The Thermodynamics of Intracellular Ice Nucleation in the Freezing of Erythrocytes,"

A theoretical model describing the thermodynamics of intracellular ice nucleation is developed for red blood cells as a model biomaterial. Analytical expressions based on current theories of ice nucleation by both homogeneous and heterogeneous nucleation processes are coupled with a thermodynamic model for the loss of intracellular water during freezing. Numerical solutions for both modes of nucleation identify two cooling regionshigh cooling rates and low cooling rates-separated by a sharp demarcation zone. The nucleation temperature for high cooling rates is approximately 20°K higher than the nucleation temperature for low cooling rates and is essentially independent of cooling rate in each region. The nucleation temperatures for heterogeneous nucleation are approximately 30°K higher than the nucleation temperatures for homogeneous nucleation in the two regions. For the case of heterogeneous nucleation, it is possible to increase the nucleation temperature by packing of catalysts via the concentration polarization effect. If the cell suspension is allowed to supercool before nucleation occurs in the extracellular medium, the sharp transition from low cooling rates to high cooling rates for heterogeneous nucleation shifts to much lower cooling rates. The dependence of the transition cooling rate on the degree of supercooling has been established for a typical freezing situation

Alexia without Agraphia

The patient is a 69 year old left handed man with a history of hypertension, insulin dependent diabetes mellitus and atrial fibrillation. Treated with coumadin, adjusted to keep the INR between 2 and 3. On the morning of admission he awoke at 4 a.m., sat momentarily on the side of the bed and then stood up and walked without difficulty a distance of ten feet before falling to the ground. His wife found him disoriented and mildly confused. He told her that he could only see half of her face. On examination in the ER, he had rapid atrial fibrillation (127 beats per minute) and an elevated blood pressure 215/128, which quickly fell to a stable level of 150/90. He was alert and oriented to Mass General Hospital and to the month, but gave the year incorrectly as 1992. His attention fluctuated. On memory testing he had a diminished five-minute recall for a name, address and flower, and recall for well known events through which he had lived, for example, John F. Kennedy assassination. He could not recall the names of the last five Presidents. He followed one-step commands correctly. His speech was normal apart from minor errors naming objects. His reading was severely impaired (alexia). He was unable to recognize written words on the page and had difficulty with most single letters when presented visually. In contrast, when words were spelled out to him, he could recognize them without difficulty and his ability to spell was intact. His writing was fluent when asked to spontaneously write a description of the weather and also correct on dictation with no spelling errors. He was asked to write his name and address which he did correctly, and three words, house, rose and mountain. He wrote the words correctly and was then distracted for approximately 5 minutes and asked to re-read them. He was unable to read the words out loud. When the patient listened to the spelling of these words out loud, he was able to identify the word correctly. He was unable to read single letters. Color Vision: He was given the Ishihara pseudo-isochromatic test of color vision and performed it without error, as he could read single and two digit numbers or he traced them out correctly with his finger. Color Anomia: He was unable to name colors correctly (color anomia). When shown different colored bottle caps, he was able to name red and blue correctly but called green purple and yellow orange. He matched two red objects correctly. He was able to identify famous faces and had no visual disorientation (simultanagnosia). Neuro-ophthalmological Examination: Visual acuity of 20/60 or better, (making errors reading the Snellen chart) Automated perimetry: dense right homonymous hemianopia (Figure 1). Pupils, ocular motility and fundus examination normal Neurological Examination: •A slight right facial weakness with blunting of the nasolabial fold •A mild right hemiparesis with right drift •Mild hyperreflexia on the right with an extensor plantar response •No sensory extinction, apraxia, astereognosis, or agraphesthesia. A chest x-ray showed cardiomegaly. EKG atrial fibrillation with normal axis. MRI with diffusion weighted imaging (DWI), a bright lesion in the left thalamus and internal capsule consistent with an infarct in the distribution of the posterior choroidal vessels. The new stroke presentation was characterized by: •Alexia without agraphia •A dense right homonymous hemianopia •Color anomia Repeat MRI with DWI showed a new left occipital lobe infarct in the distribution of the left P2 division of the posterior cerebral artery (PCA). (Figure 2-5). The MRI supported the diagnosis of a disconnection syndrome affecting connections involved in naming a seen object and in reading. Disconnection Syndrome: With destruction of the left visual cortex and splenium (or intervening white matter), words perceived in the right visual cortex cannot cross over to the language areas and the patient cannot read. Figure 3 shows diagrammatically how a visual pattern is transferred from the visual cortex and association areas to the angular gyrus, which arouses the auditory pattern in the Wernicke area. The auditory pattern is transmitted to Broca's area, where the articulatory form is aroused and transferred to the contiguous face area of the motor cortex. Diagnosis: Embolic infarct of the left visual cortex and spenium of the corpus callosum with a dense right homonymous hemianopia Disconnection Syndrome Alexia without agraphia Color anomia Pure alexia. See also: http://content.lib.utah.edu/cdm/ref/collection/ehsl-shw/id/11

Bilateral Internuclear Ophthalmoplegia

This patient was seen at the Yale Eye Center at the age of 37. She had a long history of multiple sclerosis. At age 22, she had an acute attack of optic neuritis in the left eye which recovered fully within three weeks. Some months later she had a recurrent episode in the same eye, which also recovered fully. At age 26, her third attack of MS, was more severe with acute numbness of the left side of the body from the waist down and involving the leg. On exertion and when exposed to heat the left leg became weak and she had difficulty walking. (positive Uhthoff's sign). On this occasion however her signs and symptoms did not remit and over the next few years her deficits gradually progressed until by 1989 she was wheelchair bound. In that year, she was admitted to the Mass General Hospital for evaluation and was found to be very depressed, owing to having to leave her job as a proof reader because of disturbing oscillopsia and blurring of vision. Neuro-ophthalmological examination: Visual acuity (VA): 20/200 OU Reads J2 OD, J4 OS. She was unable to insert her contact lenses owing to marked ataxia of the upper extremities and impaired dexterous movements of the hands. Ocular motility: •Paresis of adduction of the right eye on gaze left •Abducting nystagmus of the left eye on gaze left •Paresis of adduction of the left eye on gaze right •Abducting nystagmus of the right eye on gaze right •Normal convergence •Full vertical gaze •Pendular horizontal oscillations •Intermittent primary position upbeat nystagmus Spinal tap: Eight years and 15 years after the onset of progressive relapsing MS, the cerebrospinal fluid showed an elevation of the protein (60-75mg/dl), an increase in the number of white blood cells (11-15), and elevated IgG with positive oligoclonal bands. Brain MRI: The brain MRI, with T1 and T2 weighted images in the axial and sagittal view showed considerable periventricular bright signals in the T2 WI scans involving the frontal and occipital lobes. The bright signals were greatest in the occipital lobe. A small punctate hyperintense signal was present in the white matter in the posterior limb of the internal capsule on the left side. Several other small punctate hyperintense signals were present in the centrum semiovale bilaterally. Electronystagmogram: 1.Spontaneous and gaze nystagmus - Irregular horizontal eye movement with eyes open and eyes closed. On right lateral gaze with eyes open nystagmus present in the right eye, fast phase to the right. 2.Optokinetic nystagmus (OKN) - Horizontal OKN was attempted with a sinusoidal full field strimulus. No nystagmus was provoked. Down beating OKN provoked with an up moving stimulus. No upbeating nystagmus provoked with down moving stimulus. Impression: Left internuclear ophthalmoplegia (INO) and saccadic breakdown of visual-vestibular interaction consistent with a cerebellar or brainstem lesion because of rotation induced nystagmus and absent optokinetic nystagmus. Oscillopsia, an illusion of movement of the visual world, was the major visual disability in this patient. She was seen in the Low Vision Aid Clinic to see if optical devices could stabilize the retinal image. a) High plus lenses combined with a high minus contact lens (Rushton and Cox, 1987, JNNP Vol 50, 411-415) b)Base out prisms to induce convergence with minus lenses to correct accommodation (as used in congenital nystagmus by (Dickenson Physiological Optics 1986). Prism therapy failed to stabilize her vision. Drug therapy with three different medications, baclofen, meclazine and cogentin was also unsuccessful and because conservative measures failed she was referred for consideration of Botulinum toxin therapy. Botulinium Toxin In 1991 the use of botulinum toxin (botox) to suppress involuntary eye movements had not been well studied. Halgerson reported getting beneficial effects in some patients with nystagmus using intraorbital injections into the eye muscles. At that time no large medical studies were available. The patient was, however, anxious to be treated in an effort to improve her vision to watch TV and, after being fully informed of all the risks and possible complications, she agreed to a trial of botox. The procedure plan was to obtain pre-injection video tapes of her eye movements and then inject botox into the extraocular muscles of the right eye under EMG control. Since her oscillopsia was due to acquired pendular horizontal oscillations, the goal was to dampen and hopefully stop the oscillations by injecting botox into the lateral and medical recti of the right eye. The risk of injecting botox only into these two muscles was the possibility that it would cause diplopia, and that diplopia might be more problematic to her than oscillopsia. The procedure went ahead as planned and the dose of botox into the medial rectus and lateral rectus muscles was sufficient to cause substantial dampening of the horizontal pendular oscillations, but they were not completely stopped. Immediately following, the patient had partial ptosis and diplopia but nevertheless was pleased with the result and she was willing to patch the left eye to prevent diplopia to watch TV. Four weeks after the injection her visual acuity in the right eye had improved to 20/70, and in the uninjected left eye it remained at 20/200. The future botox treatment plan was to let the botox effect of the first set of injections wear off over three months and then reexamine her. At that time, a new injection strategy was to be planned to eliminate toxin spread to the levator palpebra superioris muscle and prevent the development of ptosis. Unfortunately, she was lost to follow up. See also: http://content.lib.utah.edu/cdm/ref/collection/ehsl-shw/id/10

Alcoholic Cerebellar Degeneration

The patient is a 72 year old woman who presented with a 4 year history of progressive difficulty with balance, frequent falls and unsteadiness walking. She required a cane to steady herself. Past History: Significant for alcohol abuse. In 1980, she came to Boston for a second opinion and was seen in consultation by Dr Raymond Adams. Neuro-ophthalmological examination: Visual acuity, visual fields, pupils and fundus examination normal. Ocular motility: •Square wave jerks •Saccadic hypermetria, right gaze to center and left gaze to center •Horizontal gaze evoked nystagmus •Saccadic horizontal pursuit •Smooth vertical pursuit •A mild eso deviation of the eyes Neurological examination: Motor strength normal Reflexes 1+ symmetric Absent ankle jerk, plantar responses flexor Co-ordination: Slight titubation No limb ataxia Trunkal ataxia Gait ataxia Inability to tandem walk Hematological studies: Metabolic workup and liver function tests normal Diagnosis: Alcoholic cerebellar degeneration Treatment: The patient received intravenous thiamin and nutrition counseling prior to discharge. See also: http://content.lib.utah.edu/cdm/ref/collection/ehsl-shw/id/7

Thalamic Infarct

The patient is a 64 year old man with no major past medical history who, on the day of admission, suddenly developed loss of vision in both eyes and then was unable to open his eyes on his own unless he used his hands. Holding his eyelids open his vision was very blurry. Within minutes he lost consciousness and his wife was unable to arouse him. In the emergency room he was described as unresponsive to pain, with 8 mm sluggish reacting pupils, moving all four extremities with bilateral decorticate posturing and bilateral upgoing toes. A non-contrast Brain CT was read as normal. The patient was admitted to the Intensive Care Unit. Diagnosis: ‘Top of the basilar syndrome'. Neurological examination: Over the next two hours, his level of consciousness fluctuated, ranging from impairment of arousal to occasionally conversing with yes and no to asking questions. When awake he was oriented x3 and then he would drift back to sleep. Repetition, naming and comprehension were intact. He had bilateral ptosis Pupils 6 mm OU, sluggish to light. Eyes straight in primary gaze Normal horizontal and vertical oculocephalic reflex Motor system: Left hemiplegia involving face, arm and leg with normal tone. Reflexes 2+ symmetric with bilateral upgoing toes. Sensory examination: Left hemi-sensory loss. On day 1, the patient was heparinized and placed on pressors to keep the systolic blood pressure greater than 180 as his level of alertness fluctuated markedly with his blood pressure and was dependent on maintaining a systolic blood pressure over 180. On day 3, he was awake and alert and fully oriented. The left sided weakness and hemi-sensory loss had completely resolved and he had no ptosis. On day 5, he tried to get out of bed, which resulted in a drop of systolic blood pressure to 120. Almost immediately he became confused, dysarthric and hemiparetic. As soon as his systolic blood pressure was greater than 180, he was alert and his signs resolved. 2/7/94 CT of the Brain with contrast: 1.Acute right thalamic infarct with the possibility of involvement of the left thalamus not completely excluded. 2.No intracranial hemorrhage or mass 3.Appearance of an old left cerebellar hemispheric infarct. 2/10/90 Brain MRI: Axial T2 WI images show 1.An area of T2 bright signal within the right medial thalamus suggestive of an infarct. 2.Abnormal signal within the left cerebellar hemisphere and punctate areas within the right anterior cerebellar hemisphere, both consistent with infarction. (Figures 1 and 2) Brain MR Angiogram: On MRA the right vertebral artery was segmentally visualized and diminutive in size. probably representing a small hypoplastic vertebral artery with slow flow. However, the possibilities of thrombus and/or dissection could not be excluded. 2/15/94 Cerebral Angiogram: Showed no evidence of vertebral artery dissection or of a basilar tip aneurysm. The basilar artery was normal. A Holter monitor demonstrated some sinus node dysfunction, but cardiology felt that in the absence of syncable symptoms the patient did not require a pacer. On 2/17/94, 13 days post stroke, Neurovisual Consult: The patient was fully alert. He complained that he could not look down and he was unable to read his menu. He had intermittent vertical double vision watching TV, one image being slightly higher than the other, but at the time of the examination this was improving. He mentioned that he was sleeping a lot. He denied headache, vertigo and confusion and he emphasized that his memory "was good". On examination: Visual acuity OD: 20/25 OS: 20/40, pinhole 20/25 Confrontation fields full OU and normal fundus exam. Pupils 4 mm OU reacting normally to light and near Ocular motility: Eyes straight in primary gaze Full horizontal gaze right and left with gaze evoked nystagmus. Full upgaze, no nystagmus Supranuclear paralysis of downgaze Saccades limited to 5 to 10 degrees. Pursuit 20 to 30 degrees down. Intact vertical oculocephalic reflex Absent convergence Intact horizontal optokinetic nystagmus Absent vertical optokinetic nystagmus No skew deviation. Diagnosis: 1.Isolated global supranuclear paralysis of downgaze 2.Right medial thalamic infarct extending into the right mesencephalic reticular formation (MRF) 3.Embolic cerebellar infarcts Etiology: Embolic infarction of the thalamus and MRF supplied by the posterior thalamosubthalamic paramedian artery (Artery of Percherson) Top of the basilar artery syndrome A transthoracic echo cardiogram showed no embolic source from the heart. A transesophageal echo cardiogram showed a small patent foramen ovale. Lower extremity arterial non-invasive study showed no evidence of deep venous thrombosis. Discharge: At the time of discharge the patient was doing very well. The residual neurological findings were: 1.Supranuclear paralysis of downgaze 2.Absent convergence and 3.Increased somnolence. He was discharged home on Coumadin. Follow-Up: The patient's stroke occurred on February 4, 1994. On follow-up on March 23, 1994 he had full vertical gaze down and normal convergence. His wife reported that "he was very sleepy and lethargic in mid-afternoon and generally sleeps a lote and takes frequent naps". See also: http://content.lib.utah.edu/cdm/ref/collection/ehsl-shw/id/11

Upbeat Nystagmus

The patient, a 36 year old Italian, presented in October 1967, at the age of 27, with acute dizziness and ataxia. He was evaluated in Rome. A pneumoencephalogram showed hydrocephalus, attributed to arachnoiditis, and a ventriculo-atrial shunt was placed. Three months post shunt placement he had a return of dizziness and ataxia accompanied by daily bi-occipital headache, diplopia, clumsiness and weakness of the left arm. In January 1968, he was readmitted and a large tumor of the left cerebellar hemisphere with invasion of the vermis was biopsied. A diagnosis of glioblastoma multiforme was made. He was treated with radiation therapy. Post operatively his major deficits were ocular dysmetria, left limb and gait ataxia. In 1970 he immigrated to the US. In 1971 he was referred to Dr. William Sweet, Chief of Neurosurgery at the Massachusetts General Hospital (MGH) with increasing gait ataxia and oscillopsia. Neurological examination: Cranial nerves intact (apart from the eye movements) Motor strength normal Decreased tone in the left extremities Reflexes 2+ throughout with flexor/plantar responses. Coordination: ataxia left extremities Gait ataxia, Romberg negative. Sensory examination normal. Neuro-ophthalmological examination: Visual acuity 20/20 OU Visual fields and pupils normal Fundus exam showed bilateral optic disc drusen Eye movements: •Upbeat nystagmus in primary gaze, increased on up gaze •Square wave jerks •Horizontal gaze evoked nystagmus left > right •Full vertical gaze •Upbeat nystagmus on upgaze •No nystagmus on downgaze •Pursuit, (horizontal and vertical) smooth to a very slow target, markedly saccadic to a fast target •Convergence normal •Marked saccadic hypermetria Right gaze to center overshoot (hypermetria) taking the eyes almost fully to the left Left gaze to center hypermetria taking the eyes almost fully to the right Upgaze to center hypermetria Downgaze to center hypermetria CT scan: In the region of the vermis and the medial portion of the left hemisphere there was an area of high absorption with contrast enhancement involving the cerebellar vermis and medial left cerebellar hemisphere with an apparent associated cystic component consistent with recurrent tumor. Cerebral Arteriogram: A cerebral arteriogram confirmed a highly vascular tumor of the inferior portion of the midline of the cerebellum, bulging into the fourth ventricle. Pathology: The slides from the original biopsy were obtained from Rome and reviewed by Dr E. P. Richardson, Chief of Neuropathology at the MGH. Diagnosis: A high-grade astrocytoma grade 3-4. Surgical procedure: A posterior fossa craniotomy was performed. To access the tumor, the most inferior aspect of the vermis was split to reach the roof of the 4th ventricle. In so doing, a well demarcated tumor nodule was found extending to both sides of the cerebellum, mostly to the left side. It was possible to separate the superior most aspect of the tumor easily from the 4th ventricle. Several small branches of the posterior inferior cerebellar arteries had to be divided to devascularize the tumor which was then gently dissected away from the floor of the 4th ventricle. At the end, the surgeon felt he had as close to a grossly total removal of the tumor as was possible and no visible tumor was left behind. Post operative status: The patient made a good post-operative recovery and was able to walk with an elbow crutch. He continued to be followed by neurosurgery until he was 66 years of age. During that time he had required a shunt revision on two occasions and therapy for an episode of meningitis/cerebritis. See also: http://content.lib.utah.edu/cdm/ref/collection/ehsl-shw/id/28