In this issue...

• White Matter Lesions, Retinopathy And Stroke : Exploring The Link
• Lower The Body Temperature, Larger The Penumbral Volume
  
• Statins Beneficial In Acute Ischemic Stroke
• Therapeutic Benefits Of Botulinum Toxin Type A In Post-Stroke Leg Rehabilitation
• The American Stroke Association (ASA) Guidelines For Early Management Of Patients With Ischemic Stroke
• Key Messages
• Even Benign Strokes May Need Aggressive Therapy
• Fish Once A Month Reduces Ischemic Stroke Risk In Men
• New Approvals Internationally
• TICKLE YOUR BRAIN

White Matter Lesions, Retinopathy And Stroke :
Exploring The Link

White matter lesions (WMLs), as detected by magnetic resonance imaging (MRI), are found in 27% to 87% of population aged 65 years and older. These lesions have been hypothesized to be ischemic complications of cerebral microvascular disease.

In people with a history of stroke, WMLs have been suggested to increase the risk of recurrent stroke and cognitive decline.

As retinal arterioles share similar anatomy, physiology, and embryology with the cerebral arterioles, retinal microvascular changes (e.g. microaneurysm, retinal hemorrhage) due to aging, etc also appear to reflect cerebral microvascular disease and are associated with an increased incidence of stroke.

The patients of 'The Atherosclerosis Risk In Communities' study (ARIC) were analyzed to examine the association of cerebral WMLs and retinal microvascular abnormalities in association with incidence of stroke. These patients underwent cerebral MRI as well as retinal photography. Incidence of clinical stroke was ascertained after a median follow up of 4.7 years, according to presence or absence of WMLs and retinopathy.

The investigators found that persons with retinopathy were more likely to have WMLs than those without retinopathy (22.9% vs. 9.9%). In this 5-year cumulative study, incidence of clinicalstroke was high with association of WMLs (6.8% vs. 1.4%). Also, people with both WMLs and retinopathy had a significantly higher incidence of stroke than those without WMLs or retinopathy (20.0% vs. 1.4%) (Fig.1).

This study thus provides key insights into the underlying pathogenic mechanisms and clinical significance of WMLs in a cohort of middle-aged persons who are initially stroke-free. The study also demonstrates a strong independent association between retinopathy and WMLs. A person with retinopathy is 2.1 to 4.0 times as likely to have WMLs than a person without retinal signs. Also WMLs are independently associated with risk of clinical strokes; and in presence of retinopathy, persons with WMLs are 18.1 times as likely to develop stroke than those without either WMLs or retinopathy.

These findings may have important clinical implications, as per study investigators. This data offers additional evidence that asymptomatic persons with WMLs may be at an increased risk of stroke independent of conventional stroke risk factors. Additionally this risk of stroke associated with WMLs appears to be substantially elevated in the presence of retinopathy.

JAMA 2002; 288: 67-74

 

Lower The Body Temperature, Larger The Penumbral Volume

Researchers have shown for the first time that lowering body temperature may preserve penumbral tissue in patients with acute ischemic stroke, providing a greater opportunity for tissue rescue.

Chief investigator Peter M. Wright, from the National Stroke Research Center, University of Melbourne, presented the findings at the 55th Annual Meeting of American Academy of Neurology.

In this prospective study, the researchers performed diffusion and perfusion magnetic resonance imaging studies in 35 men and 25 women with ischemic stroke (mean age = 74 years). The patients underwent the imaging studies within 24 hours of stroke onset (median 4.23 hours).

The diffusion lesion was used to estimate the volume of infarcted tissue. Data was also collected on patient's body temperature, oxygen saturation level, blood glucose, blood pressure and blood viscosity.

The study showed that for any given diffusion lesion volume, body temperature predicted penumbral volume (p = 0.005). There was no relationship between penumbral volume and blood pressure, viscosity or oxygenation.

On sub-analysis of patients imaged before and 6 hours after stroke onset, only body temperature correlated with penumbral volume, with lower temperatures being associated with larger penumbras. Specifically the penumbra increased 24 ml for every 1 degree celsius decrease in temperature.

"For a given infarct volume, body temperature has the most significant impact on penumbral volume of all the physiological variables studied," concluded Dr. Wright.

Presented at the 55th Annual Meeting of American Academy of Neurology; April 3rd, 2003

Statins Beneficial In Acute Ischemic Stroke

As per a study presented at the 55th Annual Meeting of the American Academy of Neurology, patients who receive statins following acute ischemic stroke have better functional outcomes at 3 months as compared to placebo.

Dr. Moonis et al aimed to evaluate the benefit of statin therapy before and after ischemic stroke. Since no studies had shown whether using statins would improve the outcome of an established stroke, the investigators sought to determine the answer by analyzing an established database of 852 patients, from a previous trial. They analyzed patients on statins prior to stroke and those who started statins within the first two weeks of stroke onset. The variables that were considered included age, gender, vascular risk factors and stroke subtypes. Around 28.1% of strokes were cardioembolic, 9.9% originated in small vessels, 46.1% were atherothrombotic and 15.3% were of undetermined origin.

Among the patients in this database, 15.1% had used statins before stroke onset and 14.4% had used them within two weeks after the onset of stroke. The assessment of patients was based on their Modified Rankin Scale (MRS), the Barthel Index (BI) and the NIH Stroke Scale (NIHSS).

The investigators found that a favourable outcome i.e. MRS decrease of 2 or more was associated with the use of statins after stroke (p = 0.0084). The factors linked to an unfavourable outcome were advanced age, diabetes, and a prior history of stroke or transient ischemic attack. The investigators also found that post-stroke statin use was a highly significant predictor for positive results both for the reduction of at least 2 points on the NIHSS (p = 0.0027) as well as a BI of at least 90 (p = 0.0029).

"These results are highly significant and cannot be explained by the small difference in the baseline assessment scores," Dr. Moonis concluded.

Presented at the 55th Annual Meeting of the American Academy of Neurology; April 8th, 2003

Therapeutic Benefits Of Botulinum Toxin Type A In Post-Stroke Leg Rehabilitation

Botulinum toxin type A reduces calf spasticity, limb pain and dependence on walking aids in stroke patients.

It is believed that following stroke, calf muscle hypertonicity impairs leg rehabilitation and according to the investigators of a new study, botulinum toxin could help relieve this condition. This multicenter double-blind randomized placebo-controlled evaluation trial, which evaluated three doses of botulinum toxin type A in the treatment of spastic equinovarus deformity after stroke, included 234 stroke patients.

Following treatment with 500, 1,000 or 1,500 units of toxin or placebo, patients were assessed every 4 weeks for 12 weeks. There was a small but significant improvement in calf spasticity and limb pain after treatment with botulinum toxin type A as compared with placebo. Also, the treated patients showed a reduction in their use of walking aids. Although some improvement was seen with lower doses, the greatest effect was observed with the 1,500-unit dose. There were no severe adverse events considered to be treatment-related.

Cerebrovascular Diseases 2003; 15(4): 289-300

The American Stroke Association (ASA) Guidelines For Early Management Of Patients With Ischemic Stroke

The American Stroke Association (ASA) has recently updated the urgent stroke care guidelines, which is a revision of the statement written in 1994 and 1996. "With a considerable research done in the last decade on stroke, the guidelines for physicians need to reflect the new information",said Dr. Harold P Adams, chair of the panel that wrote these guidelines.

These guidelines aim at providing updated recommendations that can be used by emergency medicine physicians, neurologists etc who provide acute stroke care through first 24-48 hours of hospitalization, by addressing the emergent treatment of acute ischemic stroke in addition to the management of neurological and medical complications.

One of the key messages is the importance of early treatment of stroke. Public awareness of the symptoms of stroke and seeking medical attention immediately are critical to early treatment. Beyond that, physicians need to treat stroke as the emergency it is.

Treatment Of Acute Ischemic Stroke

Thrombolysis
The concept of the existence of an ischemic penumbra is fundamental to the current approach to treat ischemic stroke and hence restoration of blood flow needs to be achieved as quickly as possible. Till date, intravenous administration of rtPA is the only FDA-approved therapy for treatment of patients with acute ischemic stroke and there is no data to support the clinical use of either streptokinase or defibrinating agents like ancrod. Use of rtPA is associated with improved outcomes for a broad spectrum of carefully selected patients who can be treated within 3 hours of onset of stroke. As management of intracranial hemorrhage following rtPA treatment is problematic, the best method to prevent bleeding complications is careful selection of patients (Table 1).

Table 1: Characteristics of patients with ischemic stroke who could be treated with rtPA

Diagnosis of ischemic stroke causing measurable neurological deficit The neurological signs should not be clearing spontaneously The neurological signs should not be minor and isolated Caution should be exercised in treating a patient with major deficits The symptoms of stroke should not be suggestive of subarachnoid hemorrhage Onset of symptoms < 3 hours before beginning treatment No head trauma or prior stroke in previous 3 months No myocardial infarction in the previous 3 months No gastrointestinal or urinary tract hemorrhage in previous 21 days No major surgery in the previous 14 days No arterial puncture at a noncompressible site in the previous 7 days No history of previous intracranial hemorrhage Blood pressure not elevated (systolic < 185 mmHg and diastolic < 110 mmHg). No evidence of active bleeding or acute trauma (fracture) on examination Not taking an oral anticoagulant or if anticoagulant being taken, INR < 1.5 If receiving heparin in previous 48 hours, aPTT must be in normal range Platelet count > 100 000mm3 Blood glucose concentration > 50 mg/dL (2.7 mmol/L) No seizure with postictal residual neurological impairments CT does not show a multilobar infarction (hypodensity > 1/3 cerebral hemisphere) The patient or family understand the potential risks and benefits from treatment

 

Intra-arterial Thrombolysis
The 1996 guidelines had concluded that intra-arterial thrombolysis was experimental and should be used only within a clinical trial setting. But now this intervention is an option for treatment of selected patients with major stroke of < 6 hours duration due to large vessel occlusions of the middle cerebral artery. This therapy is not FDA-approved. Also the drug, recombinant prourokinase, tested in several trials is not available for clinical use. Hence extrapolation to available thrombolytic i.e. rtPA is based on the consensus as supported by case series data. Importantly, the availability of this option should not preclude the administration of intravenous rtPA in otherwise eligible patients.

Anticoagulation
The use of emergent anticoagulation for acute stroke care has been a subject of debate. Parenteral anticoagulants should be prescribed only after excluding the possibility of a primary intracranial hemorrhage. Dose-adjusted, unfractionated heparin is not recommended for reducing morbidity, mortality, or early recurrent stroke in patients with acute stroke (i.e. within first 24 hours) as evidence indicates it is not efficacious and may be associated with increased bleeding complications. Low molecular weight heparin (LMWH)/heparinoids have not shown either benefit or harm in reducing morbidity, mortality or early recurrent stroke in patients with acute stroke, and hence LMWH/heparinoids are therefore not recommended for any subgroup of patients with acute ischemic stroke.

Antiplatelet Agents
Recent clinical trials have evaluated the potential utility of antiplatelet agents in setting of acute stroke and additional research is in progress. Although the panel recommends the use of aspirin within first 24-48 hours of stroke, it should not be used as a substitute for other acute interventions, especially intravenous administration of rtPA. The administration of aspirin within 24 hrs of the use of thrombolytic agents is not recommended.

Volume Expansion, Vasodilators, and Induced Hypertension
Although drug-induced hypertension and isovolemic or hypervolemic hemodilution have been successful in secondary prevention of ischemia due to vasospasm following subarachnoid hemorrhage, this strategy has been inconclusive, and generally negative in the setting of acute ischemic stroke. Hence strategies to improve blood flow by changing the rheological characteristics of the blood or by increasing perfusion pressure are not recommended for the treatment of most of the patients with acute ischemic stroke.

Surgical Interventions

Carotid Endarterectomy
The indication for immediate carotid endarterectomy in a patient with an acute ipsilateral ischemic stroke and an intraluminal thrombus associated with an atherosclerotic plaque at the carotid bifurcation is controversial. Also, emergency carotid endarterectomy is not recommended in settings of acute ischemic stroke, due to high risk. Due to the lack of evidence for the safety and efficacy of emergency carotid endarterectomy or other surgical procedures like extracranial-intracranial arterial bypass, they are not recommended for treatment of most patients with acute ischemic stroke.

Endovascular Treatment
Several new interventional neuroradiology techniques designed to augment vascular recanalization like balloon angioplasty, intravascular stenting, suction thrombectomy, laser thrombolysis of emboli etc, have been examined. However due to lack of evidence about the safety and efficacy of these procedures, they cannot be recommended for patients suffering from acute ischemic stroke.

Neuroprotective Agents
A large number of trials testing a variety of putative neuroprotective agents have now been completed, but no consistent benefit of this approach has been demonstrated.

After the success of nimodipine in preventing ischemic neurologic impairments following subarachnoid hemorrhage, the drug has been tested in cases of acute brain ischemia, but the results were largely negative. Also trials with flunarizine, glutamate antagonist, the GABA agonist as well as gangliosides have produced negative results. Hence considerable work is still necessary in this field and no neuroprotective agent can be recommended for the treatment of acute ischemic stroke.

Treatment Of Acute Complications

Ventilatory Support And Supplemental Oxygen
Maintaining adequate tissue oxygenation is of importance during acute cerebral ischemia to prevent worsening of neurological injury. Though recent trials do not support the use of supplemental oxygen therapy at 3 L/min for most patients with acute ischemic stroke, such patients should be monitored with pulse oximetry with a target oxygen saturation level of > 95%. Supplemental oxygen should be administered if there is evidence of hypoxia by blood gas determination, or desaturation, as detected by pulse oximetry.

Fever
Increased body temperature in the setting of acute ischemic stroke has been associated with poor neurological outcome. Lowering elevated body temperature with antipyretics and use of cooling devices can improve the prognosis.

Arterial Hypertension
The use of antihypertensive agents should be withheld unless the diastolic blood pressure is >120 mm Hg or the systolic blood pressure is > 220 mm Hg.
Aggressive reduction in blood pressure could be detrimental due to secondary reduction of perfusion in the ischemic area. Hence whenever indicated, lowering of blood pressure should be done cautiously.

Arterial Hypotension
Persistent arterial hypotension is rare in case of acute ischemic stroke. But if present, correction of hypovolemia and optimization of cardiac output are important priorities during the first hours after stroke. Treatment includes volume replacement with normal saline and correction of arrhythmias. Vasopressor agents like dopamine may be used if these measures are ineffective.

Hypoglycemia
Hypoglycemia may mimic stroke, hence prompt measurement of the serum glucose concentration and rapid correction of a low serum glucose concentration is important.

Hyperglycemia
Hyperglycemia can be a consequence of a severe stroke and thus, the elevated blood sugar can be a marker of a serious vascular event. By consensus, goal would be to lower markedly elevated glucose levels to < 300 mg/dl.

Treatment Of Acute Neurological Complications
The most important acute neurological complications of stroke include:

Cerebral Edema And Intracranial Pressure
Clinically significant edema requiring medical intervention develops in less than 10-20% of patients. Patients with raised intracranial pressure (ICP) and deteriorating neurological condition can be treated with hyperventilation, osmotic diuretics, and drainage of cerebrospinal fluid or surgery. Hyperventilation, an emergency measure can act almost immediately and can lower the intracranial pressure by 25-30%. Corticosteroids are not recommended for the management of cerebral edema and increased ICP following ischemic stroke.

Seizures
The frequency of seizures during the first day after stroke ranges from 4-43%, with a greater risk of occurrence within 24 hrs of stroke. The data for efficacy of anticonvulsants in treatment of stroke patients who experience seizures is scarce. Hence the recommendations are based on the established management of seizures that may complicate any acute neurological illness.

General Care
Patient's neurological status should be assessed frequently for the first 24 hrs after admission. Though the treatment begins with bed rest, mobilization should begin as soon as the patient's condition is judged to be stable, to avoid the risk of further complications like pneumonia, deep vein thrombosis, pulmonary embolism and pressure sores.

Importance Of Alimentation
Sustaining nutrition is important as malnutrition that develops after stroke might interfere with recovery. Research also indicates that percutaneous placement of an endogastric tube is superior to nasogastric tube feeding if a prolonged need for devices is anticipated.

Controlling Infections
Pneumonia, an important cause of death following stroke usually occurs in patients who are immobile or are unable to cough. Urinary tract infections are common and sepsis can develop in around 5% of patients. Antibiotics to treat such complications of stroke are strongly recommended.

Prevention Of Venous Thrombosis
Pulmonary embolism accounts for approximately 10% of deaths after stroke. In addition to advanced age, immobility, paralysis, atrial fibrillation and hormone replacement therapy may increase the risk of deep vein thrombosis. Subcutaneous administration of heparin, LMWH and heparinoids are effective in preventing deep vein thrombosis.

Stroke 2003; 34: 1056-1083

For a full text of the guidelines log-on to www.cipladoc.com or
write to Vitalis team Cipla Ltd, Mumbai Central, Mumbai-8

Key Messages

• Because time is critical in acute stroke care, institutions should have diagnostic equipment and staff available 24 hours a day.
  
  
• Urgent treatment should include measures that protect the airway, breathing, and circulation, especially among seriously ill or comatose patients. An elevated blood pressure should be lowered cautiously.
  
  
• The committee reemphasizes the potential use of rtPA within 3 hours of ischemic stroke onset. To date, no other clot-busting agent has been established as a safe alternative to rtPA.
  
  
• Routine use of anticoagulants cannot be recommended.
  
  
• Aspirin may be given within 48 hours of stroke onset for most patients, but not within first 24 hours of treatment with thrombolytic therapy.
  
  
• Intra-arterial thrombolytic therapy holds promise for some strokes, even after six hours of symptom onset.
  
  
• No medication with neuroprotective effects has been shown to be useful for ischemic stroke patients.
  
  
• Stroke units, including comprehensive rehabilitation services and specialized stroke
  treatment centers should be developed.
  
  
• Steps should be taken to prevent additional strokes. Rehabilitation is an important component of acute care.

Even Benign Strokes May Need Aggressive Therapy

There may be no such thing as a "benign" stroke, according to findings of a new study. The study showed that patients who present with relatively mild stroke symptoms and apparently good outcomes in the emergency room could have poor long-term outcomes.

"Knowing who is likely to follow this negative course could help physicians identify patients who would benefit from more aggressive treatment,"
reported Dr. Elizabeth Noser (University of Texas, Medical School at Houston), in a poster session at the 28th Annual International Stroke Conference, held in February 2003.

Use of thrombolytic therapy that is costly may be controversial in patients with mild stroke, but may be necessary in a substantial number of cases. But determining the candidates for aggressive treatment may require at least some time in hospital for observation, monitoring and testing.

The study evaluated 42 patients suffering from mild stroke with an average age of 64 years having mean National Institute of Health Stroke Scale (NIHSS) score of 3. All patients were admitted within the allowable window for receiving thrombolytic therapy, although all the patients did not receive the therapy.

On transcranial doppler evaluation, 7 patients had stenosis while 10 had persistent proximal intra-or-extracranial occlusion. According to the investigators, 66% of those who had stenosis or occlusion deteriorated, while 36% of those with persisting arterial lesions remained stable in hospital. The authors concluded that any patient even with a mild stroke has a 20% chance of deterioration, subsequent fluctuation or recurrent stroke during their acute hospital stay.

The authors suggest that urgent vascular studies are needed in these patients, as there is a good probability that they would yield positive, useful results and might indicate which patients would benefit from more aggressive therapy.

Presented at the 28th Annual International Stroke Conference; February 13th, 2003

Fish Once A Month Reduces Ischemic Stroke Risk In Men

Researchers from United States have discovered that eating fish as infrequently as once a month can reduce the risk of ischemic stroke in men. They also say that once a week consumption may be optimal.

This large cohort study that included 43, 671 men (age-group 40-75 years) was jointly carried out at Harvard University and the Brigham and Women's Hospital in Boston, Massachusetts. The follow-up period was 12 years. A significantly lower risk of ischemic stroke was observed in men who consumed fish once per month or more, as compared to those who ate fish less often. In addition, the investigators stated that there was no significant association between fish consumption or long chain omega 3-polyunsaturated fatty acid (PUFA) intake and risk of hemorrhagic stroke.

Results of the study indicate that the relative risk (RR) of ischemic stroke was significantly lower among men who had fish one to three times a month (RR=0.57). Higher frequency of fish intake was not associated with further risk reduction.

JAMA 2002; 288: 3130-3136

New Approvals Internationally

 

LAMOTRIGINE The US FDA has approved Lamotrigine in January 2003 as an adjunctive therapy in pediatric patients (age 2 years and above) to treat uncontrolled, partial seizures that may severely impact a child's intellectual and social development. Lamotrigine had been approved for use in adult patients way back in year 1994.

ELETRIPTAN The U.S FDA has approved eletriptan, a new anti-migraine drug, in December 2002. Eletriptan is a selective 5-hydroxy tryptamine 1B/1D receptor agonist. Doses of 20 mg and 40 mg are recommended for acute treatment of migraine in adults. This treatment is not intended for the prophylactic therapy of migraine.

TICKLE YOUR BRAIN

Across

1.   A type of syncope seen with stress, pain or fear and often occurring in young folk.
2.   Atrial fibrillation is the most common cause of this type of stroke. This stroke has a       characteristically abrupt onset.
4.   Occlusion of the artery of ________, supplying the anterior 2/3 of the lumbar spinal cord,       produces paraplegia, loss of temperature and pain sensation & poor bowel and bladder       control.
6.   This chemical contaminant of a recreational drug rapidly produces Parkinson-like       syndrome.
8.   Parkinson's disease is associated with this sort of tremor.
10. In addition to behavioral and movement disorders, this hereditary deficiency of        ceruloplasmin produces Keyser-Fleischer rings and hemolytic anemia __________'s        disease.
11. This cerebral structure is particularly affected by chronic alcohol use.
13. A generalized, non-convulsive seizure.
15. _______'s head maneuver, AKA the vestibulo-ocular reflex, produces eye movements in        a comatose patient by moving the head from side to side.
19. Elevated phytanic acid in the blood is diagnostic of this autosomal recessive disease.
20. In addition to the thalamus, pons and cerebellum, chronic HTN can lead to bleeding in        this brain structure. Clinically: gaze to the side of the hemorrhage, contralateral        paralysis and impaired consciousness.
21. An uncoordinated gait seen with cerebellar dysfunction.
22. Central pontine myelinolysis is primarily iatrogenic and is produced by the overly rapid        replacement of this ion in the depleted patient.
23. This type of tumor is often found in myasthenia gravis. Its removal results in a decrease        in circulating anti- acetylcholine receptor antibodies.
26. Human equivalent of mad-cow disease, its etiologic factor is a prion. Abbr.
30. Characterized by cataplexy, vivid dreams that occurs at the beginning and end of sleep,        and sleep paralysis.
32. Head tremor often seen with benign essential tremor.
34. Lesions of the Edinger-Westphal nucleus in the mesencephalon make a pupil do this.
35. _______'s syndrome is characterized by tardive dyskinesia and dystonia, with very        pronounced blepharospasm.
36. Multiple sclerosis is due to the focal loss of this protein in many parts of the CNS.

Down
1.    This straining maneuver can increase intracranial pressure.
3.    Ischemic strokes can be seen in young patients who abuse this drug.
5.    This chronic encephalopathy is found in thiamine-deficient alcoholics and is        characterized by anterograde and retrograde memory deficit and poor problem solving.
7.    A type of syncope usually seen in elderly people after eating and drinking (usually        alcoholic drink).
9. This tumor of the optic nerve is often seen in neurofibromatosis patients.
12. Often presents as an isolated case of optic neuritis before progressing into the
       full-blown disease. Abbr.
14. A presynaptic site contacts a muscle fiber at this point. Abbr.
16. This type of muscular dystrophy is caused by an x-linked recessive mutation in the        dystrophin gene.
17. The classic migraine has this associated set of visual illusion in the visual hemifield        contralateral to the side of the head with pain.
18. In Eaton-Lambert syndrome antibodies against this ion's channels impair presynaptic        function.
21. Lou Gehrig's disease. Abbr.
25. After seizure.
26. This type of headache usually strikes middle-aged men, is unilateral and affects the        periorbital region. A single attack lasts 30- 90 mins, but headaches come frequently for        a few weeks.
27. Carpal tunnel syndrome involves this nerve.
28. Deficiency of this vitamin causes the 3Ds of Pellagra: dementia, diarrhea & dermatitis.
29. Deficient of this compound, due to prolonged antibiotic use/eating too many raw eggs,        can cause a central necrosis of the head of the caudate nucleus.
31. ______'s sign: patient loses balance when his eyes are closed and he is standing with        his feet close together.
33. The preferred imaging protocol to look for a subdural hematoma.

Across 1. VASOVAGAL 2. ISCHEMIC 4. ADAMKIEWICZ 6. MPTP 8. RESTING 10. WILSON 11. VERMIS 13. ABSENCE 15. DOLL 19. REFSUM 20. PUTAMEN 21. ATAXIA 22. NA 23. THYMOMA 26. CJD 30. NACROLEPSY 32. TITUBATION 34. DILATE 35. MEIGE 36. MYELIN

Down 1. VALSALVA 3. COCAINE 5. KORSAKOFF 7. POSTPRANDIAL 9. GLIOMA 12. MS 14. NMJ 16. DUCHENNE 17. AURA 18. CA 21. ALS 25. POSTICTAL 26. CLUSTER 27. MEDIAN 28. NIACIN 29. BIOTIN 31. ROMBERG 33. CT SCAN