We have used the technique of antibody mediated cell dependent immune lysis to examine paired samples of serum and CSF for antibody to herpes simplex virus. The 40 patients studied had no inflammatory disease of the nervous system, yet 20 of the CSF specimens did have antiviral antibody. This is an extremely sensitive technique for the detection of at least one type of antiviral antibody and “in vitro” is a very effective way of killing virus infected cells. There is no correlation between the level of antiviral antibody in the CSF with the total protein content, but the high CSF: serum antibody ratio in some subjects who are particularly susceptible to recurrent herpes infection raises the possibility that local stimulation and production of this antibody may occur.

It is proposed that the basic mechanism of vasospasm which sometimes follows subarachnoid hemorrhage is dependent on increased free intracellular calcium ion produced by spasmogens from closely applied extravasated blood. Relaxation of this spasm occurs when the intracellular cyclic AMP levels are raised, resulting in sequestration of calcium ion by the vascular smooth muscle cell sarcoplasmic reticulum.

Routine neuropathological examination could not explain the dramatic improvement exhibited by one patient with “normal pressure” hydrocephalus after shunting. The improved patient contrasted remarkably with the unchanged condition of four others also shunted successfully. The five brains were analysed by quantitative morphometry to determine the degree of neurofibrillary tangle formation in mesial temporal neurons. The density of tangle-bearing nerve cells in the four unimproved cases was markedly greater than in age-matched control brains from nineteen normal subjects, and fell in the same range as that of eight dements with neuropathologically confirmed Alzheimer's disease. The density of the one who recovered was within normal limits.

The duration of dementia before shunting, and the total duration of dementia in these five patients rank in the same order as their degree of neurofibrillary formation. Furthermore, a positive linear correlation exists between the Tangle Indices and the total duration of dementia. The data suggest that early diagnosis may improve the chances of reversing the dementia of normal pressure hydrocephalus before histological alterations prove too severe.

This paper presents the results of neurophysiological studies of the effects of cerebellar stimulation on H reflexes, late reflexes, blink reflexes, evoked potentials and EEG patterns in 18 human subjects (Male 13, Female 5, Age 25.8 ±10.0, Epileptic 9, Cerebral Palsy 9).

In addition to the effects of cerebellar stimulation on the H reflex studies on salens we assessed V1 and V2, “late” responses (Upton et al., 1971), cortical somatosensory evoked potentials (SSEP) after median nerve stimulation, and visual evoked responses (VER) after flash stimulation. Experiments were extended to assess recovery curves of all the potentials and we examined the effects of changes on the rate or voltage of cerebellar stimulation.

Cerebellar stimulation was inhibitory to all the responses except the visual evoked potentials. Serial studies in five patients produced consistent results. Preoperative and postoperative results were compared in two patients with no significant difference in the results in the absence of cerebellar stimulation.

Ipsilateral cerebellar stimulation (CS) had the greatest inhibitory effects on H, V1 and V2 responses in the arm and leg whereas contralateral CS produced the greatest effects on cortical SSEPs. There was a greater bilateral effect on SSEPs and reflex responses after right CS than left CS and this may be the first indication of “dominance” in the cerebellar hemispheres. Cerebellar stimulation in patients on diphenylhydantoin produced minimal effects on SSEP“s and this observation has led to further studies in patients taking diphenylhydantoin.

Recovery of amplitude of the reflex and cortical responses took eight to 30 minutes after one minute of cerebellar stimulation. Serial CS of one minute on and one minute off produced increasing inhibition of SSEP's and reflexes for up to five stimulations. Recovery after cessation of cerebellar stimullion was associated with rebound excitation in six patients, the rebound being noted in the amplitude of H reflexes and SSEP's as well as in the frequency of paroxysmal spike and wave discharges in the EEG.

The correlation of the results of such quantitative neurophysiological tests with clinical improvement may allow prediction of clinical results after cerebellar stimulation. These techniques have already been used to measure the threshold of stimulation and may allow optimal stimulation characteristics to be assessed. The prolonged neurophysiological effects of stimulation may allow the use of maximum effective intervals between optimal epochs of stimulation so that any cerebellar damage can be minimized.

The responses of canine middle cerebral arteries to changes in pCO2 and pO2 were tested in vitro. It was found that there was no response to changes in pCO2 from 38.1 mm. Hg to 26.6 mm. Hg. but there was some constriction of the vessels with lowering of the pCO2 below 26.6 mm. Hg and there was minimal dilatation of the vessels when the pCO2 was increased from 38.1 nan. Hg to 87.2 mm. Hg. There was no reresponse to changes in pO2 from more than 500 mm. Hg to 59.6 mm. Hg, but when pO2 was lowered below 50 mm. Hg there was a sudden, massive constriction of the arteries tested. It is postulated that this constriction is due to build-up of a substance (substances) during a period of hypoxia (pO2 < 50 mm. Hg). The significance of the results obtained are discussed.

The general outline of the complete prospective study of 50 cases of spino-cerebellar degeneration is given. The general protocol followed, the criteria for inclusion and the mode of analysis are described. The aim of this study was to establish a base of clinical, physiological and biochemical facts upon which a logical and systematic approach to pathogenesis and treatment of Friedreich's ataxia could be attempted.

A short outline is given of the pioneer efforts of Nicolaus Friedreich in the description of the spinocerebellar degeneration which now bears his name.

The 50 patients in this survey were classified by a panel of neurologists into 4 clinical sub-groups: Group la (“typical” Friedreich's ataxia, complete picture), Group lb (“typical” Friedreich's ataxia, incomplete picture), Group Ila (“atypical” Friedreich's ataxia, possible recessive Roussy-Levy syndrome), Group lib (heterogeneous ataxias). The clinical symptoms and signs were analyzed for each of these groups. A constellation of signs constantly present in Friedreich's ataxia and obligatory for diagnosis was described. Other important symptoms, such as the Babinski sign, kyphoscoliosis and pes cavus were found to be progressive, but not essential for the diagnosis at any given time. Finally, a host of other symptoms can only be called accessory. The progression of scoliosis was found to be an important tool in the differential diagnosis of ataxias. Our study also indicates, in contrast to the opinion of some authors, that absent deep tendon reflexes in the lower limbs and early dysarthria are essential in “typical” Friedreich's ataxia.

This study consists of two parts: I. A detailed genetic analysis of 35 sibships in which 58 individuals were affected with Friedreich’s ataxia; and 2. Clinical and laboratory examinations of parents and siblings, in an attempt at carrier detection and diagnosis of the pre-clinical state.

The increased parental consanguinity, the lack of affected individuals in other generations, and the lack of significance of extrinsic etiological variables, all suggested an autosomal recessive mode of inheritance, and this was confirmed by formal genetic analyses, employing several different methods.

Associated abnormalities in our series of 58 patients included cardiomyopathy (51.7%), diabetes melitus (19.0%), optic atrophy (5.2%), nerve deafness (5.2%) and congenital malformations (6.9%). The incidence of diabetes mellitus. congenital malformations, and epilepsy and lor febrile convulsions was elevated in first degree relatives of patients with Friedreich’s ataxia.

Examinations in first degree relatives revealed an increased frequency of neurological and skeletal abnormalities (26.3%). but no abnormalities on neuro-ophthalmological examination. Frequent EMG abnormalities were noted in parents (56.3%). but not in siblings; and these could usually be attributed to extrinsic causes. There was an increased incidence of ECG abnormalities in both parents (50.0%) and siblings (25.0% and some of these abnormalities may represent cardiomyopathy. An increased frequency of EEG abnormalities was also recorded in parents (14.3%) and siblings (27.2%). but these were not specific. None of these examinations resulted in a practicable method of carrier detection or preclinical diagnosis.

Since carrier detection is still not feasible, genetic counselling remains the only possible means of prevention of Friedreich’s ataxia.

A preliminary genealogical investigation of all the known ancestors from the year 1608 of 4 apparently unrelated French Canadian kindreds with Friedreich’s ataxia reveals that the original ataxia gene in the province of Quebec was present within a core of no more than 10 families living in Quebec City in the mid-1600's.

No chromosomal anomaly was found in 15 cases of typical Friedreich’s ataxia and three cases of atypical recessive ataxia studied with Q and G banding techniques. No difference between frequency of chromosomes gaps or breakages was noted amongst patients with Friedreich’s ataxia and controls.

Electroencephalographic tracings of 50 patients who presented the classical features of Friedreich’s ataxia were reviewed. Mild nonspecific abnormalities were found in 33% and consisted of:

a) Abnormal slow or irregular background rhythms in 15 patients (30%).

b) Intermittent paroxysmal rhythms, considered to be projected from diencephalic or upper midbrain structures, in 4 patients (8%).

c) Unilaterally absent driving responses in 2 affected siblings (4%).

There was no response to intermittent photic stimulation in 60% of the patients. This finding is not considered a definite abnormality, and its significance remains unclear.

Four patients (8%) had epileptic seizures, but of these only two had interictal epileptic abnormalities.

There was no correlation between the duration and severity of the disease and the presence of electroencephalographic abnormalities.

Friedreich’s ataxia is mainly a spinal disorder. Involvement of supraspinal and in particular brain stem or diencephalic structures may be more extensive in those patients who show electrographic abnormalities. This would require confirmation with comparative data based on pathological observations.

Impaired function of brain stem inhibitory mechanism may be responsible for the slightly raised incidence of seizures in patients with Friedreich’s ataxia and other cerebellar degenerations.

Twenty-six of 50 patients were investigated with nerve conduction studies and electromyography using a standard protocol and were compared to the findings in 50 normal control subjects. Almost all cases of typical Friedreich's ataxia had absent sensory action potentials (SAP) in the digital (92%) or sural (96%) nerves. The others had markedly decreased S.A.P's. In these same patients motor conduction auvelocities were either normal or only slightly decreased. In the second, atypical group of 9 patients, the motor conduction velocities were considerably decreased.

Because of the absence of sensory action potentials in Friedreich's ataxia, and that the absence was noted in our very mild cases, it is proposed that this measure be used to facilitate early diagnosis.