Li Zizhong 1, Bu Dingfang 2, Mu Ying 3, Qu Chuanyan 4,
Liu Shenru 2, Li Zhihuai 5, Wu Yuwei 6, Pan Yanlai 7

[Abstract] Objective In order to confirm the curative effect of Li's Prescription No.5 in treatment of various encephalic diseases, a follow-up study was carried out on 1 164 patients for three successive months. Method Criteria for case selection and for interpreting curative effect were established. A retrospective therapeutic analysis was made on the basis of reexamination. Results After treatment with Li's Prescription No.5, 641 (55.1%) cases showed notable effect and 452 (38.8%) cases showed general effect, the total effective rate being 93.9%. Those with protracted course of seqelae or retrograde affection also showed improvement in varying degrees after treatment. Conclusions Li's Prescription No.5 does have curative effect on encephalopathy. There isn't any direct connection between curative effect and the cause and kind of the disease and the patient's age, this suggests that the mechanism of the drug action is nonspecifically promoting restoration of damaged brain functions.
[Key words] Li's Prescription No.5 Encephalopathy Retrospective survey

Wound and disablement of nervous system caused by such factors as abnormal development, genetic disease, perinatal injury, trauma, vascular disease, infection, degeneration or retrograde affection are frequently encountered in clinical practice. At present, no specific remedies for such diseases are available. In foreign countries, treatment relies mainly on physical therapy and dirigation and in this country on acupuncture
and moxibustion, massage, pharmacotherapy
and dirigation. For more than 10 years, we have used Li's traditional Chinese medicinal
prescription to treat various diseases that

Authors' units: 1. Guangdong Gaoming Medical and Medicinal Institute of Encephalopathy. 2. Department of Pediatric Neurology, Beijing Medical University. 3. Department of Genetic Diseases, Beijing Medical University. 4. Center for Maternity and Infant Health, Beijing Medical University. 5. Guangdong Institute of Geriatrics. 6. Department of Neurointernal Medicine, the People's Hospital of Guangdong Province. 7. The People's Hospital of Guangdong Province.
affect the functioning of the brain and got satisfactory results. In 1994, a follow-up study had been carried out on 1 864 patients with encephalopathy seen in Gansu Province. During the period May-August 1997, a retrospective therapeutic survey was made on patients treated previously in provinces of Zhejiang, Jiangxi, Yunnan and Guangdong. Reported herein are the results of the second survey.
Subjects and Methods
Subjects
Case Selection All patients who had been treated previously were informed of their going back to the follow-up survey spots for a follow-up study by telephone or by sending off letters. All return-visit patients served as subjects of therapeutic survey without selection, except those taking Li's Prescription No.5 for less than three months; receiving acupuncture and moxibustion, massage, breathing exercises and other traditional Chinese or Western medicines at the same time, or receiving radicotomy of back or orthopedic therapy within a recent year; and having infection or injury of nervous system for less than a year, or showing improvement in symptoms in recent 6 months though the disease lasted for over a year.
Methods
Methods of Investigation A repeated inquiry about cause of disease and a repeated physical examination were made with consulting films of both CT scanning and MRI and relevant laboratory findings including EEG to check the diagnosis. Detailed inquiries were made of patients and their families about changes in the following aspects before and after treatment: (1) motor function including function and posture of lifting head, standing, sitting, walking, running and hands, myodynamia, muscular tension, involuntary movement, coordinate movement and stiff joint; (2) linguistic function including the number of words and phrases, the length of sentences, the ability to express clearly, the degree of enunciation, and the comprehension and response to speech; (3) learning and cognition including the awareness of the name, form of address, age and occupation of oneself and his (her) family members, numeral and counting ability, attention, school records, and memory; (4) social adaptive capacity including the ability to take care of oneself in daily life, housework, the ability to communicate with others, sense of shame, risk consciousness, and status of attending school and working; (5) mental symptoms including restlessness, excitation, aggressive and destructive behavior, or timidness, shrink and eccentric behavior; and (6) development of body height, body weight and head circumference, strabismus and hearing ability.
Interpretation of Curative Effect Notable effect: A significant improvement in at least 3 of the above items(1)-(6) with increased social adaptive capacity. General effect: An improvement in at least 2 of the above items (1)-(6) with partially increased motor function or social adaptive capacity. Failure: Showing no change or improvement in only 1 item. In a small number of patients who had only one abnormality (such as limb paralysis, deafness, etc.), the interpretation of curative effect was based on the change of the symptom before and after treatment.
Results
Cases and Status of Treatment
Cases followed up accounted for 85% of the total number of cases that should be followed up. There were 1 164 cases in all that satisfied the criteria for case selection. All the patients selected took Li's Prescription No.5 only. Of the 1 164 patients, 436 had taken the medicine for 3-6 months, 504 for 6-12 months, 128 for 12-18 months, and 72 for more than 18 months. There were 596 patients who had been taking the medicine, 261 patients had withdrawal of the medicine for less than a year, and 283 patients had withdrawal of the medicine for a year or over. No adverse reaction to Li's Prescription No.5 was found during the follow-up study.
Curative Effect
Curative Effect on Mental Retardation and Cerebral Palsy
As shown in Table 1, of the 590 cases of mental retardation (MR), 386 had concomitant cerebral palsy. Simple cerebral palsy was seen in 178 cases. MR patients in this series had IQ<50 in most cases, their cerebral palsy was mostly spastic and in a small number of cases it was extrapyramidal or mixed type. EEG showed diffused inactive echoes in most cases and spike wave, sharp wave and spike and ware complex in a small number of cases. Disseminated low-density change of cerebral hemisphere and peripheral hydrocephalus were commonly found in skull CT scanning. Acquired factors such as perinatal suffocation, anoxia, ischemia, nuclear jaundice, brain infection in early infancy, and severe general infection were, for the most part, the contributing factors in the development of disease, and in a small number of cases the cause of disease was unknown. For treatment of encephalopathy due to congenital factors, see Table 2.
After treatment with Li's Prescription No.5, the vast majority of cases showed marked improvement in cerebral palsy and feeblemindedness, epilepsy was controlled, and visuoauditory function got improved. Of the 590 MR cases, 524 showed progress in speech, as manifested by increased number of words and phrases, increased length of sentences, and clear enunciation as well as awareness of family members' names. Thirty-eight patients who had had unclear enunciation could sing "Ma ma is the best in the world" or could even recite some Tang poems. Two hundred and sixty-four patients showed highly increased ability to take care of themselves in daily life and to do housework. Forty-one patients had a desire to go to school or to work on a job. One hundred and eighty-nine patients had their restlessness, aggressive behavior, catalepsy or timidness basically controlled and became obedient and active in getting in touch with others. Of the 564 patients with cerebral palsy, 79 who had been unable to stand were able to walk, and 126 who had walked unsteadily were able to walk steadily for a longer distance. Disappearance or abatement of scissors' gait was observed in cases showing effectiveness. One hundred and ninety-two patients had reduced muscular tension of upper limbs with fingers stretched out. In short, the total effective rate of treating MR or cerebral palsy was over 90%.


Table 1 The curative effect of treating MR and cerebral palsy
No.of Notable General Failure
cases effectiveness effectiveness
Mental retardation (MR) 204 110 84 10
MR with concomitant cerebral palsy 386 217 150 19
Simple cerebral palsy 178 93 79 6
Total 768 420 313 35

Typical Cases
Case 1 Cui ×× was a boy of seven year and six months of age. No obvious abnormalities were found during gestational, perinatal and neonatal period. When he was 8 months old, he was found to stretch his upper limbs backward when putting forth his strength. He started to walk independently at 4 and speak at 5. Physical examination showed restlessness, strabismus of both eyes, increased muscular tension of extremities,
70°abduction angle of both thighs and positive ankle-clonus. Skull MRI showed negative findings. He was diagnosed as having mental retardation with concomitant cerebral

palsy. After oral administration of Li's
Prescription No.5 for seven successive months, he could walk steadily, go upstairs and downstairs alone and run and could catch a rubber ball with hands. Before treatment he could only utter a few words and hum a tune and now could say "Grandfather eats orange with his mouth arching repeatedly" and sing the song "Ma ma is the best in the world". He could take care of himself in daily life and started to attend first grade of primary school.
Case 2 Zhao××，male, aged 19 years. No obvious abnormalities were found during gestational, perinatal and neonatal period. Only at the age of 2 could he sit and only at the age of 3 could he speak. He had hypophrenia. Physical examination showed sluggish expression, strabismus of both eyes, basically normal muscular tension, and tendon reflex (++), no pathologic sign was elicited. Skull CT scanning showed mildly enlarged ventricles. He was diagnosed as having mental retardation and was given Li's Prescription No.5 for oral administration. Eight months later he made marked progress in speech and other aspects. He could only utter a few words with unclear enunciation before treatment. After treatment he could say "I cherish the memory of maternal grandfather. If he were alive, I would call at his home." Before treatment he could only carry a pail of water and after treatment he could not only carry a pail of water, make a fire and feed pigs but also buy some things in shop according to parents' request. He became more lively than he had been before and active in getting in touch with others. He actively asked his parents to take him to the hospital of Director Li to buy medicine.
Curative Effect on MR Caused by Congenital Deformity Syndrome See Table 2. Deformity syndrome included chromosome abnormalities, diseases of gene mutation, environmental teratogenesis, and congenital deformities of unknown causes. In our series of patients, 49 patients were found to have had trisomy 21 syndrome and 39 patients to have had Gillian Turner-type X-linked mental deficiency syndrome, Prader-Willi's syndrome, Cohen's syndrome, hypothyroidism (cretinism) and phenylketonuria, respectively. Patients with trisomy 21 syndrome all had typical appearance, one-line palm and separation of the first and the sencond toes, all of which were confirmed by chromosome examination in part of the patients. The clinical manifestations of Gillian Turner-type X-linked mental deficiency syndrome in many patients were testicular enlargement, large ears with prominence, and prominent forehead and chin, all of which were demonstrated by chromosome examination. Prader-Willi's syndrome was manifested as hypomyotonia, obesity and small hands and feet. The clinical manifestations of Cohen's syndrome were maldevelopment of incisor protuberance, obesity and hypomyotonia. Phenylketonuria, caused by hereditary phenylalanine metabolic disturbance, was manifested as urinous odor, positive FeCl3 reaction, and elevated blood phenylalanine. Cretinism was characterized by dwarf, pachycheilia, macroglossia, and low levels of T4 and TSH. No manifestations of paralysis were observed in hypophrenia caused by chromosomal aberration or gene mutation. Of the 49 patients with trisomy 21 syndrome, 36 showed increased and fluent talk and responded quickly to conversation after treatment. Twenty-four patients had learned to entertain a guest warmly and to do housework actively. Seventeen patients showed an increased ability to take care of themselves in daily life and began to pay attention to hygiene and clothing, they also gave increased points in IQ test. The other 39 patients with deformity also showed marked improvement in ability to take care of themselves in daily life, speech and adaptive capacity. Typical cases are as follows:
Case 1 Mr.Yang, aged 22 years, had typical trisomy 21 syndrome and showed a karyotype of 47XY+21. After taking the medicine for 7 successive months he showed an increased and fluent talk and liked to talk about television and movie with his family members. He poured a cup of tea and gave a cigarette to a guest, being very warm. He could keep in mind the guest whom he had contacted with once. He liked to do housework seriously and orderly. He grew taller by 2 cm in the recent year.
Case 2 He××，a boy aged 12 years, was fat with small palpebral fissure, downwards oblique external canthus of both eyes, protuberance on upper incisor teeth, mild thoracic kyphosis and hypophrenia. He was diagnosed as having Cohen's syndrome. After taking the medicine for 19 successive months, he had learned addition and subtraction within two digits. He could distinguish banknotes of different denominations, make a phone call, know and write some words, and recite some children's songs, his enunciation was more clear than before. His hands were more nimble than before and the posture of camptocormia and rotation in moving disappeared.

Table 2 Curative effect on MR caused by congenital deformity syndrome
No.of cases Notable effectiveness General effectiveness Failure
Trisomy 21 syndrome 49 13 27 9
Other deformities 39 26 12 1
Total 88 39 39 10

Curative Effect on Sequelae of Infection of the Brain, Cerebrovascular Diseases and Brain Trauma (Table 3)


Table 3 Curative effect on sequelae of infection of the brain, cerebrovascular diseases and
brain trauma
No.of Notable General Failure
cases effectiveness effectiveness
Sequela of encephalitis 48 26 15 7
Sequelae of toxic encephalopathy 52 30 22 0
due to infection and meningitis
Brain injury due to convulsion and epilepsy 21 5 13 3
Sequelae of cerebrovascular diseases 35 14 18 3
Sequela of brain trauma 19 6 9 4
Sequela of brain operation 3 3 0 0
Fish bile poisoning 2 2 0 0
Others 15 9 6 0
Total 195 95 83 17

Included in this series were hypophrenia and dyskinesia caused by brain injury, cerebrovascular diseases, inflammation and other etiological factors after infancy. The diagnosis was based mainly on medical history, physical examination and data of accessory examinations. Preschool children and school-age children predominated in patients of this series, 13 patients were less than 3 years of age and 92 patients more than 18 years of age. Dyskinesia was found in 176 cases, intellectual disturbance in 92 cases, complicated epilepsy in 56 cases, and complicated behavior disorder in 40 cases.
Treatment with Li's Prescription No.5 led to improvement in symptoms and signs in varying degrees. Satisfactory results, especially the promotion of intelligence, were obtained in treating sequelae due to viral encephalitis, toxic encephalopathy due to infection and meningitis. Even better curative effect can be expected if this medication is combined with acupuncture and moxibustion, massage and rehabilitation training. Typical case is as follows:
Case Mr.Shang, aged 31 years, had encephalitis in March 1993 and experienced coma for more than a month, which was followed by hemiplegia on the right side, mental and reactive retardation, stubbornness, involuntary laugh, and choke and cough in drinking water. He failed to respond to medical treatment in many ways. Six months after treatment with Li's Prescription No.5, he could walk some 50 metres alone, understand what other persons said, and say complete sentences. Only 3 months after oral administration of the medicine could he sell good in his own shop and work out accounts with electronic calculator. Such symptoms as involuntary laugh disappeared basically.
Curative Effect on Retrograde Encephalopathy (Table 4)


Table 4 Curative effect on retrograde encephalopathy
No.of Notable General Faliure
cases effectiveness effectiveness
Senile dementia 32 23 9 0
Extrapyramidal diseases 45 27 17 1
Cerebellar and spino-cerebellar degeneration 16 9 6 1
Others 8 0 5 3
Total 101 59 37 5

Senile dementia in this series included Alzheimer's disease, vascular dementia and mixed type dementia. Extrapyramidal diseases included Parkinson's disease, Parkinson's syndrome and torsion dystonia. Cerebellar diseases included cerebellar atrophy caused by arteriosclerosis and cerebral infarction, olivo-ponto-cerebellar atrophy, cerebellar cortical degeneration and Friedreich ataxia. Other cases included demyelinating disease, leukodystrophy, mitochondrial encephalomyopathy, etc.
Li's Prescription No.5 has notable curative effect on dementia as manifested by improvement in memory, affective disorder, psychonosema, and personal care. Curative effect is, of course, related to such factors as duration of illness, age, type of dementia and the degree of support enjoyed from society and family. Li's Prescription No.5 is effective in controlling tremor and hypermyotonia. It controls the advance of illness, reduces the dosage of dopamine preparation or even stops the use of dopamine preparation. It is less effective in treating torsion dystonia and athetosis. Cerebellar degeneration belongs to retrograde affection of nervous system, many cases of cerebellar degeneration are concerned in heredity and are in progressive development. At present, no specific remedy for cerebellar degeneration is available in modern medicine. Of the 16 cases treated with Li's Prescription No.5 and followed up, 9 showed notable effectiveness, and 6 showed general effectiveness. The effect of the treatment varied with the individual. Typical cases are as follows:
Case 1 Mrs. Zheng, age 74 years, had hypomnesis 6 years ago, with unclear enunciation and eccentric behavior. In the recent two years, she could neither recognize any of her family members nor recollect the past. She always defecated and urinated anywhere without the sense of shame, and always stuck out her tongue. Skull CT scanning showed encephalatrophy. She was diagnosed as having Alzheimer's disease and was given Li's Prescription No.5 for oral administration. Three months later her memory got highly improved, she could recognize her family members and call their names, could understand what other persons said, and could talk with others on her own initiative. She now kept her tongue within her mouth and no longer defecated and urinated anywhere.
Case 2 Mr.Ai, aged 63 years, had cerebral infarction three years ago. When discharged from hospital, he had weakness of right limbs, slurred speech with an irrelevant answer, and expressional sluggishness. One month later he had tremor of fingers, bradypragia, festinating gait and marked hypomnesis. Skull CT scanning showed lacunar cerebral infarction and mild encephalatrophy. He was diagnosed as having lacunar cerebral infarction and Parkinson's syndrome and was given oral administration of Li's Prescription No.5. Forty days later tremor of fingers disappeared, and he became articulate, could step forward, and felt clearheaded.
Curative Effect on Visuoauditory Disturbance and Autism (Table 5)


Table 5 Curative effect on visuoauditory disturbance and autism
No.of Notable General Failure
cases effectiveness effectiveness
Sound perception nerve deafness 5 2 3 0
Optic atrophy 6 1 1 4
Autism 7 1 5 1
Total 18 4 9 5

The curative effect of Li's Prescription No.5 on sound perception nerve deafness, optic atrophy and autism warrants further observation and study. Two patients had deafness due to streptomycin poisoning. One, aged 3 years and 6 months, had his hearing improved after taking the medicine for three successive months, could learn to speak following his parents, and could say "I want to eat something ," "I want to have a bowel movement." His eyes could trace the direction of a sound. The other, aged 16 years, had an account in his own words after taking the medicine for 17 successive months: " My right ear can hear you, my left ear is ringing but also can hear a little." The patient could hear you if you spoke loudly behind him. The treatment also led to improved hearing in the other three cases. One of the 6 MR children with concomitant cerebral palsy and optic atrophy in Table 1 had his naked visual acuity increased from 0.1-0.2 to 0.6-0.8 after taking the medicine, and another patient had his visual acuity improved after taking the medicine for a year and could get out of the obstacle when walking. Seven affected children with autism showed improvement in intelligence and in dystropy after treatment.
The Total Curative Effect of Li's Prescription No.5 on Various Encephalic Diseases (Table 6)

Table 6 Total curative effect of Li's Prescription No.5 on various encephalic diseases
Notable General Failure
effectiveness effectiveness
No.of cases 641 452 71
Percentage (%) 55.1% 38.8% 6.1%

The total effective rate was as high as 93.9%. It is evident that Li's Chinese medicinal prescription does have curative effect on diseases of central nervous system regardless of the site (cerebral cortex, basal ganglion, brain stem or cerebellum) of pathologic change, the nature (trauma, vascular disease, inflammation, degenerative disease or congenital disease) of lesion and the length of duration of illness. This is the conclusion drawn from treatment of several ten thousand patients over ten years and has been demonstrated by this retrospective survey.
Discussion
Li's Prescription No.5 consists mainly of tortoise plastron, wolfberry fruit, Siberian solomonseal rhizome, grassleaved sweetflag rhizome, bitter cardamon, Chinese angelica root, polygala root and safflower and has the efficiency of tonifying the kidney and marrow, promoting qi circulation and activating collaterals, promoting the production of blood and strengthening the bone, and promoting blood circulation by removing blood stasis. This retrospective survey made on 1 164 cases of encephalopathy has demonstrated that Li's Prescription No.5 has notable therapeutic effect on various diseases that affect the functioning of the brain. What is the mechanism of its action? The serial experimental studies which we have carried out for years may help to elucidate the mechanism. In 1995, Wu Yongjie, a pharmacological professor of Lanzhou Medical College, demonstrated by animal experiments that Li's Prescription No.5 promoted the mice's learning and memory capacities; increased the effect of anti-ischemia and anti-anoxia, inhibited the formation of free radicals, improved energy metabolism of the brain; enhanced levodopa-induced mechanical movement in the mice, indicating that it has the action of enhancing dopaminergic nervous function; and promoted development of the brain and the body. (1) Wu later demonstrated that Li's Prescription No.5 markedly decreased cell apoptosis of in vitro cultured mesencephalic neurons of rat embryo; made the cell bodies of dopaminergic neruons of dense area of black substance of rats in study group larger than those in control group, the extent of the increase being related to the dosage of Li's Prescription No.5; and had nerve protective effect on striate body of black substance of experimental Parkinson's disease model. (2) The in vitro culture of nerve cells is an ideal extracorporeal model for studying mechanism of neuronal injury and drug action. PC12 cell is the clone formed by pheochromocytoma of adrenal medulla of rat and has the characteristics of typical neuroendocrine cells. (3) A study in collaboration with professor Liu Guoqing of China Pharmaceutical University and professor Li Rui of Guangzhou University of Traditional Chinese Medicine and Materia Medica showed that decoction (containing volatile oil ingredient ) of Li's Prescription No.5 and medicated serum of Li's Prescription No.5 do promote the proliferation of PC12 cells, the proliferation rate being 63.9% and inhibit ischemic and anoxic injury, the inhibition rate being as high as 93%. (4) The experimental studies demonstrated that Li's Prescription No.5 has the effects of improving metabolism of brain cells, inhibiting apoptosis of brain cells, facilitating development of brain cells, and improving functioning of brain cells. It is, therefore, applicable to clinical treatment of mental retardation, cerebral palsy, retrogressive diseases (senile dementia, Parkinson's disease), brain trauma, cerebrovascular disease, sequela of encephalitis and congenital brain diseases caused by chromosomal aberration, gene mutation and hereditary metabolic disease.
According to the theory advanced based on clinical and experimental study that there might exist a functional adjusting point in the brain, Li's Prescription No.5 is easy to permeate blood-brain barrier, improves the metabolism of brain cells, regulates the anion-cation imbalance in the brain, maintains a high-energy magnetic field, and interferes with and improves the brain function in the form of electromagnetic wave.
The discovery of the plasticity of central nervous system after injury in the 1950s demonstrated the axonal growth after neuronal injury and the relationship between axonal regeneration and neuronal type and control of axonal microenvironment (5), thus overthrowing the conclusive statement in the beginning of the 20th century that damaged brain cells had no power of regeneration. In November 1998, Peter S.Eriksson of Sahlgrenska University Hospital, Goteborg; Sweden, Fred H.Gage of Salk Biological Institute, California, U.S.A. and their colleagues published the astonishing news: the human adult brain does routinely produce neurons in at least one part－hippocampus. (6) Like bone marrow, the cerebrum also has stem cells. These stem cells exist only in certain parts of the brain such as hippocampus. Researchers are looking for regulatory factors to make the stem cells proliferate, then migrate and differentiate, and finally restore the structure and function of the brain. This will be an arduous and long-term effort. Li's Prescription No.5 produced on the basis of long standing and well established traditional Chinese medicine provides good micro-environment for the axonal regeneration of neurons and the proliferaiton and differentiation of cerebral stem cells, greatly enhances the plasticity of central nervous system, and facilitates regeneration of central nerve cells. Gratifying dawn emerges in the treatment of encephalopathy.
References
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2. Li Zizhong. Studies on treatment of nerve retrograde affection with Naokang Capsule (originally Li's Prescription No.5). Symposium of 98' Seminar on Traditional Medicine of Asia-Pacific Region, May 1998; 5.
3. Peruche B, Krieglstein J. Neuroblastoma cells for testing neuroprotective effects. J. Pharmacol Meth, 1991, 23:63.
4. Liu Guoqing, Li Rui, Jiang Xuehua, et al. Protection on ischemia-like injury and improving effects on proliferation of Lishi No.5 on neuron. Pharmacol and Clin of Chin Materia Medica, 1999, 15 (2):32.
5. Lund RD (1978). Development and plasticity of the brain, New York; Oxford University Press.
6. Gerd kempermann and Fred H Gage. New nerve cells of human adult brain. Scientific American, May 1999; 48-53.