Clinical Studies

An Overview

NF capillary microscopic studies have been performed in a large number of disease groups by a variety of microvascular techniques. The authors wished to determine the reason for the development and/or persistence of microvascular changes in disorders in which NF abnormalities were present. Serial studies to document progression or regression of pathological changes in the NF, as related to the evolution of the disease or to the effect of therapy, have also been performed. Data obtained from the NF studies in various diseases are presented here as a short summary.

Selected Disorders

Since NF capillaroscopic studies in human disease range from every subspecialty of medical and surgical fields to mental disorders, genetics, and epidemiology, only some selected disorders are listed here: disorders in which some concordance exist between the findings of different investigators and in which high specificity has been found for diagnosis, or microvascular findings have helped to subdivide a clinical entity or help with differential diagnosis.

1. Diabetes Mellitus

Capillary density is within normal range in both type i and ii diabetes, but capillary pressure has been reported to be increased in type i, especially in those with poor glycemic control. Abnormalities in capillary perfusion have also been reported in both types of diabetes, especially in response to arterial occlusion producing reactive hyperemia. Transcapillary and interstitial diffusion of IV injected sodium fluorescein has been shown to be significantly faster in long-term diabetes than in normal controls.

2. Hypertension

Capillary density is reportedly lower (rarefaction) and capillary pressure higher in patients with hypertension; capillary flow velocity may be reduced.

3. Raynaud Phenomenon

(a) Primary RP. Capillary morphology is within normal range in this disorder and so is the capillary density. Capillary flow, as measured by RBC velocity, is lower than normal in baseline conditions and responds strongly to cold stimuli (local or whole body) leading to a flow stop of variable duration (measured in seconds or minutes, "complete" standstill or stop being defined differently by different investigators). During an RP attack, NF capillaries usually remain filled by RBC. Transcapillary diffusion of sodium fluorescein in NF capillaries is within normal limits.

(b) Secondary RP. There are a large number of disorders reportedly associated with RP, i.e., these disorders are considered primary, leading to a secondary RP. They are too numerous to review here and may or may not include microvascular studies. The most important group of secondary RP is found in connective tissue disease (CTD), especially in scleroderma (SD).

4. Scleroderma Spectrum

Scleroderma spectrum (SDS) disorders: Scleroderma (SD) and related disorders, such as CREST (calcinosis, RP, esophageal dysfunction, sclerodactyly, and telangiectasis), MCTD (mixed connective tissue disease), and UCTD (undifferentiated connective tissue disease), form a spectrum with many similarities in clinical and laboratory parameters including microvascular pathology. Dermato-myositis (DM, a closely related disease) shows similar but more acute, microvascular pathology. An overlap between SD and DM sometimes occurs.

only in this disease group is the nail fold microvascular pathology highly specific and helpful for diagnosis. Enlarged NF capillaries have been described in other disorders, but what is characteristic here is the presence of capillaries in the NF that are enlarged in all three portions of the loop (arterial and venous limbs and the apex), resulting in a considerable increase in the total width of the loop (Figure 2, left). Other capillaries with less specific changes in size and shape may also be present.

These characteristic loops are located mainly along the edge of the NF but in an irregular manner: sometimes between quasi-normal-looking capillaries or in groups of variable size. The dimensions of these capillary loops vary considerably from slightly enlarged to giant loops; the size

Figure 4 Cuticle deposits in a scleroderma patient compared to a normal control. (a) A scleroderma patient showing severe cuticle deposits (grade 6, arrows). (b) A normal control subject showing a grade 1 cuticle deposit (arrow), the most extreme encountered in the normal population. Bar = 100 mm.

and number of such loops vary within an NF or between NFs of the same patient. The number of capillaries per millimeter is greatly decreased because of their size, but also because they are often associated with small avascular areas along the NF edge, sometimes called dropout. However, capillary loss often extends into the proximal part of the NF and can be measured in mm2. This characteristic pattern can be recognized even without measurements. (Pattern recognition is well known to be quite reliable.)

Other specific abnormalities, not always present but more often seen during an active phase of the disease, are "bushy formations" (Figure 3) adjacent to avascular areas (seen more often in DM than in SD).

They can be recognized even at low magnification. At higher magnification, they show many thin capillary loops springing from an arteriole or the deep end of the arterial limb. On serial photographs, they seem to be associated with filling in of an avascular area by capillaries [8]. Therefore, they are believed to be indicators of capillary regeneration. These "bushy formations" should not be confused with ramified or branched capillaries described by other authors in other disorders and even in normal subjects.

A yellow-orange discoloration of the cuticle is also associated with SD and DM. It corresponds to deposits of macromolecules (immunoglobulins, fibrinogens) in the cuticle demonstrated by biopsy (Figure 4 [6]) and reflects the permeability change of both the capillary wall and the dermoepidermal junction. In these cases, the capillary hemorrhages, often seen in SD and DM patients, do not remain self-limited when gradually growing out with the cuticle as in normal subjects, but the heme products diffuse widely throughout the cuticle.

Studies with video microscopy after injecting sodium fluorescein show an abnormally rapid diffusion of this dye, but not with a homogenous pattern as seen in long-term diabetes, but diffusing out through only certain parts of the capillary wall.

The capillary blood flow can be slow even at an average room temperature in the classical SD and has a striking response to local or whole-body cooling, leading to a complete standstill in the whole NF area at 16°C. This can actually be better appreciated by continued watching and scanning the field of NF than by automated systems. A complete stop of capillary flow can be easily recognized by standstill of all RBCs in an NF loop by observing it for at least 1 minute. When this is repeated in other loops and the whole endrow, as well as more proximal NF, scanned for any RBC movement for a total time of about 3 minutes, a conclusion of total shutoff the NF capillaries can be reached. This has not been observed in other vasospastic conditions, such as RP; its observed flow stop is of much shorter duration, intermittent, and not present in the whole NF.

CREST, a more benign variant of SD, shows similar NF capillary abnormalities but in a slightly different pattern: Giant loops at the edge of the NF are more prominent and numerous while avascular areas are quite limited or nonexistent. These patients also show characteristic capillary telangiectases elsewhere on the fingers, especially on the finger pads. These telangiectases can be microscopic, but in most cases many are large enough to be detected with the naked eye. "Bushy formations" are absent. Their capillary blood flow response to cold is similar to that of SD.

MCTD shows SD-pattern NF capillary abnormalities and more "bushy formations" than in classical SD.

UCTD also has SD-type NF capillary patterns, but usually fewer fingers are involved and show fewer abnormalities. There are some patients, however, with active disease who show marked loss of capillaries and rapid progression to definite diagnosis of SD. Both MCTD and UCTD can show capillary flow dysfunction when exposed to cold.

DM shows more extreme avascular areas and more numerous "bushy formations" than any of the conditions described earlier; the cuticular deposits and capillary hemorrhages with diffuse extension into the cuticle are also frequent. These lesions can vary from finger to finger; patients may show even completely normal NF capillaries in some fingers, and abnormalities can return to normal in remission [8].

5. Other Connective Tissue Diseases

(a) Rheumatoid arthritis. An extensive visible subpapillary plexus may be present in a relatively large proportion of these patients.

(b) Systemic lupus erythematosus. Most patients with this disorder have NF capillaries within the normal range. In the acute phase, they may show a peculiar pattern of disappearance of all superficial (papillary) capillaries in most of the NF area, with only subpapillary venous plexus visible. The capillaries reappear in remission. SD-SLE overlaps also occur.

(c) Discoid lupus erythematosus. In this form of lupus, the proximal NF may be completely devoid of capillaries, showing only a prominent venular plexus; at the edge of the NF there are large looplike formations, which are probably part of the edge of the venular plexus rather than capillaries. These microvascular lesions are not present on all NFs and correspond most likely to discoid lesions occurring in the NF area.

6. Hereditary Hemorrhagic Telangiectasia

This disease is mentioned here because numerous capillary telangiectases are present on skin, lips, fingers, and NF, which may sometimes need differential diagnosis with CREST.

7. Schizophrenia

This disorder was studied by NF capillaroscopy soon after Muller's work. Many of these patients show an extensive subpapillary plexus on most of their fingers having a PVS of more than 10 (often 20 to 40 on a semiquantitative scale). This subgroup of schizophrenia also has a significantly lower finger blood flow and appear to correspond clinically to so-called process schizophrenics (those with negative symptoms). It is interesting to note that, although there is a higher than normal frequency of high pVS in both schizophrenia and RA, these disorders appear to be mutually exclusive.

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