / day to around 80 mg / kg / day, provided that the total amount of ganaxolone administered does not exceed 1800 mg / day. MA / a / ZUZZ / UUOUI 4 In certain modalities, the dose of ganaxolone is adjusted by 15 mg / kg / day up to 100 mg / kg / day up to a maximum dose of 1800 mg per day during treatment. In certain modalities, the treatment method comprises administering at least 33 mg / kg / day of ganaxolone in one, two, three or four doses, with a maximum daily dose of around 1800 mg. In certain regimens, the human subject is between approximately 0.6 and approximately 7 years of age and is administered a dose of ganaxolone of approximately 1.5 mg / kg (twice daily (BID)) (3 mg / kg / day) to 12 mg / kg (three times daily (TID)) (36 mg / kg / day). In regimens where the human receives a dosage regimen of 12 mg / kg TID, trough concentrations of at least approximately 38.5 ± 37.4 ng / mL are achieved. In certain formulations, ganaxolone is administered orally at doses of 6 mg / kg BID (12 mg / kg / day) to 12 mg / kg TID (36 mg / kg / day) in a βcyclodextrin formulation with food, and plasma concentrations of ganaxolone of up to 22.1 ng / mL and 5.7 to 43.7 ng / mL are achieved at week 4 and week 8, respectively, of administration. In certain formulations, ganaxolone is administered orally with food at doses of 1 to 12 mg / kg TID (3 to 36 mg / kg / day), and plasma concentrations of ganaxolone are achieved from up to 5.78 ng / mL (1 mg / kg TID) to 10.3 to 16.1 ng / mL (12 mg / kg TID). In certain formulations, ganaxolone is achieved orally at a dose of 3 to 18 mg / kg TID (9 to 54 mg / kg / day) in an oral suspension formulation, with a Cmax of ganaxolone of around 123 ng / mL and a minimum concentration of around 23 ng / mL. In certain modalities, the mean Cmin of ganaxolone (trough) is 55 ng / ml to about 100 ng / ml, and Cmax levels are about 240 ng / ml to 400 ng / ml (e.g., 262 ng / ml), based on oral administration three times a day of 1000 mg of ganaxolone. In certain modalities, the methods result in mean Cmin (valley) and Cmax levels of around 56.9 ng / ml and around 262 ng / ml, respectively, based on twice-daily oral administration of 1000 mg of ganaxolone. In certain formulations, ganaxolone administration provides a Cmin / Cmax ratio greater than 3, 3.5, 4, 4.5, 5, or 6. This Cmin / Cmax ratio can be achieved after a single dose and / or after steady-state administration. In certain formulations, the Cmin / Cmax ratio MA / a / ZUZZ / UUOUI 4 remains the same, regardless of the dose of ganaxolone administered. In certain formulations, the administered dose is determined using a pediatric pharmacokinetic model that allows the determination of the ganaxolone dose in various pediatric age ranges that will produce a Cmax and AUC exposure similar to that achieved after a specific effective dose in the adult population with epilepsy. The model could, for example, be constructed using standard methods and considering the pharmacokinetic data in this application. In certain modalities, the neurosteroid pregnenolone can be administered to the patient using several titration stages until a therapeutically effective dosage regimen is achieved. For example, approximately six to eight titration stages may be used, depending on the patient's size. In certain modalities, the methods described herein comprise establishing a baseline seizure frequency for the patient, initially administering a dose of ganaxolone to the patient in an amount of approximately 0.5 mg / kg / day to approximately 15 mg / kg / day; and progressively increasing the dose of ganaxolone over the course of 4 weeks to an amount of approximately 18 mg / kg / day to approximately 60 mg / kg / day, where the total dose of ganaxolone is up to approximately 1800 mg / day for patients whose body weight is greater than 30 kg. For patients whose body weight is 30 kg or less, the total daily dose of ganaxolone may be lower (e.g., approximately 63 mg / day). In certain preferred modalities, the initial dose of ganaxolone is approximately 4.5 mg / kg / day. In certain preferred modalities, the dose of ganaxolone is increased to around 36 mg / kg / day.In certain preferred modalities, the dose of ganaxolone is reduced to a previous level if the patient experiences dose-limiting adverse events. In certain regimens, for subjects weighing more than 30 kg, treatment is initiated with a dose of 900 mg / day in divided doses. The dose is then increased by approximately 20% to 50% (e.g., an increase from 900 mg / day to 1200 mg / day is a 33% increase) at intervals of no less than 3 days and no more than 2 weeks, provided the current dose is reasonably tolerated, until the desired efficacy is achieved or a maximum tolerated dose (MTD) level is reached. Subsequent dose adjustments may be made in increments of approximately 20% to 50% with a minimum of 3 days between dose changes, unless required for safety reasons. The maximum permitted dose in these regimens is 1800 mg / day. In certain regimens, for subjects weighing 30 kg or less, treatment is initiated at 18 mg / kg / day and may be increased in increments of approximately 20% to 50% at intervals of no less than 3 days and no more than 2 weeks, provided the current dose is reasonably tolerated, until the desired efficacy is achieved or a maximum tolerated dose (MTD) level is reached. Subsequent dose adjustments may be made in increments of approximately 20% to 50% with a minimum of 3 days between dose changes, unless required for safety reasons. The maximum permitted dose in these regimens is 63 mg / kg / day. For humans weighing > 28 kg (62 lbs), ganaxolone can be initiated at a dose of approximately 300 mg / day to approximately 600 mg / day (e.g., 400 mg / day) in divided doses. The dose will be increased by 450 mg / day every 7 days until a maximum tolerated dose of 1800 mg / day or the maximum tolerated dose is reached. For humans weighing < 28 kg (62 lbs), ganaxolone can be started at a dose from about 10 mg / kg / day to about 30 mg / kg / day (e.g., 18 mg / kg / day), increasing by about 15 mg / kg / day every week until reaching 63 mg / kg / day. In certain formulations, ganaxolone is administered in increments of 10 mg / day to 20 mg / day (e.g., 15 mg / kg / day) up to 63 mg / kg / day (maximum 1800 mg / day) as an oral suspension or in increments of 225 mg / day to 900 mg / day (e.g., 450 mg / day) as an oral capsule. In some of these formulations, ganaxolone may, for example, be dosed as follows: 6 mg / kg three times a day (TID) (18 mg / kg / day) as a suspension / 225 mg / kg twice a day (BID) (450 mg / day) as a capsule – Days 1–7; 11 mg / kg TID (33 mg / kg / day) as a suspension / 450 mg / kg BID (900 mg / day) as a capsule – Days 8–14; 16 mg / kg TID (48 mg / kg / day) in suspension / 675 BID (1350 mg / day) in capsules - Days 15-21; 21 mg / kg TID in suspension (63 mg / kg / day not to exceed 1800 mg / day) / 900 BID in capsules (1800 mg / day) - Days 22-28. In certain formulations, ganaxolone is administered as an oral suspension and the following titration schedule is used: 133 kg! Titration stage n.: mg / kg Dose (mg); Dose increase (mg / kg) Change in total mg 0.4 H to .'C u change in dose Suspension in total - 18 270 5.4 2 24 359 6 89 337; 7.2 3 32 478 8 119 337; 9.6 4 42 635 11 158 317. 12.7 5 54 810 12 175 27% 16 2 6 63 945 9 135 167; 18.9 44 kg; hours; Titration stage n.= mg / kg Dose img: Dose increase mg / kg Change in mg total % of dose change Suspension in total - 18 360 7.2 2 24 479 6 119 337. 9.6 3 32 637 8 158 337: 12.7 4 42 847 10 210 317: 16.9 5 54 1080 12 233 27% 21.6 6 63 1263 9 18C 16 7; 25.2 155 lbs Titration stage n.: mg / kg Dose img Dose increase mg / kg Change in mg total 0 / H to •Ό mC change in dose Suspension in mi total 18 450 9.3 2 24 599 6 149 337; 12.3 3 32 796 8 198 337: 15.9 4 42 1359 10 263 317; 21.2 5 54 1350 12 291 27% 27.0 6 63 1575 9 225 167. 31.5 3Ckg ' Titration step n.: mg / kg Dose (mg); Dose increase (mg / kg) Total mg change % of dose change Suspension (mg / kg) Total 1 18 540 13 8 2 24 718 6 178 33% 14.4 3 32 955 8 237 33% 19.1 4 42 1273 10 315 31% 25.4 5 50 1500 8 230 18% 30.0 6 55 1653 150 11% 33.0 7 60 1803 15% 9% 36.0 In certain modalities, ganaxolone is administered in capsules and the following titration schedule is used: 200 mg capsules 225 mg capsules Titration step Total daily dose Qty of caps. AM Number of caps. PM Total daily dose Qty of caps. AM Number of caps. PM 1 400 1 1 450 1 1 ·> 600 1 675 1 -> Λ 800 n 900 -> 4 1000 Λ 1125 3 and 5 1200 1350 and 6 1400 .3 4 1575 3 4 7 1600 4 4 1800 4 4 8 1800 4 5 In certain formulations, the minimum concentrations associated with maximum efficacy are in the range of about 55 ng / mL, about 60 ng / mL or about 65 ng / mL (0.3 micron suspension; TID dosing) and a dose of 1800 mg / day (0.3 micron capsules, BID dosing) provides minimum plasma concentrations in this range. The treatment methods described herein include the administration of neurosteroids (e.g., ganaxolone) with or without food. In certain modalities, ganaxolone is administered with food. V. Duration of treatment The duration of treatment according to the methods described herein can range from one day to more than two years. For example, the duration of treatment can be from approximately one day to approximately 80 years, from approximately one day to approximately 70 years, from approximately one day to approximately 60 years, from approximately one day to approximately 50 years, from approximately one day to approximately 45 years, from approximately two days to approximately 45 years, from approximately two days to approximately 40 years, from approximately five days to approximately 35 years, from approximately ten days to approximately 30 years, from approximately ten days to approximately 30 years, or from approximately fifteen days to approximately 30 years. In some modalities, the duration of treatment is as long as the subject continues to derive a therapeutic benefit from the administration of the neurosteroid (e.g., ganaxolone).In some modalities, the duration of treatment is 14 days, 28 days, 30 days, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 6 months, 1 year, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, 5 years, 5.5 years, 6 years, 6.5 years, 7 years, 7.5 years, 8 years, 8.5 years, 9 years, 9.5 years or 10 years. In certain modalities, at the end of the treatment period, or when treatment is discontinued, the dose is gradually reduced over a period of 1 to 4 weeks, depending on the subject's age, weight, dose and duration of treatment. VI. Formulations Any desired formulation comprising a pregnenolone neurosteroid (e.g., ganaxolone) and one or more pharmaceutically acceptable excipients may be administered according to the methods described herein. The pregnenolone neurosteroid is included in a therapeutically effective amount to treat one or more symptoms of TSC or TSC-related epilepsy. In certain formulations, the formulations are free of cyclodextrins, including sulfoalkyl ether cyclodextrins and modified forms thereof. In preferred modalities, the amount of pregnenolone neurosteroid in the formulation is therapeutically effective for treating a symptom of TSC-related epilepsy, for example, after oral administration of the formulation for 1 week and / or 2 weeks and / or 3 weeks and / or 4 weeks and / or 6 weeks and / or 7 weeks and / or 8 weeks and / or 9 weeks and / or 10 weeks and / or 11 weeks and / or 12 weeks, or more. In preferred embodiments, pregnenolone neurosteroids (e.g., ganaxolone) are incorporated into a pharmaceutically acceptable composition for oral administration. Such a formulation in certain preferred embodiments may be a liquid (e.g., an aqueous liquid encompassing suspensions, solutions, and the like). In other preferred embodiments, the oral formulation may be a solid oral dosage form (e.g., an oral capsule or tablet). In the most preferred embodiments, the oral formulation is an oral suspension comprising the pregnenolone neurosteroid or an oral capsule comprising the pregnenolone neurosteroid. Preferably, a unit dose of the oral formulation contains a therapeutically effective amount of the pregnenolone neurosteroid that can be administered orally to the patient (e.g., a human being) (e.g., an infant, child, adolescent, or adult).In certain formulations, the oral suspension is administered to the patient using an oral syringe. For example, the oral suspension is intended for use in individuals weighing less than approximately 30 kg (e.g., around 28 kg). Alternatively, the oral suspension can be administered to individuals who would have difficulty swallowing a solid oral dosage form. Children weighing more than 30 kg may take a solid dosage form, such as ganaxolone capsules. Ganaxolone oral suspension can be administered via an oral dosing syringe, for example, three times daily. Ganaxolone capsules can be administered, for example, twice daily. Patients experience improved absorption of ganaxolone when taken with food (such as milk). As described in U.S. Patent No. 8,022,054, the liquid formulation may be an aqueous dispersion of stabilized pregnenolone neurosteroid particles (e.g., ganaxolone) comprising ganaxolone, a hydrophilic polymer, a wetting agent, and an effective amount of a complexing agent that stabilizes particle growth after reaching an initial particle growth and an endpoint, the complexing agent being selected from the group of small organic molecules having a molecular weight less than 550 and containing a moiety selected from the group consisting of a phenol moiety, an aromatic ester moiety, and an aromatic acid moiety, wherein the stabilized particles have a volume-weighted average particle diameter (D50) of about 50 nm to about 500 nm, the complexing agent being present in an amount of about 0.0.5% to about 5% w / w based on the weight of the particles, the particles dispersed in an aqueous solution that further contains at least two preservatives in sufficient quantity to inhibit microbial growth. The hydrophilic polymer may be present in an amount of about 3% to about 50% w / w, based on the weight of the solid particles. The wetting agent may be present in an amount of about 0.01% to about 10% w / w, depending on the weight of the solid particles. The pregnenolone neurosteroid (e.g., ganaxolone) may be present in an amount of about 10% to about 80% (and in certain formulations from about 50% to about 80%) depending on the weight of the stabilized particles.Stabilized particles may exhibit an increase in volume-weighted mean diameter (D50) of no more than about 150% when the particles are dispersed in simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) at a concentration of 0.5 to 1 mg of ganaxolone / mL and placed in a bath heated to 36° to 38°C for 1 hour compared to the D50 of the stabilized particles when the particles are dispersed in distilled water under the same conditions, where the volume-weighted mean diameter (D50) of the stabilized particles dispersed in SGF or. IVIA / a / ZUZZ / UUOU 14 The volume-weighted average diameter (D50) of the stabilized particles may exhibit an increase in the volume-weighted average diameter (D50) of no more than approximately 150% when the formulation is dispersed in 15 mL of SGF or SIF at a concentration of 0.5 to 1 mg of ganaxolone / mL, compared to the D50 of the stabilized particles when dispersed in distilled water under the same conditions, where the volume-weighted average diameter (D50) of the stabilized particles dispersed in SGF or SIF is less than approximately 750 nm. The complexing agent may be a paraben, benzoic acid, phenol, sodium benzoate, methyl anthranilate, or similar compounds. The hydrophilic polymer may be a cellulosic polymer, a vinyl polymer, or mixtures thereof. The cellulosic polymer may be a cellulose ether, for example, hydroxypropyl methylcellulose.The vinyl polymer may be polyvinyl alcohol, for example, vinylpyrrolidone / vinyl acetate copolymer (S630). The wetting agent may be sodium lauryl sulfate, a pharmaceutically acceptable docusate salt, and mixtures thereof. The aqueous dispersion may further comprise a sweetener, for example, sucralose. The preservative is selected from the group consisting of potassium sorbate, methylparaben, propylparaben, benzoic acid, butylparaben, ethyl alcohol, benzyl alcohol, phenol, benzalkonium chloride, and mixtures thereof. In some embodiments, liquid formulations of pregnenolone neurosteroids (e.g., ganaxolone) are provided, comprising the ganaxolone particles described herein and at least one dispersing or suspending agent for oral administration to a subject. The ganaxolone formulation may be a powder and / or granules for suspension and, when mixed with water, yields a substantially uniform suspension. As described herein, the aqueous dispersion may comprise amorphous and amorphous ganaxolone particles consisting of multiple effective particle sizes, such that the ganaxolone particles having a smaller effective particle size are absorbed more rapidly and the ganaxolone particles having a larger effective particle size are absorbed more slowly. In certain embodiments, the aqueous dispersion or suspension is an immediate-release formulation.In one embodiment, an aqueous dispersion comprising amorphous ganaxolone particles is formulated such that approximately 50% of the ganaxolone particles are absorbed within about 3 hours of administration and approximately 90% are absorbed within about 10 hours of administration. In other embodiments, the addition of a complexing agent to the aqueous dispersion results in a greater number of ganaxolone-containing particles to extend the drug absorption phase, such that 50-80% of the particles are absorbed within the first 3 hours and approximately 90% are absorbed within about 10 hours. A suspension is substantially uniform when it is mostly homogeneous, meaning that the suspension consists of approximately the same concentration of pregnenolone neurosteroid (e.g., ganaxolone) at any point within the suspension. Preferred formulations are those that provide essentially equal concentrations (within 15%) when measured at various points in an aqueous oral formulation of ganaxolone after shaking. Aqueous suspensions and dispersions that maintain homogeneity (up to 15% variation) when measured 2 hours after shaking are especially preferred. Homogeneity should be determined by a sampling method consistent with the determination of homogeneity of the entire composition. In one formulation, an aqueous suspension can be resuspended into a homogeneous suspension by physical shaking lasting less than 1 minute.In another embodiment, an aqueous suspension can be resuspended into a homogeneous suspension by physical stirring lasting less than 45 seconds. In yet another embodiment, an aqueous suspension can be resuspended into a homogeneous suspension by physical stirring lasting less than 30 seconds. In yet another embodiment, stirring is not required to maintain a homogeneous aqueous dispersion. In some embodiments, the pregnenolone neurosteroid powders (e.g., ganaxolone) for aqueous dispersion described herein comprise stable ganaxolone particles having an effective weight particle size less than 500 nm formulated with ganaxolone particles having an effective weight particle size greater than 500 nm. In such embodiments, the formulations have a particle size distribution where about 10% to about 100% of the ganaxolone particles by weight are between about 75 nm and about 500 nm, about 0% to about 90% of the ganaxolone particles by weight are between about 150 nm and about 400 nm, and about 0% to about 30% of the ganaxolone particles by weight are larger than about 600 nm.Ganaxolone particles described herein may be amorphous, semi-amorphous, crystalline, semi-crystalline, or mixtures thereof. MA / a / ZUZZ / UUOUI 4 In one embodiment, the aqueous suspensions or dispersions described herein comprise ganaxolone particles or ganaxolone complex at a concentration of approximately 20 mg / ml to approximately 150 mg / ml of suspension. In another embodiment, the aqueous oral dispersions described herein comprise ganaxolone particles or ganaxolone complex particles at a concentration of approximately 25 mg / ml to approximately 75 mg / ml of solution. In yet another embodiment, the aqueous oral dispersions described herein comprise ganaxolone particles or ganaxolone complex at a concentration of approximately 50 mg / ml of suspension. The aqueous dispersions described herein are particularly beneficial for the administration of ganaxolone to infants (under 2 years of age), children under 10 years of age, and any group of patients who are unable to swallow or ingest solid oral dosage forms. Liquid dosage forms of pregnenolone neurosteroid formulations (e.g., ganaxolone) for oral administration may be aqueous suspensions selected from the group that includes, but is not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, and syrups. See, for example, Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Supplementary Ed., pp. 754–757 (2002). In addition to ganaxolone particles, liquid dosage forms may comprise additives such as: (a) disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) at least one preservative; (e) viscosity-enhancing agents; (f) at least one sweetening agent; (g) at least one flavoring agent; (h) a complexing agent; and (i) an ion dispersion modulator. In some embodiments, aqueous dispersions may further comprise a crystalline inhibitor. Examples of disintegrating agents for use in aqueous suspensions and dispersions include, but are not limited to, a starch, for example, a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijele®, or sodium starch glycolate such as Promogel® or Explotab®; a cellulose such as a wood product, microcrystalline cellulose, for example, Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tía® and Solka-Floc®, methylcellulose, croscarmellose, or a crosslinked cellulose such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose or crosslinked croscarmellose; a crosslinked starch such as sodium starch glycolate; a crosslinked polymer such as crospovidone; a crosslinked polyvinylpyrrolidone; alginate such as alginic acid or a salt of alginic acid such as sodium alginate; a clay such as MA / a / ZUZZ / UUOUI 4 Veegum® HV (magnesium aluminum silicate); a gum such as agar, guar, locust bean, karaya, pectin or tragacanth; sodium starch glycolate; bentonite; a natural sponge; a surfactant; a resin such as a cation exchange resin; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate in starch combination; and the like. In some embodiments, suitable dispersing agents for the aqueous suspensions and dispersions described herein are known in the art and include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP;commercially known as Plasdone®) and carbohydrate-based dispersing agents such as, for example, hydroxypropylcellulose and hydroxypropylcellulose ethers (e.g., HPC, HPC-SL and HPC-L), hydroxypropylmethylcellulose and hydroxypropylmethylcellulose ethers (e.g., HPMC K100, HPMC K4M, HPMC K15M and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate, non-crystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone / vinyl acetate copolymer (Plasdone®, e.g., S-630), 4-(1,1,3,3-tetramethylbutyl)phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88® and F108®, which are block copolymers of ethylene oxide and propylene oxide);and poloxamines (for example, Tetronic 9080, also known as Poloxamine 9080, which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, NJ)). In other embodiments, the dispersing agent is selected from a group that does not comprise any of the following agents: hydrophilic polymers; electrolytes; Tween® 60 or 80; PEG; polyvinylpyrrolidone (PVP); hydroxypropylcellulose and hydroxypropylcellulose ethers (for example, HPC, HPC-SL, and HPC-L); hydroxypropylmethylcellulose and hydroxypropylmethylcellulose ethers (for example, HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and Pharmacoat® USP 2910 (Shin-Etsu)); sodium carboxymethylcellulose; methylcellulose; hydroxyethylcellulose; hydroxypropyl methylcellulose phthalate; hydroxypropyl methylcellulose acetate stearate; non-crystalline cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl alcohol (PVA);polymer of 4-(1,1,3,3-tetramethylbutyl)phenol with ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics F68®, F88® and F108®, which are block copolymers of ethylene oxide and propylene oxide); or poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908%).; The wetting agents (including surfactants) suitable for the aqueous suspensions and dispersions described herein are known in the art and include, but are not limited to, acetyl alcohol, glyceryl monostearate, polyoxyethylsorbitan fatty acid esters (e.g., commercially available Tweens® such as Tween 20® and Tween 80® (ICI Specialty Chemicals)), and polyethylene glycols (e.g., Carbowaxs 3350® and 1450®, and Carpool 934® (Union Carbide)), oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylsorbitan monooleate, polyoxyethylsorbitan monolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, sodium taurocholate, simethicone, phosphotidylcholine and the like. Suitable preservatives for the aqueous suspensions or dispersions described herein include, for example, potassium sorbate, parabens (e.g., methylparaben and propylparaben) and their salts, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. The preservatives, as used herein, are incorporated into the dosage form at a concentration sufficient to inhibit microbial growth. In one embodiment, the aqueous liquid dispersion may comprise methylparaben and propylparaben in a concentration ranging from about 0.01% to about 0.3% by weight of methylparaben relative to the weight of the aqueous dispersion and from 0.005% to 0.03% by weight of propylparaben relative to the total weight of the aqueous dispersion.In yet another embodiment, the aqueous liquid dispersion may comprise from 0.05 to about 0.1% by weight of methylparaben and from 0.01 to 0.02% by weight of propylparaben of the aqueous dispersion. Suitable viscosity enhancers for the aqueous suspensions or dispersions described herein include, but are not limited to, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, Plasdone.RTM. S-630, carbomer, polyvinyl alcohol, alginates, acacia, chitosan, and combinations thereof. The concentration of the viscosity enhancer will depend on the selected agent and the desired viscosity. Examples of natural and artificial sweetening agents suitable for the aqueous suspensions or dispersions described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berries, MA / a / ZUZZ / UUOUI 4 blackcurrant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubblegum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, fresh cherry, fresh citrus, cyclamate, cillamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, iodine, lemon, lime, lemon cream, monoammonium glycyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, peppermint cream, mixed berries, neohesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet®.Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sucralose, sorbitol, Swiss cream, tagatose, mandarin, thaumatin, tutti frutti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol or any combination of these flavoring ingredients, for example, anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, mint-chocolate, honey-lemon, lime-lemon, mint-lemon, menthol-eucalyptus, cream-orange, mint-vanilla, and mixtures of these. In one embodiment, the aqueous liquid dispersion may comprise a sweetening agent or a flavoring agent in a concentration ranging from about 0.0001% to about 10.0% of the weight of the aqueous dispersion.In another embodiment, the aqueous liquid dispersion may comprise a sweetening agent or a flavoring agent in a concentration ranging from about 0.0005% to about 5.0% by weight of the aqueous dispersion. In yet another embodiment, the aqueous liquid dispersion may comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.0001% to 0.1% by weight, from about 0.001% to about 0.01% by weight, or from 0.0005% to 0.004% of the aqueous dispersion. In addition to the additives listed above, liquid formulations of pregnenolone neurosteroids (e.g., ganaxolone) may also comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers. In some embodiments, the pregnenolone neurosteroid pharmaceutical formulations (e.g., ganaxolone) described herein may be self-emulsifying drug delivery systems (SEDDS). Emulsions are dispersions of one immiscible phase in another, usually in the form of droplets. Generally, emulsions are created by vigorous mechanical dispersion. SEDDS, unlike emulsions or microemulsions, form emulsions spontaneously when added to MA / a / ZUZZ / UUOUI 4 an excess of water without external dispersion or mechanical agitation. One advantage of SEDDS is that only gentle mixing is needed to distribute the microdroplets throughout the solution. In addition, water or the aqueous phase can be added just before administration, ensuring the stability of an unstable or hydrophobic active ingredient. Therefore, SEDDS provide an efficient delivery system for the oral and parenteral administration of hydrophobic active ingredients. SEDDS can provide improvements in the bioavailability of hydrophobic active ingredients. Methods for producing self-emulsifying dosage forms known in the art include, but are not limited to, U.S. Patents Nos. 5,858,401, 6,667,048, and 6,960,563, each of which is specifically incorporated by reference. Example emulsifiers include ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, sodium lauryl sulfate, sodium docusate, cholesterol, cholesterol esters, taurocholic acid, phosphatidylcholine, oils such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan or mixtures of these substances, and the like. In certain preferred embodiments, the liquid pharmaceutical formulation comprises ganaxolone, hydroxypropyl methylcellulose, polyvinyl alcohol, sodium lauryl sulfate, simethicone, methylparaben, propylparaben, sodium benzoate, citric acid, and sodium citrate at a pH of 3.8 to 4.2. The suspension may comprise ganaxolone at a concentration of 50 mg / ml. The formulation may further comprise a pharmaceutically acceptable sweetener (e.g., sucralose) and / or a pharmaceutically acceptable flavoring (e.g., cherry). The formulation may be placed, for example, in a 120 ml, 180 ml, 240 ml, or 480 ml bottle. In certain preferred embodiments, a solid oral formulation is used as described and prepared in Applicant's prior U.S. patent No. 7,858,609, entitled “Solid Ganaxolone Formulations and Methods for the Making and Use Thereof,” incorporated herein by reference in its entirety. The pregnenolone neurosteroid solid oral dosage formulation (e.g., oral capsules or tablets) may be prepared according to any suitable method. For example, as described in U.S. Patent No. 7,858,609, the MA / a / ZUZZ / UUOUI 4 Oral solid formulation comprises stabilized particles comprising the neurosteroid pregenolone (e.g., ganaxolone), a hydrophilic polymer, a wetting agent, and an effective amount of a complexing agent that stabilizes particle growth after reaching an initial particle growth and an endpoint, wherein the complexing agent is a small organic molecule having a molecular weight of less than 550 and containing a moiety selected from the group consisting of a phenol moiety, an aromatic ester moiety, and an aromatic acid moiety, wherein the stabilized particles have a volume-weighted average diameter (D50) of the particles of about 50 nm to about 500 nm, wherein the complexing agent is present in an amount of about 0.05% to about 5% w / w, depending on the particle weight of the solid.The hydrophilic polymer may be present in an amount of approximately 3% to approximately 50% w / w, based on the weight of the solid particles. The wetting agent may be present in an amount of approximately 0.01% to approximately 10% w / w, depending on the weight of the solid particles. The pregnenolone neurosteroid (e.g., ganaxolone) may be present in an amount of approximately 10% to approximately 80% (and in certain formulations, approximately 50% to approximately 80%) depending on the weight of the stabilized particles. The stabilized particles may exhibit an increase in volume-weighted average diameter (D50) of no more than approximately 150% when the particles are dispersed in simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) at a concentration of 0.5 to 1 mg of ganaxolone / mL and placed in a heated bath at 36° to 38°C for 1 hour compared to the D50 of the stabilized particles when the particles are dispersed in distilled water under the same conditions, where the volume-weighted average diameter (D50) of the stabilized particles dispersed in SGF or SIF is less than about 750 nm. The stabilized particles may exhibit an increase in the volume-weighted average diameter (D50) of no more than about 150% when the formulation is dispersed in 15 mL of SGF or SIF at a concentration of 0.5 to 1 mg of ganaxolone / mL, compared to the D50 of the stabilized particles when the particles are dispersed in distilled water under the same conditions, where the volume-weighted average diameter (D50) of the stabilized particles dispersed in SGF or SIF is less than about 750 nm.The stabilized solid particles can be combined with optional excipients and prepared for administration as a powder, or they can be incorporated into a selected dosage form from the group consisting of a tablet or capsule. The complexing agent can be a paraben or acid. MA / a / ZUZZ / UUOUI 4 benzoic acid, phenol, sodium benzoate, methyl anthranilate, and the like. The hydrophilic polymer may be a cellulosic polymer, a vinyl polymer, and mixtures thereof. The cellulosic polymer may be a cellulose ether, for example, hydroxypropyl methylcellulose. The vinyl polymer may be polyvinyl alcohol, for example, vini1 pyrrolidone / vinyl acetate copolymer (S630). The wetting agent may be sodium lauryl sulfate, a pharmaceutically acceptable docusate salt, and mixtures thereof. When the particles are incorporated into a solid dosage form, the solid dosage form may further comprise at least one pharmaceutically acceptable excipient, for example, an ion dispersion modulator, a water-soluble spacer, a disintegrant, a binder, a surfactant, a plasticizer, a lubricant, a diluent, and any combination or mixture thereof.The water-soluble spacer can be a saccharide or an ammonium salt, for example, fructose, sucrose, glucose, lactose, or mannitol. The surfactant can be, for example, polysorbate. The plasticizer can be, for example, polyethylene glycol. The disintegrant can be crosslinked sodium carboxymethylcellulose, crospovidone, mixtures of these, and similar substances. A capsule can be prepared, for example, by placing the bulk pregnenolone neurosteroid mixture formulation (e.g., ganaxolone), described herein, into a capsule. In some formulations, ganaxolone formulations (suspensions and non-aqueous solutions) are placed in a soft gelatin capsule. In other formulations, ganaxolone formulations are placed in standard gelatin capsules or non-gelatin capsules, such as capsules comprising HPMC. In still other formulations, ganaxolone formulations are placed in a sprinkler capsule, where the capsule can be swallowed whole or opened and the contents sprinkled onto food before eating. The therapeutic dose can be divided into multiple capsules (e.g., two, three, or four). In some formulations, the entire dose of the ganaxolone formulation is administered in capsule form. Preferably, each capsule contains about 200 to about 600 mg of ganaxolone, about 300 to about 600 mg of ganaxolone, about 400 to about 600 mg of ganaxolone, about 500 to about 600 mg of ganaxolone, about 200 mg of ganaxolone, about 250 mg of ganaxolone, about 300 mg of ganaxolone, about 500 mg of ganaxolone, or about 600 mg of ganaxolone. In certain formulations, each capsule contains 200 mg or 225 mg of MA / a / ZUZZ / UUOUI 4 Ganaxolone and hydroxypropyl methylcellulose, sucrose, polyethylene glycol 3350, polyethylene glycol 400, sodium lauryl sulfate, sodium benzoate, anhydrous citric acid, sodium methylparaben, microcrystalline cellulose, 30% simethicone emulsion, gelatin capsules, polysorbate 80, and sodium chloride. In some formulations, the capsule size is 00. Alternatively, the oral dosage forms may be in the form of a controlled-release dosage form, as described in U.S. Patent No. 7,858,609. Suitable formulations of pregnenolone neurosteroids (e.g., ganaxolone) can also be administered parenterally. In such modalities, the formulations are suitable for intramuscular, subcutaneous, or intravenous injection and may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, cremofor, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. In addition, ganaxolone can be dissolved at concentrations >1 mg / mL using water-soluble beta-cyclodextrins (e.g., beta-sulfobutylcyclodextrin and 2-hydroxypropylbetacyclodextrin).A particularly suitable cyclodextrin is a substituted β-cyclodextrin such as Captisol®. Adequate flowability can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants. Ganaxolone formulations suitable for subcutaneous injection may also contain additives such as preservatives, humectants, emulsifiers, and dispensing agents. Prevention of microbial growth can be ensured by various antibacterial and antifungal agents, such as parabens, benzoic acid, benzyl alcohol, chlorobutanol, phenol, sorbic acid, and the like. It may also be convenient to include isotonic agents such as sugars, sodium chloride, and the like.Prolonged absorption of the drug from the injectable dosage form can be achieved through the use of absorption-delaying agents such as aluminum monostearate and gelatin. Ganaxone suspension formulations designed for prolonged release via subcutaneous or intramuscular injection can bypass first-pass metabolism, and lower doses of ganaxolone will be required to maintain plasma levels of approximately 50 ng / mL. In such formulations, the particle size and particle size range of the ganaxolone particles can be used to control drug release by regulating the rate of dissolution in fat or muscle. Particularly useful injectable formulations are described in applicant's U.S. patent publication no. 2017 / 0258812 (U.S. serial no. 15 / 294,135, filed October 14, 2016), which is incorporated herein by reference in its entirety. Other useful injectable formulations of pregnenolone neurosteroids known to those skilled in the art may also be used. Vil. Combination treatment The description includes modalities in which the neurosteroid is the sole active agent and modalities in which the neurosteroid is administered in combination with one or more additional active agents. When used in combination with an additional active agent, the neurosteroid and the additional active agent may be combined in the same formulation or administered separately. The neurosteroid may be administered concurrently with the additional active agent (concurrent administration) or before or after the additional active agent (sequential administration). The description includes formulations in which the additional active agent is an anticonvulsant. Anticonvulsants include GABAA receptor modulators, sodium channel blockers, GAT-1 GABA transporter modulators, GABA transaminase modulators, voltage-gated calcium channel blockers, and peroxisome proliferator-activated alpha modulators. The description includes modalities in which the patient is given an anesthetic or sedative in combination with a neurosteroid. The anesthetic or sedative may be administered at a concentration sufficient to cause the patient to lose consciousness, such as a concentration sufficient to medically induce a coma or a concentration effective to induce general anesthesia. Or the anesthetic or sedative may be administered at a lower dose that is effective for sedation but not sufficient to induce unconsciousness. Benzodiazepines are used both as anticonvulsants and anesthetics. Benzodiazepines useful as anesthetics include diazepam, flunitrazepam, lorazepam, and midazolam. IVIA / a / ZUZZ / UUOU 14 In certain modalities, the neurosteroid is administered concomitantly with a benzodiazepine (e.g., clobazam, diazepam, clonazepam, midazolam, clorazepic acid, levetiracetam, felbamate, lamotrigine, a fatty acid derivative (e.g., valproic acid), a carboxamide derivative (rufinamide, carbamazepine, oxcarbazepine, etc.), an amino acid derivative (e.g., levocarnitine), a barbiturate (e.g., phenobarbital), or a combination of two or more of the above agents. The injectable neurosteroid nanoparticle formulation described herein may be administered with another anticonvulsant agent. Anticonvulsants include several classes of drugs and overlap to some extent with coma-inducing drugs, anesthetics, and sedatives that may be used in combination with a neurosteroid. Anticonvulsants that may be used in combination with the injectable neurosteroid nanoparticle formulation described herein include aldehydes, such as paraldehyde; aromatic allylic alcohols, such as stiripentol; barbiturates, including those listed above, as well as methylphenobarbital and barbexaclone;Benzodiazepines include alprazolam, bretazenil, bromazepam, brotizolam, chloridazepoxide, cinolazepam, clonazepam, clorazepate, clopazam, clotiazepam, cloxazolam, delorazepam, diazepam, estazolam, etizolam, ethyl loflazepate, flunitrazepam, flurazepam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, phenenazepam, pinazepam, prazepam, premazepam, pyrazolam, quazepam, temazepam, tatrazepam and triazolam; bromurs, such as potassium bromide; carboxamides, such as carbamazepine, oxcarbazepine and eslicarbazepine acetate; fatty acids, such as valproic acid, sodium valproate and sodium divalproate; fructose derivatives, such as topiramate; GABA analogues such as gabapentin and pregabalin, hydantoins such as ethotoin, phenytoin, mephenytoin and fosphenytoin;Other neurosteroids, such as allopregnanolone; oxalodinediones, such as paramethadione, trimethadione, and ethadione; propionates, such as beclamide; pyrimidinediones, such as primidone; pyrrolidines, such as brivaracetam, levetiracetam, and seletracetam; succinimides, such as ethosuximide, pennuximide, and mesuximide; sulfonamides, such as acetazolamide, sultiame, methazolamide, and zonisamide; triazines, such as lamotrigine; ureas, such as pheneturide and phenacemide; NMDA antagonists, such as felbamate; and valproylamides, such as valpromide and valnoctamide; and perampanel. IVIA / a / ZUZZ / UUOU 14 VIII. Biomarker Predictive biomarkers are used to identify patient populations that are more homogeneous and have a greater propensity to respond to a therapy. Allopregnanolone, a progesterone metabolite, is a positive allosteric modulator (PAM) of the GABAA receptor. Humans with TSC-related epilepsy may have this allopregnanolone deficiency, supporting the hypothesis that treatment with a pharmaceutically acceptable pregnenolone (e.g., ganaxolone) may reduce seizure frequency and possibly improve additional symptoms of TSC-related epilepsy. Therefore, in certain modalities, allopregnanolone sulfate (Allo-S) is used as a predictive biomarker for response to ganaxolone, an analogue of allopregnanolone. In these modalities, an Allo-S plasma level of 2500 pg ml⁻¹ or less indicates that a subject is likely to respond to and benefit from ganaxolone therapy; and an Allo-S plasma level above 2500 pg ml⁻¹ indicates that a subject is unlikely to respond to ganaxolone therapy and that a different therapeutic agent should be used. EXAMPLES The following examples of formulations according to the present invention should not be interpreted as limiting the present invention in any way and are only samples of the various formulations described herein. During the development of ganaxolone formulations, a variety of formulations were evaluated to establish one that demonstrates suitable pharmacokinetic (PK) parameters and is appropriate for development and commercialization. Other ganaxolone formulations used included ganaxolone mixed with sodium lauryl sulfate, with hydroxypropyl-beta-cyclodextrin (HRP-β-CD) in solution and with beta-cyclodextrin (βCD) administered as a variety of suspensions, as well as 0.5-micron ganaxolone particles in suspension and tablet formulations, and controlled-release capsule formulations, and an IV solution using sulfobutyl ether cyclodextrin (Captisol®) for ganaxolone solubilization. The development effort led to an oral suspension comprising immediate-release ganaxolone particles of 0.5 microns.3 microns, described in Example 1, and an oral capsule formulation comprising 0.3 micron immediate-release ganaxolone particles, described in Example 2. IVIA / a / ZUZZ / UUOU 14 Example 1. A 50 mg / ml ganaxolone suspension was prepared with the ingredients listed in Table 1 below: Table 1 Composition of Ganaxolone 50 mg / ml Suspension Ingredient Grade % w / w mg / ml Ganaxolone GMP 4.91 50.0 Hypromellose (Pharmacoat 603) USP / EP 5.0 50.91 Polyvinyl alcohol USP / EP 1.0 10.18 Sodium lauryl sulfate USP / EP 0.1 1.02 Methylparaben NF / EP 0.1 1.02 Propylparaben NF / EP 0.02 0.20 Sodium benzoate USP / EP 0.09 0.92 Citric acid, anhydrous USP / EP 0.12 1.22 Sodium citrate dihydrate USP / EP 0.0093 0.095 Cherry artificial flavor Firmenich No. 57679 A Pharmaceutical 0.0025 0.025 Sucralose NF 0.02 0.20 Simethicone 30% Emulsion (Dow Corning Q7-2587) USP 0.0333 0.34 Purified Water USP qs 100.0 qs 1.0 mL Table 2 shows the function of the excipients used in the 25 g ganaxolone 50 mg / ml suspension. Table 2. Summary of the function of the ingredients of the 50 mg / ml ganaxolone suspension Ingredient Function Ganaxolone Active pharmaceutical ingredient Hypromellose (Pharmacoat 603), USP / EP Spherical stabilizer of polymeric nanoparticles Sodium lauryl sulfate, USP, EP, NF Electrostatic stabilizer of anionic nanoparticles Table 2. Summary of the function of the ingredients of the 50 mg / ml ganaxolone suspension IVIA / a / ZUZZ / UUOU 14 Ingredient Function 30% Simethicone Emulsion (Dow Corning Q7-2587) Antifoaming Agent Methylparaben USP / NF Nanoparticle Stabilizer and Antimicrobial Preservative Sodium Benzoate Nanoparticle Stabilizer and Antimicrobial Preservative Anhydrous Citric Acid, USP / EP pH Adjustment Propylparaben NF Nanoparticle Stabilizer and Antimicrobial Preservative Sodium Citrate Dihydrate, USP / FCC pH Adjustment Polyvinyl Alcohol 4-88; Emprove® exp PhEur, USP, JPE Stabilizer Sucralose Powder, NF (micronized) Sweetener Artificial Cherry Flavor (Firmenich 502068 C) Flavor Purified Water USP / EP Diluent The oral bioavailability of the 50 mg / ml ganaxolone suspension depends on the rate and extent of drug dissolution in nanoparticles within the relevant physiological environment. The method and particle size specification are intended to ensure that the ganaxolone pharmaceutical product exhibits no agglomeration after dispersion in simulated gastrointestinal fluids. A dispersion nanomilling process was used to reduce the size of the ganaxolone particles and obtain stable ganaxolone nanoparticles. The nanomilling process involved the use of tyria-stabilized zirconia (YTZ) milling media under high-energy agitation within the nanomill. To ensure a consistent suspension particle size prior to dispersion nanomilling, Marinus developed a high-energy rotor / stator premilling process using a VakuMix DHO-1. After nanomilling, the ganaxolone dispersion was diluted from 25% w / w to 20% w / w, filtered through a 20-micron filter, and stabilizing agents (methylparaben, sodium benzoate, and anhydrous citric acid) were added to promote controlled growth during a 5- to 10-day curing period at room temperature to approximately 300 nm.The stabilized 300 nm nanoparticles exhibit good stability against particle growth in pediatric suspension and encapsulated pharmaceutical formulations. The stabilization process was controlled by the precise addition and dissolution of parabens, which are water-soluble stabilizing agents. The curing process was controlled by regulating the holding time and temperature of the stabilized dispersion before dilution of the suspension (in the case of the 50 mg / ml ganaxolone suspension) or fluidized bed bead coating (in the case of the 225 mg ganaxolone capsules described in Example 2). Three batches of dispersion prepared in the dispersion nanomilling scale-up study were diluted and stabilized with the addition of sodium methylparaben, sodium benzoate, and anhydrous citric acid and cured for 7 days. After curing, the particle size was measured and is shown in Table 3. iviA / a / ¿u¿¿ / uuom 4 Table 3. Particle size of stabilized dispersion after 7 days of curing Lot D(10) (nm) D(50) (nm) D(90) (nm) Dispersion lot 1 of 212 298 689 Dispersion lot 2 of 208 289 539; Dispersion lot 3 of 209 291 498 D=diameter As shown, the particle size D(50) stabilized within the 250-450 nm specification. Example 2. Ganaxolone capsules (225 mg) were prepared with the ingredients listed in Tables 4 and 5 below: Table 4. Composition of 225 mg Ganaxolone in IR pearl capsule Ingredient Grade % w / w Ingredient Grade % w / w Ganaxolone GMP 45.06 Hypromellose (Pharmacoat 603) USP / EP 10.28 Sodium lauryl sulfate USP / EP / NF 0.70 Methylparaben sodium USP 0.26 Sodium benzoate USP / EP 0.20 Citric acid, anhydrous USP / EP 0.39 Sodium chloride USP / EP 1.03 Simethicone Emulsion 30% (Dow Corning Q72587) USP 0.11 Sucrose - extra fine granulated EP / NF 23.04 Polyethylene glycol 3350 NF / EP 1.08 Polyethylene glycol 400 NF / EP 0.54 Polysorbate 80 NF / EP, JP 0.65 Spheres microcrystalline cellulose, Grade: CP305 NF / EP 16.65 Total 100.0 Table 5 summarizes the function of the excipients used in the formulation of the 225 mg ganaxolone capsule. MA / a / ZUZZ / UUOUI 4 Table 5. Summary of the function of the ingredients in the 225 mg ganaxolone capsule Ingredient Function Ganaxolone Active pharmaceutical ingredient Hypromellose (Pharmacoat 603) USP / EP Spherical stabilizer of polymeric nanoparticles Sodium lauryl sulfate, USP, EP, NF Electrostatic stabilizer of anionic nanoparticles Simethicone emulsion 30% USP (Dow Corning Q7-2587) Antifoaming agent Sodium methylparaben (Nipagin M Sodium) Nanoparticle stabilizer and antimicrobial preservative Sodium benzoate USP / EP Nanoparticle stabilizer and Ingredient Antimicrobial preservative function Anhydrous citric acid USP / EP pH adjustment Sucrose Binder / filler Sodium chloride Ionic strength modifier Polyethylene glycol 3350 Plasticizer Polyethylene glycol 400 Plasticizer Polysorbate 80 Nonionic surfactant, stabilizer Microcrystalline cellulose spheres (Celphere CP305) IR pearl core Hard gelatin capsule, size 00 Dosage form capsule IR=Immediate Launch IVIA / a / ZUZZ / UUOU 14 The manufacturing process used to prepare these capsules employs the same pharmaceutical product specifications, quantitative compositions, and dispersion stabilization and nanomilling dilution processes as the product in Example 2. Therefore, the product in Example 2 uses a common stabilized dispersion intermediate with the product in Example 1. Sodium methylparaben may be substituted for methylparaben. Table 6 summarizes the results of thirty-six months of formal stability data for the 225 mg ganaxolone immediate release (IR) capsule: Table 6. Thirty-six months of formal stability data for immediate release (IR) Ganaxolone 225 mg capsule (25 °C / 60 % RH) Test Specifications Initial 25 °C / 60 % RH 1 month 3 months 6 months 9 months 12 months 18 months 24 months 36 months Assay (% of label) 90-110% LC 101.4 100.9 100.3 99.2 99.8 99.3 100.6 100.6 98.4 NLT Dissolution Q=80% at 45 minutes 95 % 94 % 90 % 89 % 92 % 94 % 86 % 91 % 87% Table 6. Thirty-six months of formal stability data for immediate release (IR) Ganaxolone 225 mg capsule (25 °C / 60 % RH) IVIA / a / ¿U¿¿ / UUOU 14 Test Specifications Initial 25 °C / 60 % RH 1 month 3 months 6 months 9 months 12 months 18 months 24 months 36 months Profile 15 Result 74, 84, 79, 79, 80, 85, 81, 79, 78, 82, 90, 63, 69, 80, 66, 62, 57, 58, minutes of the 85, 88, 77, 82, 81, 70, 77, 63, 88, 86, 76, 83, 71, 70, 84, 55, 42, 74, report 87, 86 82, 92 83, 78 72, 73 82 70, 88 72, 77, 64, 74 35, 64, 68, 89, 60, 60, 48, 79, 47, 27, 70, 73 79, 60 Profile 30 Result 93, 92, 92, 94, 86, 89, 91, 87, 88, 88, 95, 88, 80, 86, 84, 83, 75, 78, minutes of 92, 94, 86, 88, 88, 89, 87, 80, 90, 92, 85, 91, 77, 76, 92, 83, 81, 83, report 96, 93 88, 97 85, 88 81, 86 94, 92, 83, 93, 78, 85, 87, 89, 66, 85, 83, 90, 79, 71, 76, 88, 86, 60, 81, 87, 86, 85, Profile 45, NLT 80%, 96, 94, 94, 96, 90, 90, 93, 90, 88, 90, 95, 95, 84, 88, 89, 90, 82, 88, minutes, 94, 95, 92, 93, 88, 91, 89, 85, 94, 93, 95, 92, 79, 83, 92, 90, 87, 88, 95, 95 93, 96 91,90 85, 90 96, 94 91, 97 80, 86, 91,93 83, 90, 88, 91, 89, 79, 85, 90, 93, 84, 88, 88 90,91 Profile 60 Result 94, 92, 95, 95, 92, 90, 94, 91, 88, 92, 95, 94, 85, 88, 93, 93, 91, 92, minutes of 95, 95, 94, 93, 89, 90, 90, 85, 94, 93, 94, 94, 80, 85, 94, 96, 88, 89, report 95, 96 95, 95 91,89 86, 91 95, 93 91, 97 84, 85, 93, 93 92, 91, 90, 91, 82, 91, 89, 91, 88, 90, 89, 88, 92, Table 6. Thirty-six months of formal stability data for immediate release (IR) Ganaxolone 225 mg capsule (25 °C / 60 % RH) IVIA / a / ZUZZ / UUOU 14 Test Specifications Initial 25 °C / 60 % RH 1 month 3 months 6 months 9 months 12 months 18 months 24 months 36 months Particle size (D50) nm 250 - 450 nm Volume weighted average diameter (D50) 339 nm 354 nm 336 nm 339 nm 335 nm 344 nm 368 nm 348 nm Example 3 Summary of previous epilepsy clinical trials in epilepsy-related TSC AFINITOR® Phase 3 EPIDIOLEX® Phase 2 EPIDIOLEX® Phase 3 Number of patients enrolled 366 18 224 Duration from baseline 8 weeks 1 month 4 weeks Median seizure frequency from baseline (per month) ~41 94 ~61 Duration of treatment (primary) 18 weeks 3 months 16 weeks Median % change in seizure frequency (placebo response) -14.9% N / A (open-label) -26.5% Median % change in seizure frequency (drug response) Low exposure: -29.3% High exposure: -39.6% -48.8% 25 mg / kg / day: -48.6% High exposure: -47.5% Example 4 A phase 2 clinical trial of ganaxolone in TSC-related epilepsy is being conducted. Approximately 30 male and / or female patients aged 2 to 65 years, inclusive, with TSC-related epilepsy are being evaluated and enrolled. Patients have a clinically confirmed diagnosis of TSC and a mutation in the TSC1 or TSC2 gene. Patients complete a diary of the effect of ganaxolone on seizures. The treatment phase includes two parts: Part A and Part B. In Part A, patients receive ganaxolone for a total of 12 weeks (4 weeks of titration, 8 weeks of maintenance) in addition to their standard anticonvulsant therapy. Patients are titrated to 63 mg / kg / day (max. 1800 mg / day) for 4 weeks and then maintained at that dose for another 8 weeks. Ganaxolone is administered in increments of 15 mg / kg / day up to 63 mg / kg / day as an oral suspension with food. Patients weighing <28 kg are dosed on a mg / kg basis. Patients weighing >28 kg receive fixed doses in increments of 450 mg / day up to 1800 mg / day. Ganaxolone is administered during the 4-week titration period as follows: Oral suspension dosage a for patients weighing < 28 kg (62 lbs) b Total Dose mg / kg / day Days 6 mg / kg TID 18 1-7 11 mg / kg TID 33 8-14 16 mg / kg TID 48 15-21 21 mg / kg TID 63 22-28 Oral suspension dosage a for patients weighing > 28 kg (62 lbs) c Dose mL per dose Total mg / day Days 150 mg TID 3 450 1-7 300 mg TID 6 900 8-14 450 mg TID 9 1350 15-21 600 mg TID 12 1800 22-28 TID = 3 times a day. To be administered in 3 divided doses after a meal or snack. Patients weighing < 28 kg will receive the dose according to their weight in kilograms. Patients > 28 kg will receive doses on a fixed regimen in increments of 450 mg / day up to 1800 mg / day. Any patient who does not tolerate the next dose stage is kept on the lowest dose stage for an additional few days before moving to the next dose. If the next dose is still not tolerated, the patient may return to the next lower dose stage. A minimum dose of 33 mg / kg / day or 900 mg / day is generally required after the dose escalation period, during the maintenance period, unless a lower dose is agreed upon with the sponsor due to tolerability issues, such as drowsiness. Dose changes, including alternative dosing paradigms (e.g., a lower dose during the day and a higher dose at night), are discussed with the Sponsor's medical monitor before making the change or within 48 hours of making the change. Patients who discontinue ganaxolone treatment before completing the maintenance period in Part A will continue to be followed according to the protocol, and at a minimum, patients will be encouraged to maintain daily seizure logs until Part A is completed. These patients will also return to the site 2 weeks after tapering for follow-up safety assessments. Patients with a seizure frequency reduction rate >35% during the 12-week treatment period in Part A compared to baseline (e.g., 4-week baseline) and who have no other contraindications to continued treatment with ganaxolone in the OLE (Part B) phase of the study may continue in Part B (OLE-eligible). Part B is an open-label extension and lasts approximately 24 weeks. Therefore, Part B is available to patients who respond to ganaxolone as defined by the protocol.The main difference between Part A and Part B is the duration of treatment, less frequent assessments, and the ability to modify drug doses (both of ganaxolone and other AED treatments, including starting and stopping other medications) based on the assessment of the patient's clinical course during Part B of treatment. In Part B, patients on ganaxolone continue treatment at the dose they were receiving at the end of Part A. During Part B, ganaxolone doses may be titrated to a maximum of 600 mg TID for patients weighing >28 kg and a maximum dose of 21 mg / kg TID for patients <28 kg. Doses of other anticonvulsant medications may be adjusted (including tapering and initiation of treatment) during Part B at the investigator's discretion. Any patient who completes Part A and does not continue to Part B, or completes Part B, or discontinues treatment with GNX, will undergo a 2-week medication tapering period, unless medically contraindicated, and return to the site 2 weeks later for a follow-up assessment. MA / a / ZUZZ / UUOUI 4 security. Patients who complete Part A and are deemed eligible for Part B continue to take ganaxolone at the same dose they had when completing Part A for an additional 24 weeks of treatment in Part B. Patients may receive a lower dose during the day and a higher dose at night. Anyone discontinuing ganaxolone undergoes a 2-week taper, unless medically contraindicated, such as a drug-induced rash. Patients who discontinue ganaxolone before the end of the maintenance treatment period continue to be followed according to the protocol and, at a minimum, patients are encouraged to keep seizure diaries until the treatment period in Part A is completed. These patients return to the site 2 weeks after tapering for follow-up safety assessments. Patients may return for a 2-week follow-up safety visit (e.g., due to early discontinuation in Parts A or B, not participating in Part B, or completing Part B). The primary efficacy endpoints are to assess the potential of ganaxolone in TSC-related epilepsy over a 12-week period and / or the percentage change in the frequency of primary seizures through the end of the 12-week treatment period (titration and maintenance) in Part A. Primary seizure types include focal motor seizures without impairment of consciousness or awareness, focal seizures with impairment of consciousness or awareness, focal seizures evolving into bilateral generalized convulsive seizures, and generalized seizures with a motor component that are countable. Secondary objectives are to evaluate the safety and tolerability of ganaxolone as adjunctive therapy through the end of the 12-week treatment period (titration and maintenance) in Part A; to evaluate pharmacokinetic (PK) parameters in patients receiving ganaxolone doses up to 63 mg / kg / day (or a maximum of 1800 mg / day) throughout the study; to evaluate the long-term safety and tolerability of GNX when administered as adjunctive therapy throughout Part B. IVIA / a / ZUZZ / UUOU 14 The exploratory objectives are to assess changes in quality of life; to assess behavioral / neuropsychiatric changes in patients receiving ganaxolone as adjunctive therapy at the end of the 12-week treatment period (titration and maintenance) in Part A; to assess the relationship between efficacy response to ganaxolone and biomarker levels (e.g., neurosteroids); to assess the potential effects of ganaxolone on EEG activity; to assess changes in other (non-primary) seizure types in TSC; to assess the effect of ganaxolone on primary seizure-free days; to assess the effect of ganaxolone on epileptic / infantile spasm-free days; and to assess the effect of ganaxolone on epileptic / infantile spasm-free days. A. Pharmacokinetic evaluations: The pharmacokinetic (PK) population will include all patients who have received at least one dose of GNX and from whom at least one sample has been collected and a valid bioanalytical result obtained. Samples will be collected between 1 and 5 hours or between 4 and 8 hours after the last dose during Part A and Part B. Pharmacokinetic analyses will be limited to the concentration list because sufficient concentration-time data will not be available for non-compartmental analyses such as Cmax, AUC, or tmax. Pharmacokinetic data from this study may be used to perform separate population PK analyses outside of this study and reported separately. B. Serum levels of neurosteroids and concomitant AED: Blood samples will be taken at the screening visit, week 12 in Part A, and the final visit in Part B to measure levels of neurosteroids (including allopregnanolone and related CNS-active endogenous steroids and sulfate metabolites, including, for example, alloprenanolone sulfate). Example 5. Biomarker Individuals (n=11) with a confirmed PCDH19 mutation and minimal seizure burden were enrolled between May 2015 and November 2015 at six centers in the US and Italy. The change in seizure frequency (%) was assessed as the primary endpoint and a response was defined as a 25% or greater reduction in seizure rate. Plasma neurosteroid levels were quantified using a previously published GC / MS method (doi:10.1016 / S0028-3908(99)00149-5). In two cases, baseline neurosteroid levels were not measured. In these cases, 6-month values ​​were used. MA / a / ZUZZ / UUOUI 4 that it was observed that neurosteroid levels did not change significantly over time. The median change in seizure frequency at 28 days (all seizure types) from baseline for all participants (n=11) was a 26% decrease. In this group, the mean plasma concentration of allopregnanolone sulfate (Allo-S) was 4,741 pg mL⁻¹ (median = 433 pg mL⁻¹). Analysis of responders and correlation with Allo-S revealed two separate populations. Responders (n=6) (>25% reduction in seizure rate) and non-responders (n=5) had plasma Allo-S concentrations of 501 ± 430 pg mL⁻¹ and 9,829 ± 6,638 pg mL⁻¹, respectively (mean ± SD, p=0.05, Mann-Whitney). The group with positive biomarkers improved significantly (p=0.02, Wilcoxon), while the group with negative biomarkers (high Allo-S) did not improve, but neither did they deteriorate significantly (p=0.25, Wilcoxon), when comparing seizure frequency at 6 months to baseline. Retrospective analysis of subjects with positive biomarkers (n=7, Allo-S < 2500 pg mL-1) versus negative biomarkers (n=4, Allo-S > 2500 pg mL-1) yielded a mean % change in seizure rates of -53.9% and 247%, respectively (p=0.006, Mann-Whitney). Furthermore, the positive biomarker group improved significantly (p=0.02, Wilcoxon Signed Rank) while the negative biomarker group did not worsen significantly (p=0.25, Wilcoxon Signed Rank) when comparing seizure frequency at 6 months with the baseline value. Example 6. Case report 1 for TSC subject enrolled in Part A of open-label phase 2 trial One subject (subject 001) with tuberous sclerosis complex was enrolled in Part A of the open-label Phase 2 trial of adjuvant ganaxolone (GNX) treatment for tuberous sclerosis complex-related epilepsy, according to the study protocol described in Example 4. The subject had a baseline seizure burden of 132.41 per 28 days. Ganoxone was administered orally three times daily at a maximum daily dose of 1800 mg for 11 weeks (78 days). The subject completed the protocol and experienced a 64% reduction in seizures from baseline. This is the first subject to have completed the protocol. Currently enrolled MA / a / ZUZZ / UUOUI 4 additional subjects but have not completed the study. Table 8. Summary of changes in seizures in TSC subjects Subject Seizure frequency from baseline (for 28 days) Treatment duration (days) % change from baseline 001 132.41 78 -64% Example 7. Preliminary pharmacokinetic and pharmacodynamic (PK / PD) analysis A preliminary PK / PD analysis was performed to explore the relationship, if any, between ganaxolone levels and the percentage change in the frequency of major motor seizures. a) Study design A global, randomized, double-blind, placebo-controlled, phase 3 clinical trial to evaluate the safety and efficacy of adjunctive ganaxolone for the treatment of seizures associated with CDD. Patients aged 2 to 21 years with a pathogenic or likely pathogenic mutation of the CDKL5 gene, neurodevelopmental impairment, and seizures refractory to treatment with at least two prior anticonvulsant medications who experienced at least 16 seizures over 28 days during the two months prior to screening were eligible for enrollment. The study consisted of a 6-week baseline followed by a 17-week double-blind phase (ganaxolone or placebo, 1:1). The dose of ganaxolone 50 mg / mL suspension was titrated over 4 weeks to 63 mg / kg / day (21 mg / kg TID), not to exceed 1800 mg / day (600 mg TID), or up to the maximum tolerated dose.Blood draws for PK analysis were scheduled for visit 3 (week 5), visit 4 (week 9) and visit 5 (week 17). b) Methods The mean ganaxolone concentration was calculated for each subject using the available results from up to three laboratory determinations during the double-blind phase. Linear regression was performed using the arithmetic and natural logarithm-transformed percentage reduction in major motor seizures (log[percentage reduction + 100]) as the dependent variable and the mean ganaxolone concentration, also transformed by natural logarithm, as the sole explanatory variable. Regression diagnostics included examining residual and normal probability plots and identifying outliers and influential values. Cases with standardized residuals > 2 or < -2 were excluded from the model, and the regression was repeated. The resulting sample was used to determine a Pearson correlation coefficient (using logarithmically transformed values). In addition, the percentage reduction in seizures was compared across three tertiles representing low (N=13), medium (N=13), and high (N=12) concentrations of ganaxolone per subject using a Kruskal-Wallis test. The number of CNS-related adverse events that suggested possible dose-related toxicity (drowsiness, sedation, lethargy, impaired attention, drooling, and hypotonia) in participants treated with ganaxolone was tabulated, as well as the onset and duration of the events, and the number of participants with CNS adverse events during each week of the double-blind phase was calculated. c) Results Forty-four participants with seizure reduction data had at least one measurement of plasma ganaxolone level (mean ± standard deviation = 103.5 ± 79.2 ng / mL). In a linear regression with the percentage of seizure reduction as the dependent variable and the mean plasma ganaxolone concentration as the independent variable, six cases were identified as outliers due to adjusted residuals > 2 or < -2. Repeating the linear regression excluding these cases (N = 38) yielded an adjusted R² of 0.227 (F(1.36) = 11.89), p = 0.001). The correlation coefficient for mean plasma ganaxolone concentration and the percentage reduction in major motor seizures using the same sample was -0.499 (p = 0.001). A robust regression including all observations (N = 44) reproduced the findings of this analysis. The mean and median percentage reduction in major motor seizures was calculated for the low, medium, and high concentration tertiles of ganaxolone (Table 9). There was a statistically significant difference between groups in the percentage reduction in the frequency of major motor seizures (H(2)=9.087, p=0.011) (Figure 2). Post-hoc pairwise comparisons of the sample distributions for the three groups showed a statistically significant difference between the low and high GNX level groups, but not for other between-group tests. Table 9. Tertiles based on mean plasma concentration of ganaxolone GNX Level Groups Mean GNX Level (ng / ml) Mean Percentage Change in Major Motor Seizures (every 28 days) Median Percentage Change in Major Motor Seizures (every 28 days) Low (n = 13) 40.2 -6.5 -8.4 Median (n = 13) 72.3 -30.3 -39.5 High (n = 12) 172.6 -44.3 -46.0 IVIA / a / ZUZZ / UU0U14 In summary, the logarithms of plasma ganaxolone levels and the percentage change in the frequency of major motor seizures were negatively correlated. Increases in plasma GNX levels were associated with greater reductions in seizure frequency in the 27–333 ng / mL range in patients with CDKL5 deficiency disorder (CDD). The inverse transformation of the logarithmic values ​​indicates that a plasma concentration of approximately 100 ng / mL (the mean in the CDD population) predicts an approximately 40% reduction in seizures in the participants of this study. Modeled pharmacokinetic curves based on previous phase 1 studies demonstrate that TID dosing can increase trough levels of GNX compared to BID dosing. Results from preliminary PK / PD analysis suggest that increased plasma ganaxolone concentrations were associated with greater seizure reduction and that concentrations of approximately 100 ng / mL are associated with significant changes in seizure frequency. Based on the modeled PK curves, TID dosing can produce plasma ganaxolone levels >100 ng / mL for approximately 78% of a 24-hour day compared to only 53% with BID dosing. While these analyses do not preserve randomization and therefore may not represent the causal effects of GNX on changes in seizure frequency, they suggest that TID dosing could provide greater anticonvulsant benefits.

Claims

1. A method for treating tuberous sclerosis complex or tuberous sclerosis complex-related epilepsy comprising administering to a subject in need a therapeutically effective amount of a pharmaceutically acceptable pregnenolone neurosteroid or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the pregnenolone neurosteroid is ganaxolone.

3. The method of any of the preceding claims, wherein the pregnenolone neurosteroid is administered three times a day.

4. The method of any of claims 1-2, wherein the pregnenolone neurosteroid is administered twice daily.

5. The method of any of the preceding claims, wherein the subject is administered from about 200 mg per day to about 1800 mg per day of ganaxolone.

6. The method of any of claims 1-4, wherein the subject is administered up to about 1800 mg per day of ganaxolone.

7. The method of any preceding claim, wherein ganaxolone is administered at approximately 1500 mg per day of ganaxolone.

8. The method of any of the preceding claims, wherein ganaxolone is administered in an amount of up to 63 mg / kg / day.

9. The method of any of the preceding claims, wherein the pregnenolone neurosteroid is administered orally.

10. The method of any of the preceding claims, wherein the pregnenolone neurosteroid is administered as an oral suspension.

11. The method of any of the preceding claims, wherein the pregnenolone neurosteroid is administered as an oral capsule.

12. The method of any of the preceding claims, wherein the epilepsy related to the tuberous sclerosis complex is infantile spasm.

13. The method of any of the preceding claims, wherein the epilepsy related to tuberous sclerosis complex is a focal seizure of altered consciousness.

14. The method of any of the preceding claims, wherein the epilepsy related to tuberous sclerosis complex is a focal seizure.

15. The method of any of the preceding claims, wherein the epilepsy 83 related to the tuberous sclerosis complex is a generalized seizure.

16. The method of any of the preceding claims, wherein the administration of the neurosteroid pregnenolone reduces the frequency of seizures and / or the severity of seizures in the subject with respect to the initial value.

17. The method of any of the preceding claims, wherein administration of the neurosteroid pregnenolone reduces the seizure frequency by about 20% or more with respect to the initial seizure frequency.

18. The method of any of the preceding claims, wherein administration of the neurosteroid pregnenolone reduces the seizure frequency by at least about 35% or more with respect to the initial seizure frequency.

19. The method of any of the preceding claims, wherein the subject is monitored by electroencephalogram (EEG).

20. The method of any of the preceding claims, wherein the convulsive activity in the subject is monitored by electroencephalogram (EEG).

21. The method of any of the preceding claims, wherein the ganaxolone is administered in a sufficient amount to provide a plasma ganaxolone concentration in the subject of about 100 ng / mL for approximately 70% or more during a 24-hour day.

22. The method of claim 21, wherein ganaxolone is administered three times a day.

23. The method of any of the preceding claims, further comprising: measuring the level of an endogenous neurosteroid in the subject prior to administering the pregnanolone neurosteroid, wherein a subject having a low endogenous neurosteroid indicates that the subject will respond to the pregnanolone neurosteroid; and administering a therapeutically effective amount of the pregnanolone neurosteroid to the subject having a low level of endogenous neurosteroid.

24. The method of claim 23, wherein the endogenous neurosteroid is allopregnanolone sulfate.

25. The method of any of claims 23 or 24, wherein the low level of endogenous neurosteroid is an amount of 2500 pg mL·1 or less.

26. The method of claim 25, wherein the pregnenolone neurosteroid is ganaxolone.

27. A method for treating tuberous sclerosis complex or tuberous sclerosis complex-related epilepsy comprising administering ganaxolone to a subject in need in a therapeutically effective amount that produces a plasma ganaxolone concentration of at least about 100 ng / ml for at least about 70% or more during a 24-hour day period.

28. The method of claim 27, wherein ganaxolone is administered three times a day.

29. The method of any of claims 27 or 28, wherein ganaxolone is administered orally.

30. The method of any of claims 27-29, wherein ganaxolone is administered as an oral suspension.

31. The method of any of claims 27-29, wherein the ganaxolone is administered as an oral capsule.

32. The method of any of claims 27-31, wherein ganaxolone is administered in an amount of up to 63 mg / kg / day.

33. The method of any of claims 27-32, wherein ganaxolone is administered in an amount of up to 1800 mg per day.

34. The method of any of claims 27-32, wherein ganaxolone is administered in an amount of up to 1500 mg / kg per day.

35. The method of any of claims 27-34, wherein the epilepsy related to tuberous sclerosis complex is infantile spasm, focal seizure of altered consciousness, focal seizure, or generalized seizure.

36. The method of any of claims 27-35, wherein the administration of ganaxolone reduces the frequency of seizures and / or the severity of seizures in the subject with respect to the initial value.

37. The method of any of claims 27-35, wherein the administration of ganaxolone reduces the main motor frequency in the subject with respect to the initial value.

38. The method of any of claims 27-35, wherein the administration of ganaxolone reduces the seizure frequency by about 20% or more with respect to the initial seizure frequency.

39. The method of any of claims 27-35, wherein the administration of ganaxolone reduces the seizure frequency by at least about 35% or more with respect to the initial seizure frequency.

40. The method of any of claims 27-39, wherein the subject is monitored by electroencephalogram (EEG).

41. The method of any of claims 27-39, wherein the convulsive activity in the subject is monitored by electroencephalogram (EEG).

42. A method for treating a subject who has or is suspected of having tuberous sclerosis-related epilepsy, comprising determining whether the subject has a low level of an endogenous neurosteroid; and administering a therapeutically effective amount of a pharmaceutically acceptable pregnenolone neurosteroid or a pharmaceutically acceptable salt thereof to the subject if the subject has a low level of the endogenous neurosteroid.

43. The method of claim 42, wherein the endogenous neurosteroid is allopregnanolone sulfate, and the pregnenolone neurosteroid is ganaxolone.

44. The method of any of claims 42 or 43, wherein the endogenous neurosteroid is allopregnanolone sulfate and the low level of the endogenous steroid is a level of 2500 pg mL·1 or less.

45. The method of any one of claims 42-44, wherein the pregnenolone neurosteroid is a compound of Formula IA: or a pharmaceutically acceptable salt thereof, wherein: XesO, SoNR10; R1 is hydrogen, hydroxyl, -CH2A, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl or optionally substituted arylalkyl;A is hydroxyl, O, S, NR11, optionally substituted five-membered heteroaryl containing nitrogen, optionally substituted five-membered heteroaryl containing nitrogen or optionally substituted bicyclic heteroaryl containing nitrogen or bicyclic heterocyclyl, R4 is hydrogen, hydroxyl, oxo, optionally substituted alkyl or optionally substituted heteroalkyl, R2, R3, R5, R6 and R7 are each independently absent, hydrogen, hydroxyl, halogen, an optionally substituted Ci-Ce alkyl, an optionally substituted CiCe alkoxyl (e.g., methoxyl) or optionally substituted heteroalkyl; R8 and R9 are each independently selected from a group consisting of hydrogen, a Ci-Ce alkyl (e.g., methyl), a halogenated Ci-Ce alkyl (e.g., trifluoromethyl), or a Ci-C6 alkoxy (e.g., methoxy), or R8 and R9 form an oxo group;R10 is hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, or optionally substituted arylalkyl, where each alkyl is a C1-C10 alkyl, C3-C6 cycloalkyl, Cs-Ce cycloalkyl, or C1-C4 alkyl, and optionally contains a single bond replaced by a double or triple bond; each heteroalkyl group is an alkyl group in which one or more methyl groups are replaced by independently chosen -O-, -S-, -N(R10)-, -S(=O)-, or -S(=O)2-, where R10 is hydrogen, alkyl, or alkyl in which one or more methylene groups are replaced by -O-, -S-, -NH, or -N-alkyl; R11 is -H2O-HR12; R12 is Ci-Ce alkyl or Ci-Ce alkoxy.

46. ​​The method of claim 45, wherein the pregnenolone neurosteroid is selected from the group consisting of allopregnanolone, pregnenolone, 5-alphaDHP (5-alphadihydroprogesterone), pregnanolone, dehydroepiandrosterone (DHEA), ganaxolone, 3αhydroxy-3P-methyl-21-(4-cyano-1H-p-razol-1'-1I)-19-nor-5P-pregnan-20-one, pharmaceutically acceptable salts of any of the foregoing and combinations of any of the foregoing.

47. The method of any of claims 42-46, wherein the pregnenolone neurosteroid is administered orally.

48. The method of any of claims 42-47, wherein the subject is administered up to approximately 63 mg / kg / day of ganaxolone.

49. The method of claim 48, wherein the subject is administered up to approximately 33 mg / kg / day of ganaxolone.

50. The method of any of claims 42-47, wherein the subject is administered up to about 1800 mg per day of ganaxolone.

51. The method of any of claims 42-47, wherein the subject is administered up to about 1,500 mg per day of ganaxolone.

52. The method of claim 42-51, wherein the tuberous sclerosis complex-related epilepsy is selected from the group consisting of a focal motor seizure, a focal seizure, or a generalized seizure.

53. The method of any of claims 42-52, wherein the administration of ganaxolone reduces the frequency of seizures and / or the severity of seizures in the subject with respect to the initial value.

54. The method of any of claims 42-53, wherein the administration of ganaxolone reduces the main motor frequency in the subject with respect to the initial value.

55. The method of any of claims 42-53, wherein the administration of ganaxolone reduces the seizure frequency by about 20% or more with respect to the initial seizure frequency.

56. The method of any of claims 42-53, wherein the administration of ganaxolone reduces the seizure frequency by at least about 35% or more with respect to the initial seizure frequency.

57. The method of any of claims 42-56, wherein the subject is monitored by electroencephalogram (EEG).

58. The method of any of claims 42-56, wherein the convulsive activity in the subject is monitored by electroencephalogram (EEG).

59. The method of claim 42, wherein the endogenous neurosteroid is allopregnanolone and a low level of allopregnanolone is 200 pg mL'1 or less.

60. The method of claim 42, wherein the endogenous neurosteroid comprises allopregnanolone, allopregnanolone sulfate, pregnenolone, pregnenolone sulfate and mixtures thereof.