Online newspaper of professor Yasser Metwally

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

December 18, 2009 — Stereotactic surgery has made a resurgence in the treatment of Parkinson disease. This is mainly because many patients with advanced PD experience significant disability or adverse effects despite optimal medical management. (Click for more details)

Our understanding of basal ganglia physiology and circuitry are improving dramatically. Both the globus pallidus (GP) and the subthalamic nucleus (STN) are hyperactive in PD. Advances in surgical techniques, neuroimaging, and electrophysiologic recordings allow stereotaxic maneuvers to be done more accurately and with lower morbidity than ever before.

• Thalamotomy and chronic thalamic stimulation are effective in reducing medically refractory tremor.

  • The mechanisms of action of thalamotomy are not known; its effects may be due to destruction of autonomous neural activity (synchronous bursts) at the same frequency as limb tremor.

  • Basal ganglia stereotactic surgery initially targeted the GP and the ansa lenticularis until Hassler and Reichert  [1] selected the ventral nucleus of the thalamus as the favored site for tremor reduction.

  • More than 90% of patients with PD who undergo this procedure have improvement in tremor and rigidity of the limbs contralateral to the side of the lesion.

  • Assessments in early studies were often qualitative rather than quantitative, but experience indicated that unilateral thalamotomies were effective for the treatment for parkinsonian tremor.

  • Long-term follow-up studies have been uncontrolled and unblinded, but thalamotomy appears to have a lasting beneficial effect.

  • Kelly and Gillingham [2] reported that 57% of patients with PD were free of tremor 10 years after the operation. Kelly et al reported improvement of tremor in 86% of 36 patients with a mean follow-up of 33 months in whom modern surgical techniques including microelectrode recording were used. Jankovic at al [10,11] reported no recurrence of tremor in 36 patients followed for a mean of 60 months. Other parkinsonian symptoms such as bradykinesia and tremor ipsilateral to the surgery progressed over time.

  • The mortality rate for thalamotomy in PD is estimated to be less than 0.3%. Death usually is the result of basal ganglia hemorrhage or indirect postoperative complications such as pulmonary embolism or infection. Persistent morbidity is uncommon, consisting mainly of dysarthria, dysphagia, or mild paresis.

  • Complications from bilateral thalamotomy are common; more than 25% of patients experience speech impairment. Mental changes also can persist after bilateral surgery. Therefore, bilateral thalamotomies generally are avoided.

• Thalamic deep brain stimulation (DBS): High-frequency stimulation(>100 Hz) during thalamotomy of the target site, usually the VIM nucleus of the thalamus, had the same effect as destruction.

  • Benabid et al [6] implanted electrodes in the ventral intermediate (VIM) nucleus to evaluate the effect of chronic stimulation, with promising results.

  • In 1997, the FDA approved the Activa Tremor Control therapy, which uses a DBS lead, an extension that connects the DBS lead to an implantable pulse generator (IPG), and the Itrel II IPG. The intracranial end of the DBS lead has 4 platinum-iridium contacts, which are 1.5 mm in length and separated by 1.5 mm. The DBS lead is connected to the IPG device by means of an extension that is tunneled under the skin. The IPG is implanted subcutaneously in the infraclavicular area.

  • Any of the stimulating contacts can be used for monopolar stimulation or any 2 or more can be used in combination for bipolar stimulation. Stimulation usually is initiated on postoperative day 1 and is adjusted by using an external programming device.

  • Adjustable parameters include pulse width, amplitude, stimulation frequency, and choice of active contacts. The patient can turn the stimulator on or off using a handheld magnet. The usual stimulation parameters are frequency of 135-185 Hz, pulse width of 60-120 microseconds, and amplitude of 1-3 V.

  • Thalamic stimulation has marked efficacy similar to that of thalamotomy in reducing contralateral tremor. Approximately 90% of patients have tremor reduction. Some patients show a microthalamotomy effect, or reduction of tremor after implantation of the electrode, even when the stimulator is not on. This is presumably due to a small lesion created by placement of the electrode.

  • The morbidity and mortality rates of thalamic stimulation are low.

  • Complications of surgery include intracerebral hemorrhage, seizures, and confusion. Complications related to the device include wire erosion, IPG infection, malfunction of the IPG, electrical shocking, and lead migration.

  • Adverse effects related to stimulation are reversible with reduction in stimulation and usually are well tolerated. Other adverse effects due to stimulation that may occur include dysarthria, disequilibrium, paresis, and gait disorder.

  • The advantages of DBS include reversibility, ability to change stimulus parameters to increase efficacy or reduce adverse effects, and ability to perform bilateral operations with reduced risk of permanent dysarthria.

  • Disadvantages include the cost of the system, presence of an implanted foreign body, future need to replace the battery, and possibility of mechanical problems.

  • The mechanism of action of DBS is unknown. Persistent depolarization, stimulation of inhibitory systems, and neuronal jamming have been proposed as possible mechanisms of action.

• Thalamotomy vs thalamic stimulation: A randomized trial comparing thalamotomy and thalamic stimulation currently is being conducted in Denmark. Studies to date suggest that the 2 procedures have equal efficacy, but DBS may be associated with fewer adverse effects.

• Pallidotomy: This procedure is effective in reducing contralateral dyskinesia.

  • Although pallidotomy was used in the 1950s, the results were inconsistent; this has been attributed to inappropriate target selection. Thalamotomy was the preferred procedure because it more reliably reduced tremor.

  • With the introduction of stereotactic frames, target localization improved, but the results of pallidotomy remained inconsistent. After the discovery of levodopa in the 1960s, the use of pallidotomy for PD waned. However, Laitinen et al reexamined posteroventral pallidotomy in 38 patients with PD and reported significant improvement in bradykinesia, rigidity, tremor, ambulation, speech, and drug-induced dyskinesias.

  • Other studies using standardized clinical rating scales also have reported significant improvement in parkinsonian symptoms after unilateral pallidotomy in PD. Baron reported results of GPi pallidotomy in 15 patients with advanced PD. The mean total Unified Parkinson Disease Rating Scale (UPDRS) score improved by 30%, mean activities of daily living (ADL) off score improved by 34%, and the motor examination off score improved by 25%. The motor on score improved by 13% at 3 months and 6 months, but worsened at 1-year follow-up. Improvement in contralateral drug-induced dyskinesias and tremor was dramatic. The results of neuropsychological assessments revealed no significant changes. Two of the patients in this study developed dementia and did not improve, suggesting that patients with moderate to severe dementia may have a poor surgical outcome. Persistent complications included superior quadrantanopia in 1 patient.

  • Lang performed a 2-year prospective study of 40 patients with PD who underwent GPi pallidotomy. At 6 months follow-up, overall improvement in off period motor scores was 28%, improvement in off period ADLs was 29%, improvement in contralateral dyskinesia scores was 82%, and improvement in ipsilateral dyskinesias was 44%. Persistent complications included contralateral facial weakness (2), dysarthria (3), dysphagia (2), impaired concentration (3), changes in personality or behavior (2), worsening of handwriting (4), worsening of balance (2), word finding difficulty (1), and worsening of dementia (1).

  • Bilateral pallidotomy rarely is recommended. Although bilateral pallidotomy causes a striking reduction in levodopa-induced dyskinesias, complications are relatively common and include speech difficulties, dysphagia, and cognitive impairment. Indications for a staged second side pallidotomy are limited and may include an excellent response to the first operation without any persistent complications, unchanged neuropsychological testing, and persistent disabling dyskinesias on the contralateral side.

  • Most centers performing pallidotomy use anatomical imaging (stereotactic CT scan or MRI) and electrical stimulation. Some also use microelectrode recordings. Although good results have been reported in some patients who underwent targeting only with imaging and macrostimulation, the authors strongly recommend the use of microelectrode recording for this procedure.

• Pallidal stimulation

  • Based on the success of thalamic DBS for tremor, Siegfried and Lippitz [16] assessed DBS of the ventroposterolateral pallidum. They implanted bilateral GPi electrodes in 3 patients with PD. The investigators reported improvement in the Webster Rating Scale scores and on-off motor fluctuations.

  • Pahwa et al [21] reported their experience with 5 patients who underwent pallidal stimulation. ADL subscores of the UPDRS improved by 19% in the off state and by 42% in the on state. Patient diaries demonstrated an increase in on time with a decrease in off time and on time with dyskinesias. One patient had an asymptomatic intracranial bleed. Another patient had facial dystonia and paresthesias that required surgical repositioning of the lead.

  • Kumar et al  [15] studied 8 patients with PD who underwent GPi stimulation (4 unilateral and 4 bilateral). At 3-month follow-up, UPDRS total motor score while off medication with the stimulator on was 27% better than at baseline. In the off state, the ADL subscores improved by 26%, and the on ADL subscores improved by 40%. Levodopa-induced dyskinesias were improved by 60%.

• Pallidotomy vs pallidal stimulation

  • Kumar et al [15] compared the effects of pallidotomy and GPi stimulation. They reported similar objective improvements with the 2 procedures. However, the risk of complications was higher in the pallidotomy group.

  • A prospective randomized study of unilateral surgery compared these 2 procedures in 13 patients with PD. The procedures provided a comparable effect on UPDRS and ADLs, and the complications were similar in the 2 groups. These results are preliminary, and further investigations are required.

• Subthalamotomy

  • In PD, the subthalamic nucleus (STN) is hyperactive, suggesting that modulation of its activity may have therapeutic benefit.

  • Surgery aimed at the STN only recently has been investigated. The procedure was performed in unilateral STN lesions (3 left and 2 right) in 5 patients whose PD was characterized by severe gait freezing and axial akinesia.

  • Cardinal PD symptoms were improved at 3 months after surgery. One patient had a large subthalamic infarct.

  • Due to the risk of surgical complications, subthalamic stimulation currently is preferred over subthalamotomy.

• Subthalamic stimulation

  • Experience with subthalamic stimulation is preliminary, but this approach appears to have considerable potential.

  • Early studies indicate that off motor scores are improved approximately 60% and ADL scores 30-58%.

  • Bradykinesia, tremor, and rigidity are improved significantly.

  • Dyskinesias are decreased because of the marked reduction of levodopa dosage (40-50%) following surgery.

  • Complications include intracerebral hemorrhages and transient mental status changes.

• Subthalamic vs pallidal stimulation

  • Krack et al [2] compared GPi and STN stimulation in 8 patients who had onset of PD while relatively young.

  • In the off state, the mean motor score improved by 71% with STN stimulation and by 39% with GPi stimulation. In the on state, dyskinesias were decreased markedly in the GPi group and decreased somewhat in the STN group. However, due to a marked reduction in the maintenance levodopa dose in the STN group, the severity of everyday dyskinesias was similar to that of the GPi group.

  • This preliminary study favored the STN target over GPi in young-onset PD patients.

 References

1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 11.1a January 2010 [Click to have a look at the home page]
2. Krack P, Pollak P, Limousin P: Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson’s disease. Brain 1998; 121: 451-7.
3. Kelly PJ, Gillingham FJ: The long-term results of stereotaxic surgery and L-dopa therapy in patients with Parkinson’s disease. A 10-year follow-up study. J Neurosurg 1980 Sep; 53(3): 332-7
4. Ballard PA, Tetrud JW, Langston JW: Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): seven cases. Neurology 1985; 35: 949-56.
5. Baron MS, Vitek JL, Bakay RA: Treatment of advanced Parkinson’s disease by posterior GPi pallidotomy: 1-year results of a pilot study. Ann Neurol 1996 Sep; 40(3): 355-66.
6. Benabid AL, Pollak P, Gervason C: Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 1991; 337: 403-6.
7. Hauser R, Zesiewicz T: Parkinson’s Disease: Questions and Answers. Merit Publishing International, Coral Springs FL 1997; 1-151.
8. Hauser RA, Zesiewicz TA: Management of early Parkinson’s disease. Med Clin North Am 1999; 83: 393-414.
9. Hauser RA, Freeman TB, Snow BJ: Long-term evaluation of bilateral fetal nigral transplantation in Parkinson’s disease. Arch Neurol 1999; 56: 179-187.
10. Jankovic J, Cardoso F, Grossman RG: Outcome after stereotactic thalamotomy for parkinsonian, essential, and other types of tremor. Neurosurgery 1995 Oct; 37(4): 680-6; discussion 686-7.
11. Jankovic J, Cardoso F, Grossman RG: Outcome after stereotactic thalamotomy for parkinsonian, essential, and other types of tremor. Neurosurgery 1995 Oct; 37(4): 680-6; discussion 686-7.
12. Kelly PJ, Ahlskog JE, Goerss SJ: Computer-assisted stereotactic ventralis lateralis thalamotomy with microelectrode recording control in patients with Parkinson’s disease. Mayo Clin Proc 1987 Aug; 62(8): 655-64.
13. Kelly PJ, Gillingham FJ: The long-term results of stereotaxic surgery and L-dopa therapy in patients with Parkinson’s disease. A 10-year follow-up study. J Neurosurg 1980 Sep; 53(3): 332-7.
14. Krack P, Pollak P, Limousin P: Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson’s disease. Brain 1998; 121: 451-7.
15. Kumar R, Lozano AM, Montgomery E: Pallidotomy and deep brain stimulation of the pallidum and subthalamic nucleus in advanced Parkinson’s disease. Mov Disord 1998; 13 Suppl 1: 73-82.
16. Laitinen LV, Bergenheim AT, Hariz MI: Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease. J Neurosurg 1992; 76: 53-61.
17. Lang AE, Lozano AM, Montgomery E: Posteroventral medial pallidotomy in advanced Parkinson’s disease. N Engl J Med 1997 Oct 9; 337(15): 1036-42.
18. Limousin P, Pollak P, Benazzouz A: Effect on parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet 1995; 345: 91-5.
19. Montastruc JL, Rascol O, Senard JM: A randomized controlled study comparing bromocriptine to which levodopa was later added, with levodopa alone in previously untreated patients with Parkinson’s disease: a five year follow up. J Neurol Neurosurg Psychiatry 1994; 57: 1034-38.
20. Murer MG, Dziewczapolski G, Menalled LB: Chronic levodopa is not toxic for remaining dopamine neurons, but instead promotes their recovery, in rats with moderate nigrostriatal lesions. Ann Neurol 1998; 43: 561-575.
21. Pahwa R, Wilkinson S, Smith D: High-frequency stimulation of the globus pallidus for the treatment of Parkinson’s disease. Neurology 1997; 49: 249-53.
22. Parkinson Study Group: Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1993; 328: 176-83.
23. Pearce RK, Banerji T, Jenner P: De novo administration of ropinirole and bromocriptine induces less dyskinesia than l-dopa in the MPTP-treated marmoset. Mov Disord 1998; 13: 234-41.
24. Polymeropoulos MH, Lavedan C, Leroy E: Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997; 276: 2045-7.
25. Saint-Cyr JA, Trepanier LL, Kumar R: Neuropsychological consequences of chronic bilateral stimulation of the subthalamic nucleus in Parkinson’s disease. Brain 2000 Oct; 123 ( Pt 10): 2091-108.
26. Siegfried J, Lippitz B: Bilateral chronic electrostimulation of ventroposterolateral pallidum: a new therapeutic approach for alleviating all parkinsonian symptoms. Neurosurgery 1994 Dec; 35(6): 1126-9; discussion 1129-30.
27. Tanner CM, Ottman R, Goldman SM: Parkinson disease in twins: an etiologic study. JAMA 1999; 281: 341-6.
28. Tatton WG, Chalmers-Redman RM: Modulation of gene expression rather than monoamine oxidase inhibition: (-)-deprenyl-related compounds in controlling neurodegeneration. Neurology 1996; 47: S171-183.
29. Watts RL: The role of dopamine agonists in early Parkinson’s disease. Neurology 1997; 49: S34-48.
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The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

December 15, 2009 —  Since the wide application of MRI as an important tool for the investigation of neurological diseases, it has been quite apparent that a group of very heterogeneous diseases, so varied clinically, etiologically, pathologically and prognostically can be grouped together under the category of "MRI white matter disease". White matter disease is thus a magnetic resonance and a pathological criterion rather than a clinical one.

The "MRI white matter disease" is observed as signal changes (mostly hyperintense on T2 and proton density, FLAIR studies, hypointense on the T1 images, and hypodense on the CT scan studies). These lesions are usually not space occupying (unless seen in the acute stages), the white matter disease could be discrete or confluent and is commonly situated in the periventricular and/or the infratentorial (cerebellum or brain stem) white matter. The MRI signal changes simply reflect low tissue specific gravity due to increased tissue water content associated with astrogliosis and microcavitations.

The MRI signal changes observed in "white matter disease" is mainly due to edema, gliosis, widened extracellular spaces, or microcavitations depending upon the disease involved, and the stage of this disease (acute, or chronic). Demyelination itself, with the breakdown of the fatty myelin sheaths within the MS lesion, probably does not contribute significantly to the prolonged T2 relaxation changes. The amount of lipid lost is not large enough to cause the magnitude of change demonstrated on MR imaging because the lipids related to myelin breakdown have an extremely short T2 relaxation time and are effectively invisible on conventional MR imaging. The loss of myelin lipid does, however, result in a more hydrophilic environment, and this increase in water content leads to the observed increases in proton density, Tl, and T2 relaxation times. These pathological changes is so nonspecific and can not be regarded as specific to a particular disease. From the radiological pathology point of view increased water content of the lesion, initially through edema and inflammation, and later through astrogliosis (astrogliosis simply mean that the number of astrocytes are increased in the lesion, the water content of the cytoplasm of these astrocytes results in net increase of the intracellular water content of the lesion) and frank replacement of tissue with fluid in microcavitations is responsible for the MRI white matter signal changes. T2 imaging is a sensitive but not particularly specific indicator of pathology in white matter disease.

From the clinical point of view the diseases that can be grouped together as diseases causing MRI white matter changes are listed in table 1

Table 1. Diseases that can be associated with "MRI white matter changes"

I. Demyelinating disorders

A. Immune-mediated (or inflammatory) myelin disorders (diseases)

• Multiple sclerosis (MS)
• Variants of multiple sclerosis
  • Benign or subclinical multiple sclerosis
• Acute multiple sclerosis
  • Marburg type
  • Schilder type
  • Balo type
  • Neuromyelitis optica (Devic type)
• Acute disseminated (postinfectious) encephalomyelitis (ADEM)
• Acute hemorrhagic leukoencephalitis (AHL)

B. Viral demyelinating disorders (diseases)

• Progressive multifocal leukoencephalitis (PML)
• Leukoencephalopathy and other white matter abnormalities in AIDS
• SSPE

C. Toxic demyelinating and/or degenerative white matter disorders

• Osmotic myelinolysis or central pontine myelinolysis (CPM)
• Marchiafava-Bignami disease (MB)
• Post-radiation white matter injury
• Necrotizing leukoencephalopathy following chemotherapy
• Solvent vapor abuse leukoencephalopathy (SVAL)

D. Leukoaraiosis, Binswanger disease, and vascular leukoencephalopathy (CADASIL)

II. Inherited metabolic diseases primarily affecting white matter (leukodystrophies)

A. Adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN)

B. Metachromatic leukodystrophy (MLD)

• Arylsulfatase pseudodeficiency
• Activator protein deficiency
• Multiple sulfatase deficiency (mucosulfatidosis)

C. Krabbe’s disease, globoid cell leukodystrophy (GLD)

D. Spongy degeneration of the central nervous system in infancy (Canavan’s disease)

E. Pelizaeus-Merzbacher disease (PMD)

F. Alexander’s disease

G. Sudanophilic (orthochromatic) leukodystrophy (SL)

H. Childhood ataxia with diffuse CNS hypomyelination (CACH) syndrome

1. Autosomal dominant-adult onset leukodystrophy

J. Nasu-Hakora disease

K. White matter changes in neuronal storage diseases

L. Mitochondrial encephalopathy/encephalomyopathy

III. Migraine

IV. Collagen vascular disease, including lupus erythematosis, Behcet disease, etc

V. Neurosarcoidosis

VI . Neurofibromatosis type 1

Although literature is full of attempts to define MRI criteria specific to a particular disease 2,13, 53, ( see table 2) in my opinion these criteria have fallen short of expectation and it is quite apparent that the clinical dilemma of "MRI white matter changes" can not be solved by MRI alone.

Table 2.  MR imaging criteria for clinical progression to ms

Paty et al, 53, 1988

• 4 lesions
• > 3 lesions, including 1 periventricular lesion

Fazekas et al, 13, 1988

3 lesions with two of the following properties:

• Infratentorial;
• Periventricular
• > 5 mm in diameter

Barkhof et al, 2, 1988

Cumulative model based on 4 lesion properties:

• > 1 juxtacortical
• >1 enhancing or > 9 nonenhancing
• >1 infratentorial
• >3 periventricular

By viewing the list of diseases in table 1, it will be quite apparent that it comprises diseases of very variable clinical pictures. This clinical picture can easily solve the dilemma of differential diagnosis among these diseases. These diseases are not related in any way to each other and would probably never had been grouped together except under the "MRI  list of diseases causing white matter changes" category. Thus white matter disease is probably an MRI or a pathological phenomenon rather than a clinical disease entity and is not specific to a particular disease entity and unless things are taken from this view point, the approach towards "the MRI dilemma of white matter changes" is further complicated.

White matter disease, as observed by MRI, always poses a great clinical dilemma. The "MRI white matter disease dilemma", in my opinion, can not be solved radiologically and can only be solved by the clinical picture of the disease involved, results of other investigations, or sometime brain biopsy. The "MRI white matter disease dilemma" actually stems from two misunderstanding:

1- The neurologist do not know that a particular disease can produce white matter changes on MRI, so when white matter changes are observed radiologically in one of his patients with this disease, an erroneous change of the clinical diagnosis is made. For example a neurologist (who is not aware that migraine can be associated with "MRI white matter changes" almost identical with multiple sclerosis) can change the clinical diagnosis from migraine to multiple sclerosis- if MRI shows white matter changes in one of his patients with migraine- even though the clinical diagnosis of migraine is quite apparent.

2- Either the neurologist or the radiologist is not aware of the fact that the list of diseases that can produce "MRI white matter changes" is quite big and that MRI white matter changes are quite nonspecific, so he made the clinical diagnosis of multiple sclerosis solely on a radiological basis in a patient who had a disease other than multiple sclerosis.

These problems are frequently encountered in neurological practice. Because of lack of specificity of the "MRI white matter changes", arriving at a correct clinical diagnosis depends to a great extent on characterizing the anatomic configuration of the changes in the white matter, and the correlation of these findings with clinical data and results of other investigations.

Although the pattern of "MRI white matter changes" is frequently equated with Multiple sclerosis, however it has become apparent that many other diseases have similar MRI appearance. The MRI appearance of hyperintense lesions (discrete, or confluent) scattered in the periventricular white matter on the MRI T2 images can only provide evidence of "in place dissemination" which is not sufficient for the diagnosis of multiple sclerosis which requires "in time" and "in place" dissemination.

Although involvement of certain anatomical sites is more suggestive of multiple sclerosis like lesions at the callososeptal interface (seen as "notching" on the undersurface of the corpus callosum on sagittal Tl-weighted imaging), however this can not be regarded as specific to multiple sclerosis. "Dissemination in time" is needed to "dissemination in place" for the ultimate diagnosis of multiple sclerosis. MRI T2 images can only provide a good evidence for the "in place dissemination" and if "in time dissemination" is added then the specificity of MRI for the diagnosis of MS is much increased.

Although dissemination in time can easily be inferred from the clinical "remission and exacerbation", however MRI can also provide evidence for " Dissemination in time". When some lesions- as seen on the T2 images- enhance on the T1 postcontrast images and others do not enhance, this simply mean that some lesions are old "burnt out" plaques (those which do not enhance) and other lesions are new and active plaques (those which enhance), and this provides evidence of " Dissemination in time". Ring enhancement also provides evidence for " Dissemination in time". In this situation the center of the lesion (the old burnt out part of the plaque) does not enhance while the periphery of the lesion (the reactivated part of the plaque) enhances. An incomplete or open ring of enhancement is more indicative of  MS lesions than metastatic disease or infection, which almost always have a complete, fully enclosed ring of enhancement. Thus dissemination in time can be provided by MRI when some plaques enhance while other do not and in case of ring enhancement of the plaques.

Although dissemination in place is seen in most of disease causing " MRI white matter changes", however dissemination in time is almost never seen in any disease other than multiple sclerosis and this pattern provides a very strong evidence for the clinical diagnosis of multiple sclerosis. In general enhancement is not seen in most of the diseases causing " MRI white matter changes" except multiple sclerosis and acute disseminating encephalomyelitis. In acute disseminating encephalomyelitis, although multiple enhancing lesions may be seen at presentation, the lesions will follow the same time course of enhancement and should not enhance on subsequent MR scans and dissemination in time is not observed in acute disseminating encephalomyelitis. Thus the specificity of MRI is low (in so far as the clinical diagnosis of MS is concerned) when all lesions are enhanced and when all lesions are not enhanced on the postcontrast MRI T1 scans.

Figure 1. (A,B) MRI T1 pre and postcontrast. Some of the lesions on the precontrast scan enhance while other do not thus providing evidence for "in time dissemination".

MRI white matter changes are very commonly seen as hyperintense lesions on the T2 images and on the T1 precontrast images the lesions are either isointense to white matter or slightly hypointense (and definitely hyperintense to the CSF signal) in most of diseases listed above as diseases causing white matter changes. Black holes (lesions as hypointense as the CSF) on the T1 precontrast images are very characteristic of multiple sclerosis and carry a very high specificity in this respect and probably is not seen in other diseases causing the "MRI white matter changes", however black holes are not seen initially in multiple sclerosis, and are regarded as evidence of advanced disease with axonal atrophy and significant clinical disability. black holes are thus highly specific but poorly sensitive in so far as the clinical diagnosis of multiple sclerosis is concerned. However in the author experience lacunar infarctions in the chronic stage can be present on the precontrast  MRI T1 images as black holes, thus casting doubts on the validity of black holes as a specific MRI criterion for the diagnosis of MS.

In Paty et al, 53, Fazekas et al, 13, and Barkhof et al, 2, 1988 criteria, too much emphasis was placed on “dissemination” in place, and too little emphasis, if at all, was placed on dissemination in time. Subsequently these criteria were helpful to determine the probability of progression to multiple sclerosis and they definitely failed to differentiate between multiple sclerosis and other diseases causing white matter changes on MRI examination.

We accordingly present this criteria for the MRI diagnosis of MS by MRI

1. The existence of more than three lesions scattered in the white matter, in the supra or the infratentorial compartment, seen on the MRI T2 images as discrete or confluent hyperintense lesions!
2. Some of the previously mentioned lesions are seen enhanced while others are not on the MRI T1 postcontrast images, or the existence of incomplete ring enhancement*

! No emphasis was put on a specific anatomical site (multiple lesions located at any anatomical site)

*This criterion is not valid if all lesions are enhanced or all lesions are not enhanced

In the above mentioned criteria we are fulfilling both "in time" and "in place" dissemination, and to the best of our knowledge no other diseases (that can cause MRI white matter changes) share multiple sclerosis with being disseminated in time and place. However the validity of these criteria is yet to be evaluated. Although absence of these criteria definitely can not exclude multiple sclerosis, and although these criteria might result in underdiagnosis of MS by MRI (since enhancement occurs only when neuroimaging studies coincide with the existence of active plaques or reactivated plaques which is not always the case), however we do believe that we still have clinical criteria and results of other investigations (like CSF analysis) to prove or disprove the diagnosis of multiple sclerosis in the face of a strong clinical suspicion despite absence of these MRI criteria. By applying these criteria we are definitely avoiding overdiagnosis of multiple sclerosis in patients who have diseases other than multiple sclerosis.

Figure 3. Two MRI T2 images of a patient with migraine showing multiple white matter high signal lesions resembling that of multiple sclerosis, signal changes are probably due to white matter ischemia/edema

Figure 4. MRI T2 image of a patient with HIV dementia showing multiple white matter high signal lesions resembling that of multiple sclerosis

References

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2. Barkhof F, Fflippi M, Miller DH, et al: Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 120(pt 11):2059, 1997

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9. Dietemann JL, Beigelman C, Rumbach L, et al: Multiple sclerosis and corpus callosum atrophy: Relationship of MRI findings to clinical data. Neuroradiology 30(6):478, 1988

10. Drayer B, Burger P, Hurwitz B, et al: Reduced signal intensity on MR images of thalamus and putamen in multiple sclerosis: Increased iron content? AJR Am j Roentgenol 149(2):357, 1987

11. Druschky A, Heckmann JG, Claus D, et al: Progression of optic neuritis to multiple sclerosis: Am 8-year follow-up study. Clin Neurol Neurosurg 101(3):189, 1999

12. Fazekas F, Barkhof F, Filippi M, et al: The contribution of magnetic resonance imaging to the diagnosis of multiple sclerosis. Neurology 53(3):448, 1999

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